Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:27])[NH:18][CH:19]([C:24](=O)[NH2:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:27])[NH:18][CH:19]([C:24]#[N:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(=O)C1CCCCC1NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a 0° C. solution of the amide of step 3 (13.2 g, 33.9 mmol) in 150 mL of anhydrous pyridine was added trifluoroacetic anhydride (5.50 mL, 38.9 mmol) dropwise slowly over a 3 min period. The reaction mixture was stirred for 15 min and then poured into a slurry of ice and 1N HCl solution. The mixture was extracted with 500 mL of ethyl acetate, and washed with three 400 mL portions of 1N HCl, 400 mL of water, dried over sodium sulfate, filtered and concentrated to give a crude solid. Recrystallization from ethyl acetate/hexanes gave 11.3 g of [2-(1-Cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester as a white solid. Yield: 90%, MS: 394 (M+Na+), mp=103.6-106.5° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:8]([C:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
20.4 g of ethyl 3-p-tolyl-3-oxopropionate (Helv. Chim. Acta 57, 2205 (1974)) are dissolved in 20 ml of CCl4. A solution of 6 ml of bromine in 30 ml of CCl4 is added dropwise at -5° C. After 1 hour at -5° C., the mixture is stirred at 20° C. for 3 h and then at 60° C. for 1 h. the solvent is removed. The title compound is used further as crude product; yield 34 g.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:29])([F:28])[C:12]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][C@H:20]([C:25]([OH:27])=O)[CH2:19][CH2:18][C:17]=2[N:16]=1)([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:25]([C@@H:20]1[CH2:19][CH2:18][C:17]2[N:16]=[C:15]([C:12]([CH3:14])([CH3:13])[C:11]([F:29])([F:10])[F:28])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:27])[CH3:57]
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)[C@@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 60.6 %

Procedure:
N-methylpyrrolidinone (1.2 mL) and N,N-diisopropylethylamine (87 uL, 0.50 mmol) were added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (75 mg, 0.20 mmol) in a 4 mL vial, and the mixture stirred at room temperature for 10 min, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (55 mg, 0.19 mmol) in N-methylpyrrolidinone (0.5 mL) was added. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (50 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.06 (d, J=11.7 Hz, 1H), 5.10 (app pentet, J=7.2 Hz, 1H), 3.00 (s, 3H), 2.93-2.76 (m, 4H), 2.68-2.59 (m, 1H), 2.25, (s, 3H), 2.09-2.03 (m, 1H), 1.88-1.76 (m, 1H), 1.54 (s, 3H), 1.35 (d, J=7.0 Hz, 3H); m/z=515.8 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])[CH:14]=1)=O>CCCCCC.O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])[CH:14]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
Trimethylaluminum (0.57 mL of a 2 M solution in hexane, 1.15 mmol) was slowly added to a solution of isopropylamine (68.2 mg, 1.15 mmol) in dioxane (5.0 mL) and stirred at 80° C. for 1 h. Then a solution of 3-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.29 mmol) in dioxane (5.0 mL) was added dropwise. The mixture was stirred at 85° C. overnight. After cooling to room temperature and extractive workup (ethyl acetate/aqueous saturated Seignette's salt solution) the organic phase was dried (Na2SO4) and filtered. Purification by chromatography (silica, ethyl acetate:heptane=3:7 to 1:1) afforded the title compound (50 mg, 46%) as a white solid. MS: m/e=373.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.25 g, 0.67 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.168 g, 1.67 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid methyl ester (0.142 g, 0.80 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 0.3 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1nc2ccccc2o1

Procedure:
To a solution of 5.0 gm. of 2-(2-fluoro-4-methylphenyl)benzoxazole in 200 cc. of carbon tetrachloride is added 4.5 gm. of N-bromosuccinimide and 50 mg. of dibenzoyl peroxide. The mixture is refluxed for 2 hours, filtered to remove succinimide and concentrated in vacuo. The residue is recrystallized from toluene to give 2-(4-bromomethyl-2-fluorophenyl)benzoxazole, m.p. 170°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7](OC1C=CC([N+]([O-])=O)=CC=1)=[O:8])[CH3:5].Cl.[C:22]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7]([N:30]1[CH2:31][CH2:32][C@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29]1)=[O:8])[CH3:5]
Reactant: c1ccc([C@H]2CCNC2)cc1
Reactant: COC(=O)C(C)(C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)N1CC[C@H](c2ccccc2)C1

Procedure:
Combine 2-methyl-2-(4-nitro-phenoxycarbonylamino)-propionic acid methyl ester (500 mg, 1.77 mmol) and (R)-3-phenyl-pyrrolidine hydrochloride (325 mg, 1.77 mmol) in 1,4-dioxane (5 mL). Add TEA (494 uL, 3.54 mmol) and heat to 130° C. for 5 min by microwave irradiation. Dilute the reaction mixture with DCM (100 mL) and extract with 1 N NaOH (30 mL) followed by 1 N HCl (30 mL). Dry the organic layer over MgSO4 and concentrate. Purify the concentrate by silica gel chromatography (40-60% EtOAc/HEP) to afford the title compound: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.51 (d, J=1.77 Hz, 6H) 1.98-2.14 (m, 1H) 2.22-2.38 (m, 1H) 3.31 (t, J=9.28 Hz, 1H) 3.35-3.48 (m, 2H) 3.53-3.65 (m, 1H) 3.70 (s, 3H) 3.80 (dd, J=9.41, 7.52 Hz, 1H) 7.15-7.40 (m, 5H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:8]([O:23][CH3:24])[CH:7]=1>O.O1CCCC1>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:25])=[O:4])=[CH:7][C:8]=1[O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(F)ccc2Cl)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH (14.1 g, 0.59 mol, 1.1 equiv.) dissolved in H2O (200 mL) was added drop-wise over 45 minutes to a solution of 34 (180 g, 0.53 mol, 1 equiv.) in tetrahydrofuran (1800 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue re-dissolved in water (ca. 3 L). The insoluble solid was filtered off. Under vigorous stirring, the aqueous filtrate solution was acidified with concentrated HCl aqueous solution (37%) until pH<2. The resulting white solid precipitate was filtered and washed with water. The wet filter cake was then transferred to a flask and dried on rotary evaporator under vacuum at 50° C. overnight to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid 35 as a dry, fine white powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.90 (s, 1H), 10.01 (s, 1H), 8.22 (d, 1H), 7.65-7.45 (m, 4H), 7.45-7.30 (m, 1H), 3.88 (s, 1H). MS (ES) m/z 322.0 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(C#N)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.73 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([S:12][C:13]#[N:14])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=C)[CH3:2].[BrH:15].C(O)(=O)C.O>C(O)(=O)C>[Br:15][C:13]1[S:12][C:3]([CH2:1][CH3:2])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:14]=1
Reactant: Br
Reactant: C=C(c1ccccc1)C(CC)SC#N
Solvent: O
Solvent: CC(=O)O
Product: CCc1sc(Br)nc1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-ethyl-2-phenylprop-2-en-1-yl thiocyanate (4.15 g, 20.2 mmol) in acetic acid (40 ml) was added a 25% hydrogen bromide/acetic acid (40 ml) solution, and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (4.02 g, 74.2%) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:17]1([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15][B:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[O:18]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(C2=CCNCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708, 500 mg, 1.617 mmol) was added 2 mL DCM and 2 mL TFA. The mixture was stirred at room temperature for 3 hours. The solvents were evaporated in vacuo to afford the title compound (323 mg, 96% yield). The product was not further purified for next step. MS (ES+): m/z 210.19 (100) [MH+]; HPLC: tR=0.55 min (UPLC, Analytical).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[O-]CC.