Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7]2)(=O)[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[N:24]1([CH:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]2[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7]3)[CH3:2])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(=O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)N1CCOCC1
Temperature: 50 °C

Procedure:
A mixture of 3-(5-acetyl-1H-indol-2-yl)-2(1H)-quinolinone (8-4, 50.0 mg, 0.165 mmol, 1 equiv), morpholine (0.070 mL, 0.83 mmol, 5.0 equiv), acetic acid (0.050 mL, 0.83 mmol, 5.0 equiv), sodium cyanoborohydride (52 mg, 0.83 mmol, 5.0 equiv), and activated powdered 3 angstrom molecular sieves in anhydrous 20% dioxane in methanol (15 mL) was heated at 50° C. for 8 hours. Additional morpholine (0.070 mL, 0.83 mmol, 5.0 equiv), acetic acid (0.050 mL, 0.83 mmol, 5.0 equiv), and sodium cyanoborohydride (52 mg, 0.83 mmol, 5.0 equiv) was added, and this was repeated (3×) every 8–12 hours over the course of two days. The reaction mixture was partitioned between a 1:1 mixture of saturated sodium carbonate solution and brine and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to provide 3-{5-[1-(4-morpholinyl) ethyl]-1H-indol-2-yl}-2(1H)quinolinone (8-5) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 11.15 (s, 1H), 9.28 (br s, 1H), 8.37 (s, 1H), 7.72 (d, 1H, J=8.0 Hz), 7.57 (s, 1H), 7.54 (br t, 1H, J=7.6 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.27 (d, 1H, J=7.8 Hz), 7.22 (d, 1H, J=7.9 Hz), 7.04 (s, 1H), 3.72 (m, 4H), 3.41 (q, 1H, J=6.6 Hz), 2.56 (m, 2H), 2.43 (m, 2H), 1.46 (d, 3H, J=6.6 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][CH:3]1[C:10]#[N:11].[BH4-].[Li+]>C1COCC1.O>[OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([CH2:6][CH2:7]2)[CH2:4][CH:3]1[C:10]#[N:11]
Reactant: N#CC1CC2(CCC1=O)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CC2(CCC1O)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-oxospiro[2.5]octane-5-carbonitrile (130 mg, 0.87 mmol) in THF (4.3 mL) was stirred at ambient temperature and lithium borohydride (76 mg, 3.5 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH:17]([CH3:22])[O:18][CH:19]([CH3:21])[CH2:20]2)[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:4][CH:3]=1
Reactant: ClCn1cncn1
Reactant: CC1CN(CCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (400 mg.) was prepared using the procedure described in Example 2b except using 400 mg. (1.25 mmoles) of 2-(4-chlorophenyl)-6-(2,6-dimethyl-4-morpholinyl)capronitrile, 0.06 g. (1.38 mmoles) of sodium hydride, 0.15 g. (1.25 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 4 ml. of DMF and was isolated as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCCNC2)nc1)C1CC1
Yield: 11.1 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)piperidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (11 mg, 11% over 2 steps) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.23 (dd, J=8.8, 1.9 Hz, 1H), 8.15 (s, 1H), 8.12 (d, J=2.6 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.58 (dd, J=9.0, 2.7 Hz, 1H), 7.36 (s, 2H), 6.82 (d, J=9.2 Hz, 1H), 4.22 (ddd, J=14.0, 10.0, 3.8 Hz, 1H), 3.63 (dd, J=12.1, 3.5 Hz, 1H), 3.02 (td, J=11.9, 3.4 Hz, 1H), 2.89 (m, 2H), 2.12 (m, 1H), 1.86 (dtt, J=14.9, 11.2, 3.7 Hz, 1H), 1.71 (q, J=10.1 Hz, 1H), 1.21 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.5% (AUC), tR=10.58 min.
