Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([OH:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CS(C)=O>[CH2:29]([O:20][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:28]=[CH2:27]
Reactant: Oc1ccc(F)cc1-c1ccccc1-c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1ccc(F)cc1-c1ccccc1-c1ccccc1
Yield: 81.8 %

Procedure:
Treatment of 5-fluoro-2′-phenylbiphenyl-2-ol (6.8 g, 25.7 mmol) with potassium carbonate (5.3 g, 38.6 mmol) and allyl bromide (3.3 mL, 38.6 mmol) in DMSO (150 mL) according to the procedure described for Example 69, Step 3 provided 6.4 g (82%) of 2-allyloxy-5-fluoro-2′-phenylbiphenyl as a white solid. MS (EI) m/z 304.1264 ([M]+); mp 48–49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=[O:11]>C1COCC1.[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: [Rh]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccccc1Cl

Procedure:
3-(2-chloro-phenyl)-acrylic acid (10.00 g, 55.00 mmol) in THF was mixed with Rh/Al2O3 (500 mg) and hydrogenated for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(2-chloro-phenyl)-propionic acid. 3-(2-chloro-phenyl)-propionic acid (10.0 g, 43.70 mmol) was then reacted with SOCl2 (6.00 mL, 82.26 mmol) and AlCl3 (8.00 g, 60.00 mmol) according to the protocols as outlined in general procedure C to afford the title chloroindanone. iv Berrier, C.; Gesson, J. P.; Jacquesy, J. C.; Renoux, A. Tetrahedron 1984, 40, 4973-4980.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][C:13]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=1[Cl:11]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C=O)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Nc2ccc(Cl)cc2Cl)c(C)c1

Procedure:
A mixture of 26.8 g. of 2,4-dimethylbenzaldehyde, 32.4 g. of 2,4-dichloroaniline, 0.20 g. of p-toluenesulfonic acid, and 150 ml of toluene is stirred under reflux using a Dean-Stark moisture trap. Evaporation of the mixture affords a solid which is recrystallized from ethanol to yield N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, mp 102°-106°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH2:28][CH3:29]
Reactant: CCC(N)CO
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: CCC(CO)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 70 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using rac-2-amino-1-butanol instead of isopropylamine, to the title compound (87 mg, 70%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCOCC1>CO>[N:21]1([CH2:27][CH2:28][NH:29][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCN1CCOCC1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN3CCOCC3)cc2s1
Yield: 44.2 %

Procedure:
the title compound (56 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-morpholin-4-ylethylamine (80 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 423.5 (M+1, 100%). Yield=43%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:23]2[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[NH:10][C:11]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>CO.[OH-].[Pd+2].[OH-].[Pd]>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:23]2[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=[CH:25][N:24]=2)[NH:10][C:11]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][CH2:19][NH:20]3)=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc2cccnc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)—N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methyl)quinoline-7-carboxamide (Example 132) (0.500 g, 1.052 mmol) in MeOH (6 mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon, wet, degussa type) (0.148 g, 1.052 mmol). The resulting mixture was then stirred at rt under H2 overnight. The resulting mixture was filtered through Celite® brand filter agent and the Celite® filter agent was washed with MeOH (2×3 mL). The combined filtrates were concentrated and the mixture was dissolved in DMSO (3 mL). The mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (2 mL). The solution was washed through PL_HCO3 MP-SPE resin and the resin was washed with MeOH (2×2 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, MeOH) δ ppm 8.94 (d, J=4.1 Hz, 1H), 8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.50-7.70 (m, 5H), 6.94-7.02 (m, 3H), 6.90 (s, 1H), 3.24-3.31 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.86-1.99 (m, 2H). MS (ESI pos. ion) m/z: 480.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:5]([NH2:7])=O.[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:12]1[N:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]#[N:7])=[CH:3][C:2]=2[CH3:1])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C(N)=O)ccc1-n1cccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1-n1cccc1Br
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
To a solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A, see first step of Scheme 6 for synthesis) in DMF (5 mL) was added N-bromosuccinimide (177 mg, 1 mmol) portionwise at 0° C., after the addition was completed, the mixture was stirred at room temperature for 35 min. The reaction mixture was poured into water, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (25 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford 50B (100 mg, yield 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-2-methylpropanoate (6 g, 29 mmol), KOH (3 g, 57 mmol) and 100 mL EtOH/H2O (4:1) was refluxed for 4 hours. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3.1 g of the product as a white solid. MS m/e=211(M−1)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[CH:22]=2)=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Fc1cccc(Br)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(-c2c(F)cccc2Br)c1
Temperature: 25 °C