[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-3-buten-2-one (27.1 g) and diethyl oxalate (21.9 g) in dry diethyl ether (200 ml) was added drop-wise over 15 minutes to a stirred suspension of sodium ethoxide (3.45 g of sodium dissolved in absolute ethanol and excess ethanol evaporated off) in dry diethyl ether (400 ml) cooled to 5°-10° C. by an ice bath. A yellow solid began to precipitate after 5 minutes.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])=O.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([C:10]1[CH:9]=[C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[N:7]=[N:6][C:5]=1[C:3]([NH:24][NH2:25])=[O:2])[CH:12]([CH3:14])[CH3:13]
Reactant: NN
Reactant: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Solvent: CCO
Solvent: O
Product: CC(C)Cc1cc(C(=O)N2CCCCC2)nnc1C(=O)NN
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The mono-methyl ester 5 (10 mg, 0.033 mmol) was dissolved in 3.5 mL anhydrous ethanol (dried over 4 Å molecular sieves). Hydrazine hydrate was added (55 μL, 1.65 mmol, 53 mg), and the reaction was stirred for 5.5 hours at room temperature under an atmosphere of nitrogen. The volatiles were evaporated under reduced pressure, and the product oil was triturated three times with ca. 3 mL diethyl ether. The bright yellow oil was dried under high vacuum to produce a 10 mg (quant.) of a pale yellow solid. MS: (ESI-TOF) MH+ expected: 306.1924, found: 306.1923.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:6]([CH:29]=1)[C:7]([N:9]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH2:16][CH:11]2[CH:10]1[CH2:17][N:18]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].O.NN>CO>[NH2:18][CH2:17][CH:10]1[CH:11]2[CH2:16][CH2:15][CH2:14][CH:12]2[CH2:13][N:9]1[C:7]([C:6]1[CH:29]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
A solution of 2-((2-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)octahydrocyclopenta[c]pyrrol-1-yl)methyl)isoindoline-1,3-dione (1 equiv.) and hydrazine monohydrate (4 equiv.) in MeOH (0.5M) was stirred at 70° C. for 3 h and then concentrated in vacuo to a yellow oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (20% MeOH in EtOAc) to firstly remove the impurities and then (2:8:1 MeOH/EtOAc/TEA) to elute the title compound which was concentrated to yield a yellow oil. MS (ESI) 326 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.Cl[C:16]1[N:21]2[N:22]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:24]=[C:20]2[N:19]=[CH:18][CH:17]=1>CN(C=O)C.CCOC(C)=O>[CH:25]1([C:23]2[CH:24]=[C:20]3[N:19]=[CH:18][CH:17]=[C:16]([S:14][C:11]4[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=4)[N:21]3[N:22]=2)[CH2:27][CH2:26]1
Reactant: Clc1ccnc2cc(C3CC3)nn12
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccnc3cc(C4CC4)nn23)cc1
Temperature: 60 °C

Procedure:
To a mixture of cesium carbonate (0.606 g, 1.86 mmol) and 4-aminobenzenethiol (116 mg, 0.930 mmol) in DMF (3 mL) at RT was added 7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine (0.180 g, 0.930 mmol). The mixture was heated to 60° C. After 2 hrs the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. After drying the organic fraction with sodium sulfate, the solvent was removed in vacuo to afford 4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)benzenamine, which was advanced without further purification. MS: Found M+H+=283.1.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]([CH2:28]C)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([OH:26])[CH2:23][C:22]2=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][N:11]([CH3:9])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][C:22]2=[O:27])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CC(O)CC2=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(S(=O)(=O)N2CC(OC(=O)C(C)(C)C)CC2=O)cc1
Reaction time: 16 h

Procedure:
0.41 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) is added at 3° C. to a solution of 1 g of [1-(4-diethylamino-benzenesulphonyl)-4-hydroxy-pyrrolidin-2-one] in 20 cm3 of methylene chloride, and then 0.43 g of pivaloyl chloride in solution in 3 cm3 of methylene chloride is added slowly, and the whole mixture is left at ambient temperature for 16 hours. Another equivalent of pivaloyl chloride and DABCO is added, the mixture is left at ambient temperature for 4 hours, brought to dryness, the residue is taken up in ethyl acetate, washed with water (at a pH of about 6), followed by filtering and bringing to dryness under reduced pressure, and the residue is chromatographed on silica (eluant: ethyl acetate - hexane 4-1). 0.6 g of expected crude product and 0.3 g of product containing a double bond in position 3,4 of the pyrrolidinone are obtained. The crude product is added to a previous preparation in order to obtain, after recrystallization from an ethyl acetate - hexane mixture (3-50), 0.86 g of the desired product. M.p.=117-118° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OC(=O)[NH:15][C@@H:16]1[CH2:20][CH2:19][N:18](C2C(C(F)(F)F)=CC=CN=2)[CH2:17]1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[Cl:8][C:7]1[C:2]([N:18]2[CH2:19][CH2:20][C@@H:16]([NH2:15])[CH2:17]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: N[C@@H]1CCN(c2ncccc2Cl)C1

Procedure:
The title compound was prepared from 2,3-dichloropyridine and 3R-(+)-3-(tert-butyloxycarbonylamino)pyrrolidine using the procedure outlined for Descriptions D1 and D2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH:20](C(OC(C)(C)C)=O)[N:14]3[C@H:13]3[CH2:28][CH2:29][N:30]=[CH:31][C@H:12]23)[CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:12]23)[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1CSc2cc(-c3cccc(Cl)c3Cl)cc3c2N1[C@H]1CCN=C[C@H]31
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCS3)c1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl(6bR,10aS)-5-(2,3-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole carboxylate (10 mg, 0.21 mmol) in CH2Cl2 (4.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 20° C. for 1 h then concentrated in vacuo. The residue was dissolved in H2O and the solution was adjusted to pH 2 by addition of 1N HCl. The aqueous layer was washed with Et2O then basified to pH 12 by addition of 50% NaOH. The solution was extracted with CHCl3, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (79 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ1.93-2.05 (br-s, 2H), 2.65-2.99 (m, 4H), 3.01-3.25 (m, 4H), 3.44-3.68 (m, 3H), 6.88 (s, 1H), 6.90 (s, 1H), 7.18 (d, J=4.6 Hz, 2H), 7.40 (t, J=4.6 Hz, 1H) ppm.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:27]1C=CC(N)=C(C)C=1.P(Cl)(Cl)(Cl)=O.N>O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:27])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(Br)ccc1N
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (20.0 g, 71.5 mmol, Intermediate 6, step b) and 4-bromo-2-methylaniline (13.3 g, 71.5 mmol) in phosphorus oxychloride (66.8 mL, 712 mmol) was heated at 105° C. After 5 hours, the mixture was cooled to room temperature and added to water (600 mL) with cooling so that the internal temperature did not exceed 35° C. The pH of the mixture was adjusted to 8-9 by the slow addition of saturated aqueous ammonia solution such that the internal temperature did not exceed 35° C. After 30 minutes of stirring at room temperature, the mixture was filtered and the solid material was suspended in acetonitrile (200 mL), sonicated and filtered. The solid material was collected and suspended in DCM (80 mL), sonicated and filtered and washed with ether (40 mL). The filtrate was concentrated, suspended in DCM (40 mL), sonicated and filtered to provide more of the desired product. To 5 g of the isolated solid, DCM (300 mL) and aqueous saturated NaHCO3 (100 mL) were added and the mixture was transferred to a separatory funnel, and the layers were separated. The DCM layer was further washed with brine (100 mL), dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude material was purified using flash-column chromatography on silica gel eluting with DCM to provide 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline as an off-white solid.