Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[CH2:19]([N:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([CH3:10])=[CH:9][C:4]=1[Br:3])[C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N(Cc2ccccc2)C(=O)C(C)C)c(Br)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
A mixture of powdered KOH (1.3 g, 23.13 mmol) in DMSO (25 mL) was stirred at 0° C. for 5 minutes. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (3.30 g, 11.56 mmol) was added cautiously followed immediately by the addition of benzylbromide (2.75 mL, 23.13 mmol) and the reaction stirred at room temperature for 48 hrs. Water was added and the mixture extracted with ethyl acetate. The organic extract was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 4.3 g of N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). 1H NMR (300 MHz; CDCl3): 1.02 (d, J=6.6 Hz, 3 H), 1.15 (d, J=6.6 Hz, 3 H), 2.16 (s, 3 H), 2.29 (m, 1 H), 3.43 (s, 3 H), 3.85 (d, J=14.1 Hz, 1 H), 5.75 (d=14.1 Hz, 1 H), 6.02 (s, 1 H), 7.18–7.27 (m, 5 H), 7.38 (s, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]
Reactant: Cn1c(=O)n(CCC(C)(C)N)c2ccccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: Cn1c(=O)n(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
Prepared according to general method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-3-methyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[CH2:12][N:13]([CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16].[C:35]([OH:44])(=[O:43])[C@@H:36]([C@H:38]([C:40]([OH:42])=[O:41])[OH:39])[OH:37].C1CCCCC1>ClCCl>[C:40]([C@@H:38]([C@H:36]([C:35]([OH:44])=[O:43])[OH:37])[OH:39])([OH:42])=[O:41].[CH3:16][CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[CH2:12][C:11]1[CH:10]=[C:9]([Cl:8])[CH:33]=[C:32]([Cl:34])[CH:31]=1
Reactant: CC(C)CN(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Product: CC(C)CN(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCCN1
Reaction time: 2 h
Yield: 33 %

Procedure:
Trifluoroacetic acid (1.5 ml, 15 mol, 10 eq) is added to a solution of tert-butyl (2S)-2-{[(3,5-dichlorobenzyl)(isobutyl)amino]methyl}pyrrolidine-1-carboxylate (0.611 g, 1.5 mmol, 1 eq) in dichloromethane (5 ml). After 16 hours if not complete by LCMS add an additional portion of trifluoroacetic acid (1.5 ml, 15 mol, 10 eq). After 72 hrs the solvent is removed in vacuo, methanol is added to the residue and the solution is loaded onto a SCX-2 (5 g) column. The column is washed with methanol (10 ml) and then the basic material is eluted with 2M ammonia in methanol (10 ml) and the solvent is removed in vacuo. The residue is dissolved in isopropanol (5 ml) and L-tartaric acid (1 eq) is added. The solution is heated to dissolve, then cooled and is left to stand in a fridge for 2 hrs, if no crystals have formed cyclohexane is added and the surface is scratched with a glass rod. The solid formed is filtered and dried in a vacuum oven at 60° C. for 16 hrs to give the N-(2-methylpropyl)-N-{[3,5-dichlorophenyl]-methyl}-(2S)-pyrrolidine-2-yl-methylamine L-Tartrate (0.23 g, 33%). 1H NMR (300 MHz, CD3OH) δH: 7.26 (3H, s) 4.29 (2H, s, tartrate) 3.44-3.78 (3H, m) 3.06-3.30 (4H, m) 2.42-2.71 (2H, m) 2.00-2.19 (3H, m) 1.83-1.99 (2H, m) 1.65-1.81 (1H, m) 1.46-1.64 (1H, m) 0.79 (6H, dd, J=6.5 and 3.2), LCMS: Rt=3.52 (12 min method) [M+H]=315.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([Cl:24])=[O:23]>C1C=CC=CC=1>[ClH:24].[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:22]([C:18]3[O:17][CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cccc(CCCN2CCNCC2)c1
Solvent: c1ccccc1
Product: Cc1cccc(CCCN2CCN(C(=O)c3ccco3)CC2)c1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 1 from a mixture of 1-[3-(m-methylphenyl)propyl]piperazine [b.p. 137° - 145°C (2 mmHg), dihydrochloride, m.p. 237°C], 2-furoyl chloride and benzene.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N:10]1[CH:14]=[C:13]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)[CH:12]=[N:11]1)C>>[CH3:22][C:17]1([CH3:23])[C:18]([CH3:20])([CH3:21])[O:19][B:15]([C:13]2[CH:12]=[N:11][N:10]([CH:2]3[CH2:6][CH2:5][CH2:4][C:3]3=[O:7])[CH:14]=2)[O:16]1
Reactant: O=C1CCCC1Cl
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2cnn(C3CCCC3=O)c2)OC1(C)C

Procedure:
Intermediate W-1 was prepared from 2-chlorocyclopentanone (1.06 g, 9 mmol) following the similar procedures of synthesizing intermediate (V), as described above. MS (m/z): 277 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C(=O)O)ccc1C#N
Solvent: ClCCl