Procedure:
Pd(Ph3P)4 in a 500-mL round-bottom flask under N2 atmosphere was treated sequentially with a solution of 1-bromo-3-fluoro-2-iodo-benzene (30 g, 0.1 mol) in toluene (250 mL), a solution of 2N aq Na2CO3 (200 mL) and 3-methyl phenylboronic acid in ethanol (62 mL). This mixture was heated at reflux under N2 for 12 h, then cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, evaporated and purified by column chromatography to give 6-bromo-2-fluoro-3′-methyl-biphenyl (12 g). 1H NMR (400 MHz, CD3OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3C3CCCCC23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthrene (48.5 mg, 0.15 mmol), 10% Pd—C (5.4 mg, 0.04 mmol), and ethanol (3 mL) and tetrahydrofuran (3 mL), degas, and add H2 at atmospheric pressure and at room temperature. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 20% ethyl acetate/hexanes to yield the titled compound (42.4 mg, 87%) as a clear oil. TLC Rf=0.51 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (d, 2H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.97 (m, 1H), 6.90 (d, 2H, J=7.9 Hz), 6.75 (m, 1H), 3.82 (m, 6H), 3.19 (m, 3H), 2.87 (dd, 1H, J=15.0, 4.0 Hz), 2.49 (m, 1H), 2.04 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H), 1.29 (m, 1H), 1.15 (m, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@@H:18]3[O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[O:20][CH2:19]3)=O)[CH2:11]2)[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][CH2:19][C@@H:18]1[CH2:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][CH:7]=2)[CH2:11]1
Reactant: COC(=O)c1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
((R*)-3-[1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)piperidin-3-yl]benzoic acid methyl ester (54 mg, 0.147 mmol) was dissolved in dry THF (4 ml) and cooled to 0° C. LiAlH4 (26 mg, 0.680 mmol) was added and the mixture was stirred at RT for 2 h. Water (1 ml), 1 M NaOH (1 ml) and again water (1 ml) were added slowly. The mixture was filtered through Celite and evaporated. Flash chromatography, using a gradient of heptane/EtOAc, gave 3.5 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OCCCCC(OC(C)(C)C)=O)=O)[CH2:14]3)[S:10](=[O:30])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>ClCCl>[C:31]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[S:10](=[O:30])[CH2:9][CH2:8]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCCCOC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Yield: 123.8 %

Procedure:
3.98 g of 4,4-diphenyl-6-tert-butyloxycarbonylbutyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the 1RS,4aSR,7aSR and 1RS,4aRS,7aRS isomers) are treated with 40 cm3 of a mixture of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 by volume) for 48 hours at 20° C. The solution is concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The oil obtained is taken up in 30 cm3 of dichloromethane, the solution is washed with 60 cm3 of a 2N aqueous solution of sodium hydroxide, the aqueous phase is extracted with 20 cm3 of dichloromethane. The organic extracts are pooled, dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is taken up in diisopropyl oxide and then concentrated to dryness at 40° C. under reduced pressure (2.7 and then 0.13 kPa). 3.0 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide are obtained in the form of a white meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH2:22][OH:23].ClCCl.[C:27](Cl)(=[O:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:23][CH2:22][C:3]1[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:29])[CH3:28]
Reactant: O=c1c2sc3c(c2cnn1-c1nccc(Cl)c1CO)CCCC3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A round-bottomed flask was charged with 230g (597 mg, 1.72 mmol), dichloromethane (50 mL), and triethylamine (5 mL). The solution was stirred at 0° C. for 0.5 h and acetyl chloride (135 mg, 1.72 mmol) was added slowly. The mixture was stirred at 0° C. for another 2.5 h. It was then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 9:1 petroleum ether/ethyl acetate to afford 230h (602 mg, 90%) as a yellow solid. MS-ESI: [M+H]+ 390.1
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCN1CCCCCC1=O
Yield: 71.9 %

Procedure:
Following example 8 and using water condenser from the start of the reaction, 10 g of 50% sodium hydride-mineral oil dispersion (5 g NaH, 0.21 M), 20 g (0.177 M) of azacycloheptan-2-one and 30.2 g (0.2 M) of 1-bromopentane on 18 hr. reflux gave 23.3 g (87%) of colorless product; b.p. 110°-115°/0.3 mm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([C:12]#[N:13])[N:6]=1)=[O:4].Cl>C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:12]#[N:13]
Reactant: COC(=O)c1ccc(Br)c(C#N)n1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1nc(C(=O)O)ccc1Br
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
To a solution of potassium trimethylsilanoate (0.80 g, 6.22 mmol) in THF (26 mL) was added 5-bromo-6-cyano-pyridine-2-carboxylic acid methyl ester (998 mg, 4.15 mmol). The mixture was heated at 50° C. for 3 h, then was cooled to rt and treated with HCl (4 N in dioxane; 1.60 mL). After 30 min, the mixture was concentrated. The residue was dissolved in hot EtOAc and filtered. The filtrate was concentrated to give the title compound (993 mg, >100%), which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([C:6]2([C:12](Cl)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[NH3:21]>O1CCCC1>[C:1]1(=[O:20])[N:5]([C:6]2([C:12]([NH2:21])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1C1(C(=O)Cl)CCCCC1
Solvent: C1CCOC1
Product: NC(=O)C1(N2C(=O)c3ccccc3C2=O)CCCCC1
Temperature: 5 °C