Reaction SMILES: Br[C:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>CCCCCC.CCOCC>[CH:19]1[C:14]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]([B:25]([OH:30])[OH:26])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under the atmosphere of argon, 10.1 g of 5-bromobenzo[c]phenanthrene was placed in a flask, and 400 mL of dehydrated ether was added. The reaction solution was cooled to −40° C., and 22 mL of a hexane solution of 1.6 M n-butyl lithium was added. The resultant was heated to 0° C., and stirred for 1 hour. The reaction solution was cooled to −60° C., and 10 mL of a dehydrated ether solution of 14.4 g of triisopropyl borate was added dropwise. While heating the reaction solution to room temperature, stirring was continued for 5 hours. 10 mL of a 10% aqueous hydrochloric acid solution was added, followed by stirring for 1 hour. An aqueous phase was removed, and an organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The resulting solids were washed with hexane, whereby 5.37 g (yield 60%) of benzo[c]phenanthrene-5-boronic acid as an intended product was obtained.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[S:12])#[N:2].[OH-].[Na+].[CH3:24]I>C(O)C>[CH3:8][C:7]1[C:3]2[C:1]([NH2:2])=[N:13][C:11]([S:12][CH3:24])=[N:10][C:4]=2[S:5][C:6]=1[CH3:9]
Reactant: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(N)c2c(C)c(C)sc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)-benzamide (Example 1a) (1.33 g, 4.22 mmol) in ethanol (25 mL) was added NaOH (2.0 N, 5.8 mL) at room temperature under nitrogen. After stirring at 100° C. under nitrogen for 0.5 h, the reaction mixture was cooled in an ice bath and MeI (0.8 mL) was added dropwise. After stirring for another 0.5 h, the resulting precipitate was collected by filtration, rinsed with water, 20% EtOH/H2O, and dried under vacuum to give the title compound (840 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ2.32 (s, 3H), 2.34 (s, 3H), 2.42 (s, 3H), 6.93 (bs, 2H). MS 226 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH3:28])[C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:23]([N:22]1[C:21]2[C:20](=[O:27])[N:19]([CH3:28])[C:18](=[O:29])[N:17]([CH3:30])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
4-[7-(2-Butynyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (2.5 g) was dissolved in trifluoroacetic acid (15 ml), and the solution was stirred at room temperature for 30 minutes. After removing the solvent by distillation at reduced pressure, the residue was purified by column chromatography using NH-silica gel (silica gel, which surface was treated with amino group: NH-DM2035 manufactured by Fuji Silysia Chemical Ltd.) to obtain 1.6 g of the title compound from a fraction eluted with ethyl acetate.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>ClCCl.CC(C)=O>[N:1]1([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#Cc1ccc(Cn2cncn2)cc1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Acetone (1500 ml), 1,2,4-triazole (200 gm; 2.895 mol. eq), cesium carbonate (142 gm; 0.436 mol. eq) and potassium iodide (9 gm) was heated to reflux (55° C.) for 4 hours. The reaction mixture was cooled to room temperature. To this, a solution of 4-bromomethyl benzonitrile (100 gm; 0.510 mol. eq) in dichloromethane (450 ml) was added over a period of 2 hours. The reaction mixture was refluxed for 3 hours. After the completion of reaction, the mass was cooled to 25° C. and the insolubles filtered. The filtrate was concentrated to residue under vacuum. The residue was dissolved in dichloromethane (500 ml), washed with saturated solution of sodium chloride, acidified to a pH 1.0 with concentrated hydrochloric acid and concentrated under vacuum. To the residue, a mixture of diisopropyl ether (160 ml) and n-Heptane (160 ml) was added, stirred at 10° C. for 30 minutes, filtered, washed with n-Heptane and dried under vacuum at 40-45° C. to give 4-[1-(1,2,4-triazole-1-yl)methyl]benzonitrile (76 gm, 81% yield, 99.0% HPLC purity).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([O:17]C)=[O:16])[CH3:2].[OH-].[K+]>O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOc1cc(-c2ccccc2)sc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(-c2ccccc2)sc1C(=O)O
Yield: 92.8 %

Procedure:
A solution of methyl 3-ethoxy-5-phenyl-2-thiophenecarboxylate (12.0 g, 46 mmoles) in tetrahydrofuran (150 mL) is added to a solution of potassium hydroxide (14.6 g, 229 mmoles) in water (150 mL). The mixture is stirred and heated under reflux for 24 hours, then the tetrahydrofuran is removed using a rotary evaporator. The aqueous suspension is cooled in an ice bath and acidified with concentrated HCl. The precipitate is collected by filtration, rinsed well with water and dried to afford the pure product (10.6 g); mp 174°-175° C.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[OH-:25].[Na+].Cl>CO>[C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([NH2:22])=[O:25])=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Reaction time: 8 h

Procedure:
3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile (300 mg), 10 N NaOH (6 mL), and methanol (1 mL) were combined at heated at 110 C overnight. The reaction was acidified with 6 N HCl to give a precipitate, which was isolated by filtration. This material was partitioned between EtOAc and 1 N NaOH by stirring vigorously overnight. The organic solution was discarded, and the aqueous solution was allowed to stand overnight, during which time a precipitate formed. Filtration provided the titled compound.