Product: Cc1cc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Cyano-3-methyl-benzoic acid is synthesized based on the method described in patent EP1512687A1. To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (20 mg, 0.09 mmol), 4-dimethylaminopyridine (22 mg, 0.01 mmol) and 4-cyano-3-methyl-benzoic acid (29 mg, 0.18 mmol) at 0° C. in dichloromethane (2 mL) is added DCC (38 mg, 0.18 mmol). After stirring for 10 min the reaction is warmed to room temperature. A precipitate forms and stirring is continued for 16 h. The mixture is filtered and the filtrate is diluted with dichloromethane (10 mL), washed with water and a saturated sodium chloride solution. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1) to furnish 1-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.47 (s, 3H), 6.91 (s, 1H), 7.14 (dd, J=8.0, 4.9 Hz, 1H), 7.43-7.48 (m, 2H), 7.49-7.54 (m, 2H), 7.61 (dd, J=8.7, 1.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.03 (d, J=1.0\Hz, 1H), 8.44 (dd, J=4.8, 1.5 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 363.1245 [(M+H)+: Calcd for C23H16N4O: 363.1246].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH2:35][F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:50][CH2:49]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH2:35][F:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCCF)c1
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OCCF)c1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12m) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 724.5 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:26]([C:23]1[CH:22]=[N:21][C:20]([N:17]2[CH2:18][CH2:19][CH:14]([O:1][C:2]3[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=3)[CH2:15][CH2:16]2)=[N:25][CH:24]=1)[CH2:27][CH3:28]
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
A stirring suspension of 4-hydroxypyridin-2(1H)-one (5.23 g, 47.1 mmol, Aldrich), 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate (11.7 g, 39.2 mmol), potassium carbonate (12.5 g, 90.0 mmol, EMD) and DMSO (48 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 100% EtOAc and then SiO2, 10% MeOH in CH2Cl2) to yield 5.00 g of desired product as an off-white solid. MS (ESI) 315 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:10]([NH:9][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[O:16])[N:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1n[nH]cc1[N+](=O)[O-]
Reactant: O=C(CCl)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 55 %

Procedure:
A mixture of N-(4-nitro-1H-pyrazol-3-yl)acetamide (0.380 g, 2.25 mmol), 2-chloro-N-(3-fluorophenyl)acetamide (0.420 g, 2.25 mmol) and potassium carbonate (00.370 g, 2.7 mmol) in dimethyl formamide (10 ml) was heated at 50° C. for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated with a mixture of 2% methanol in dichloromethane and then with diethyl ether to give 2-[3-(acetylamino)-4-nitro-1H-pyrazol-1-yl]-N-(3-fluorophenyl)acetamide
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:8].C(O)(=O)C>C(O)C>[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1
Reactant: NNc1ccccn1
Reactant: C/C=C(\N)C#N
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To an ice-cold solution of aminocrotononitrile (82 g, 1.0 mol) and 2-hydrazinopyridine (120 g, 1.1 mol) in ethanol (300 mL) was added acetic acid (132 g, 2.2 mol), and the mixture was heated under reflux for 3.5 hours. After the mixture was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure and water was added to the residue. After the solution was made basic by the addition of an aqueous sodium hydroxide solution, organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (156.3 g, 90% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:75]=[CH:74][C:67]([O:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=1>>[CH3:73][O:72][C:70](=[O:71])[CH2:69][O:68][C:67]1[CH:74]=[CH:75][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)COc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 58.8 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (80 mg, 0.138 mmol), was reacted with diisopropylethylamine (89 mg, 0.69 mmol), diphenylphosphinic chloride (80 mg, 0.34 mmol), then reacted with methyl 2-(4-aminophenoxy)acetate (Aldrich, 27 mg, 0.153 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenoxy)-acetic acid methyl ester (51 mg, 59%). MS (ES+) m/z [(M+H)30]: 628
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[C:30]2[N:29]3[CH:36]=[CH:37][CH:38]=[C:28]3[CH2:27][CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine. The reaction mixture is washed with water, 2M citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (CI): 422(M+H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH:13]([N:21]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]([NH:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[Cl:12][CH:13]([N:21]1[CH:24]([S:25]([CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:9])[CH:23]([NH:36][C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (30mg) in ethanol-free chloroform (3ml) was added in 10 minutes to a stirred solution of 1-(1-chloro-1-t-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylthio)-3-(triphenylmethylamino)azetidin-2-one (99mg) in ethanol-free chloroform (3ml) at 0°C. The mixture was stirred for a further 30 minutes at 0°C. The reaction mixture was diluted with ethanol-free chloroform (10ml) and washed successively with saturated sodium bicarbonate solution (5ml) and brine (2 × 5ml). The dried (MgSO4) organic layer was evaporated to give a gum which upon re-evaporation from dry ether gave 1-(1-chloro-1-tert-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylsulphinyl)-3-triphenylmethylamino-azetidin-2-one as a solid foam (92mg, 91%)