Procedure:
The crude 1-phthalimidocyclohexanecarbonyl chloride prepared above in Step 3 is dissolved in 3.5 l tetrahydrofuran, and the solution cooled to 5° C. Ammonia is than bubbled into the solution with stirring until infra-red analysis of the liquid phase indicates that all the acid chloride is converted to the amide. The reaction mixture is then poured into 8 l of water with stirring, the product removed by filtration, washed with water and air-dried to give 259.1 of 1-phthalimidocyclohexanecarboxamide, melting point 224°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:10][C:11]1[C:12]([S:17](Cl)(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:17]([C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:19])=[O:18]
Reactant: COc1ccccc1N
Reactant: Cc1cccnc1S(=O)(=O)Cl
Product: COc1ccccc1NS(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of 2-methoxy-phenylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)[CH:12]=[CH:11][N:10]1[CH2:28][C:29]1[N:30](C(OC(C)(C)C)=O)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.C([O-])(O)=O.[Na+].CC#N>ClCCl>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[C:29]1[CH2:28][N:10]1[CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:14][C:9]1=[O:8]
Reactant: CC(C)(C)OC(=O)n1c(Cn2ccc(-c3ccnc(NC4CCOCC4)n3)cc2=O)cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (130 mg, 0.32 mmol) in dichloromethane (3 mL) at 20° C. The mixture was stirred at room temperature for 2 hours. LC-MS showed the tert-butyl 2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was adjusted to a pH of around 8-9 with saturated NaHCO3 solution, extracted with dichloromethane, and dried with Na2SO4. The organic phase was evaporated, and the residue was purified with prep-HPLC (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford 1-((1H-indol-2-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (60 mg, 60% yield). 1H NMR (500 MHz, (CD3)2SO) δ 11.07 (s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 7.37-7.36 (m, 2H), 7.15-7.14 (m, 2H), 7.06 (m 1H), 6.96 (m, 1H), 6.88 (d, J=6 Hz, 1H), 6.35 (s, 1H), 5.26 (s, 2H), 3.97 (m, 1H), 3.88-3.86 (m, 2H), 3.42-3.37 (m, 2H), 1.85-1.83 (m, 2H), 1.56-1.48 (m, 2H); LCMS (ESI) m/z 402.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=O)[CH2:5][CH2:4]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=[S:23])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](N(C)C(=O)c2ccc3nonc3c2)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CO[C@H]1CC[C@H](N(C)C(=S)c2ccc3nonc3c2)CC1

Procedure:
N-(trans-4-Methoxycyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide (0.91 g, 3.2 mmol) and phosphorus pentasulfide (1.42 g) were refluxed in toluene (40 ml) for 3 h. The mixture was cooled, filtered through a 2 cm layer of silica gel and washed with dichloromethane. Evaporation of the solvent and trituration with diethyl ether gave a yellow solid (0.1 g). Mp=137-138° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.89-7.83 (m, 1H); 7.58-7.55 (m, 1H); 7.36-7.30 (m, 1H); 5.50-5.40 and 3.90-3.75 and 3.50-3.00 (m, 2H); 3.44 and 3.38 (s+s, 3H); 3.27 and 3.04 (s+s, 3H); 2.30-0.95 ppm (s, 8H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(OCC)(=O)C.O>[CH3:27][S:24]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.3 g of benzyl (R)-3-hydroxy-pyrrolidine-1-carboxylate and 5.56 ml of triethylamine in 80 ml of ethyl acetate was cooled to 0-5° C. under argon and treated within 30 minutes with a solution of 2.97 ml of mesyl chloride in 20 ml of ethyl acetate. After stirring at room temperature for 2 hours and leaving to stand for 16 hours the suspension was diluted with 40 ml of water, stirred for 10 minutes and the organic phase was separated. The organic phase was extracted in succession with 20 ml of 1N HCl, 20 ml of saturated NaHCO3 solution and 10 ml of saturated NaCl solution. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated to give 10.18 g of product as a beige oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=1)=[N:45]2>C1COCC1>[CH3:38][O:39][C:40]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]2[C:41]=1[C:42](=[O:64])[NH:43][C:44]([C:52]1[CH:57]=[CH:56][C:55]([N:58]3[CH2:59][CH2:60][N:61]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:8])[CH2:62][CH2:63]3)=[CH:54][CH:53]=1)=[N:45]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccs5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.9 %

Procedure:
To a solution of 2-thiophenecarboxylic acid (0.087 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography, eluting with 0% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 30%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.75-7.84 (m, 1H), 7.46-7.53 (m, 1H), 7.12-7.20 (m, 1H), 7.03 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74-3.92 (m, 4H), 3.37-3.49 (m, 4H). APCI MS m/z 477 [M+H]+.