Reaction SMILES: [CH3:1][C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2OC2)=[CH:17][CH:16]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2OC2)=[CH:6][CH:5]=1)[CH3:3].C(O)(=O)C(C)=C.C1(C=CC(O)=CC=1)O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC1C=CC=CC=1.C(C1C=CC=C(O)C=1O)(C)(C)C>>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:3])[CH3:1])=[CH:9][CH:8]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: C=C(C)C(=O)O
Agent: CC(C)(C)c1cccc(O)c1O
Agent: Oc1ccc(O)cc1
Solvent: C=Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
A diglycidyl ether of bisphenol A (500.0 grams, 2.749 epoxide equivalents) having an epoxide equivalent weight of 181.895, methacrylic acid (229.31 grams, 2.67 moles) and hydroquinone (0.292 gram, 400 ppm based on epoxide functional reactant and methacrylic acid) are added to a reactor and heated to 90° C. with stirring and sparging with air (0.5 liter per minute). Twenty six minutes later, the 90° C. reaction temperature is achieved and 33.33% aqueous chromium trichloride catalyst (0.625 gram, 0.125% wt. based on epoxide functional reactant) is added to the reactor and the temperature controller set at 110° C. and this temperature is achieved eleven minutes later. After five minutes the temperature controller is set at 115° C. and this temperature is achieved five minutes later. After 330 minutes at the 115° C. reaction temperature, titration of samples of the vinyl ester demonstrates the presence of 0.21 percent epoxide and 0.36 percent acid. Ten minutes later, cooling of the reactor to 80° C. commenced and this temperature is achieved eleven minutes later. Phenothiazine (0.145 gram, 200 ppm based on vinyl ester) is added to the reactor followed 5 minutes later by styrene inhibited with 50 ppm of t-butylcatechol (310.23 grams, 30.0% wt. of the vinyl ester after correction for sample weight removed for titration). The product is filtered through a coarse fritted glass funnel and recovered as a light green colored styrenated vinyl ester resin containing 70.0% wt. dimethacrylate of bisphenol A diglycidyl ether and 30.0% wt. styrene. A 400.0 gram aliquot of the styrenated vinyl ester resin is further diluted with styrene (109.0 grams) to provide dimethacrylate of bisphenol A containing 45.0% styrene. Gel permeation chromatographic analysis of a portion of the non-styrenated vinyl ester using polystyrenes as calibration standards revealed a single product peak with the following profile: z-average molecular weight/polydispersity ration=843/1.16, weight average molecular weight/polydispersity ratio=725/1.29, number average molecular weight/polydispersity ratio=656/1.11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol was heated in a sealed tube at 70° C. for 5 hours. The reaction was concentrated and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]2)=[C:7]([NH:20][C@H:21]([CH2:29][OH:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([O:19][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:16]=[CH:15]2)=[C:7]([NH:20][C@H:21]([CH2:29][OH:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(C(=O)OC)nc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
9-((1R,4S)-4-Hydroxy-cyclopent-2-enyl)-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate WA) is dissolved in THF (dry). Pyridine is added and the reaction mixture is cooled to 0° C. Ethyl chloroformate is added dropwise keeping the temperature below 10° C. The reaction mixture is warmed to RT and stirred for 2 hours. The reaction mixture is reduced in vacuo and portioned between EtOAc and (1 M) HCl(aq). The organics are washed with water, brine, dried (MgSO4) and reduced in vacuo. The resulting residue is columned to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[C:22](=[O:35])[NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[C:7]([Cl:36])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:36][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:22](=[O:35])[NH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34]