Reaction SMILES: [I:1][CH2:2][CH:3]([CH2:8][I:9])[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:11](O)[CH3:12]>>[CH2:11]([O:6][C:5](=[O:7])[CH2:4][CH:3]([CH2:8][I:9])[CH2:2][I:1])[CH3:12]
Reactant: CCO
Reactant: O=C(O)CC(CI)CI
Agent: Cl
Product: CCOC(=O)CC(CI)CI
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.831 g (8 mmole) 3-iodomethyl-4-iodobutyric acid in 80 mL ethanol is saturated with HCl gas at 0° C. After stirring the solution at room temperature for two days, the solvent is removed under vacuum, and the residue is dissolved in dichloromethane. The dichloromethane layer is washed with 10% aqueous sodium bicarbonate (3×100 mL), water (1×100 mL) and brine. The separated dichloromethane layer is dried over with magnesium sulfate, filtered and evaporated to give ethyl-3-iodomethyl-4-iodobutyrate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[N:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[S:35])=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:36]=[C:34]([NH:33][C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)[S:35][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: NC(=S)Nc1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(Nc4ccncc4)n3)c1)=N2
Temperature: 60 °C
Yield: 37.6 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (130 mg) (Example 193a) and 1-(4-pyridyl)-2-thiourea (46 mg) in THF (3 mL) was heated at 60° C. for 45 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was triturated with Et2O to give the title compound (55 mg) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:27]=[C:11]3[N:12]=[C:13]([CH3:26])[C:14]([C@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C>C(Cl)Cl.CCOCC>[C:32]([O:25][C@@H:20]([C:14]1[C:13]([CH3:26])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:27]=2)[C:15]=1[CH2:16][CH:17]([CH3:19])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1CC(C)C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.059 g, 0.152 mmol) and tert-butyl acetate (1 ml, 7.40 mmol) in CH2Cl2 (3 mL) was added 70% perchloric aci (0.039 ml, 0.456 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0357 g, 0.080 mmol, 52.9% yield) as brown paste. 1H NMR (500 MHz, CDCl3) δ: 7.97 (t, J=1.7 Hz, 1H), 7.86 (dt, J=7.6, 1.3 Hz, 1H), 7.40-7.31 (m, 2H), 6.79 (s, 1H), 5.36 (s, 1H), 3.70 (s, 3H), 3.53 (dd, J=13.4, 7.6 Hz, 1H), 3.14 (dd, J=13.4, 7.0 Hz, 1H), 2.69 (s, 3H), 2.65-2.54 (m, 1H), 1.25 (s, 9H), 1.03 (d, J=6.7 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H). LCMS (M+H) calcd for C24H31ClN3O3: 444.21. found: 444.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1)=O.[NH2:22]/[C:23](=[C:26](\[NH2:29])/[C:27]#[N:28])/[C:24]#[N:25].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:22]=[C:23]([C:24]#[N:25])[C:26]([C:27]#[N:28])=[N:29][C:9]=1[C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2Br)ccc1=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2Br)ccc1=O
Yield: 56 %

Procedure:
A mixture of 1-(2-bromophenyl)-2-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-1,2-ethanedione (5.30 g) and (2Z)-2,3-diamino-2-butenedinitrile (1.65 g) in a solution of DMSO (0.25 ml) and toluene (25 ml) was refluxed for 8 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (85:15 v/v) to give 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2,3-pyrazinedicarbonitrile as a solid (3.58 g).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+].C(OCC)C>C(O)(=O)C.O>[Br:1][C:6]1[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(Cl)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(Cl)cc1Br
Temperature: 80 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
A solution of bromine (1.5 mL, 29.28 mmol) in glacial acetic acid (7 mL) was slowly added to a mixture of 5-chloro-2-methoxypyridine (2.1 g, 14.63 mmol) and sodium acetate (1.2 g, 14.63 mmol) in glacial acetic acid (7 mL) and the resulting mixture was stirred at 80° C. for 6 hours. The reaction was allowed to cool down to ambient temperature and then diethyl ether and water were added. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and a 4% aqueous solution of sodium bisulphite, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (100% hexanes) to give the title compound (2.1 g, 64%) as a white solid.