Reactant: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethyl-carbamoyl]-3-phenyl-isoxazol-5-yl}-phenyl)-acetic acid methyl ester 62 is dissolved in THF (2 mL). A solution of 1 M LiOH in H2O (0.6 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl, DCM (10 mL) is added and the organic layer washed with H2O (3×5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound J1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.66 (m, 2H), 7.51 (d, J=7.9 Hz, 1H), 7.34-7.19 (m, 6H), 7.09 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.04 (t, J=5.6 Hz, NH), 3.86 (t, J=4.9 Hz, 2H), 3.63 (q, J=5.2 Hz, 2H), 3.51 (s, 2H). MS calculated for C26H20Cl3N2O5 (M+H+) 545.0, found 545.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:36]([CH3:37])=[CH:35][C:33]([NH2:34])=[C:32]([O:38][CH3:39])[CH:31]=3)[CH2:26][CH2:25]2)[CH2:20]1>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:34][C:33]2[CH:35]=[C:36]([CH3:37])[C:30]([N:27]3[CH2:28][CH2:29][CH:24]([N:21]4[CH2:22][CH2:23][C@@H:19]([F:18])[CH2:20]4)[CH2:25][CH2:26]3)=[CH:31][C:32]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)c(C)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and (R)-4-(4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylaniline (INTERMEDIATE 36).
Reaction SMILES: [CH2:1]([C:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].CCN(C(C)C)C(C)C.[Br:19][C:20]1[C:21](Cl)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]>CC#N.CCOCC>[Br:19][C:20]1[C:21]([N:6]2[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([CH3:9])[CH2:4][CH2:5]2)=[C:22]([C:28](=[O:35])[C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:23]([CH3:27])=[N:24][C:25]=1[CH3:26]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CCC1(C)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CCC1(C)CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a solution of 4-ethyl-4-methylpiperidine (0.760 g, 5.98 mmol) and DIEA (2.1 mL, 11.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.0 g, 5.98 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-15% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(4-ethyl-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 2.51 g (99%). 1H NMR (500 MHz, CDCl3) δ 5.07-5.02 (m, 1H), 3.32 (br. s, 2H), 3.18 (br.s, 2H), 2.61 (s, 3H), 2.29 (s, 3H), 1.29-1.28 (m 12H), 0.89 (s, 3H), 0.80 (t, J=7.3 Hz, 3H). UPLC (M+H)=427.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:17]1C=CC=CC=1C1(C(OC)=O)CCNCC1>>[C:14]([C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)#[N:15]
Reactant: COC(=O)C1(c2ccccc2Cl)CCNCC1
Reactant: N#CC1(c2ccccc2Cl)CCNCC1
Product: Cc1ccccc1C1(C#N)CCNCC1

Procedure:
4-(2-chlorophenyl)-4-cyanopiperidine or 4-(2-chlorophenyl)-4-(methoxycarbonyl)piperidine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([C:28](=[O:31])[CH:29]=[CH2:30])[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3c(ccc4ccccc34)S2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of 3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.50 g), sodium hydrogen carbonate (1.0 g), methylene chloride (30 ml) and water (15 ml) is added dropwise with stirring a solution of acryloyl chloride (0.90 g) in methylene chloride (10 ml) under ice cooling. The mixture is stirred at room temperature for 3 hours. The organic layer is separated, washed, dried and distilled to remove the solvent. The residue is chromatographed on silica gel (toluene: acetone=50:1) to give 3-(4-chlorophenyl)-1-propenoyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.37 g, 78%) as powder.