Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.CCOC(C)=O>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1

Procedure:
6-Bromo-1-morpholinophthalazine (191 mg, 649 μmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (170 mg, 649 μmol), and tetrakis (triphenylphosphine)palladium (75 mg, 65 μmol) were added to a microwave vial before sodium carbonate-2 N in water (1.9 mL, 3892 μmol) and ethanol (3.2 mL) were added. The reaction mixture was reacted in a microwave oven for 10 min at 160° C. The reaction was cooled, diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), and separated. The aqueous layer was acidified to pH 5 with conc. HCl and extracted 4 times with 50 mL of chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 350 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCOCCBr
Reactant: Nc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
3-Bromoaniline (3.0 mL, 4.7 g, 28 mmol), 2-bromoethylether (4.2 mL, 7.7 g, 33 mmol) and diisopropylethylamine (15 mL, 11 g, 86 mmol) were dissolved in anhydrous DMF (20 mL) under inert gas atmosphere and heated to 100° C. for 6 h. After cooling to room temperature the mixture was poured into water (300 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 2.9 g (12 mmol, 43% yield) of 4-(3-bromophenyl)morpholine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-4-methyl-pyridine.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[NH2:12][C@@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:31]([O:33][CH3:34])=[O:32])[C@H:23]2[C@H:14]1[C@:15]1([CH3:35])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][CH:18]=[CH:17][CH2:16]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCCl>[NH3:12].[NH2:12][C@@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:31]([O:33][CH3:34])=[O:32])[C@H:23]2[C@H:14]1[C@:15]1([CH3:35])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][C@@H:18]2[O:8][C@@H:17]2[CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Product: N
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Toluene-4-sulphonic acid (570 mg) was added to a solution of methyl 11α-amino-5α-androst-2-ene-17β-carboxylate (1.0 g) in 1,2-dichloroethane (25 ml). After 0.5 h m-chloroperoxybenzoic acid (810 mg) was added and the mixture was left for a further 2 h. The mixture was washed with NaHSO3 solution, 5% NaHCO3 solution and water. The aqueous phases were extracted with dichloromethane and the combined organic phase was dried and evaporated to leave a foam which was purified by preparative t.l.c. in MeOH: 0.88 NH3 (50:1) to give the title compound (369 mg) as a foam [α]D +44°, νmax 1722 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40](O)=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.[CH3:46][C:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:53][S:50]([C:47]4([CH3:46])[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: CC1(S(N)(=O)=O)CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (56) and 1-methylcyclopropylsulfonamide following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl]-(cyclopropyl)sulfonamide 11: m/z=770 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3-1.4 (d, J=6.9 Hz, 6H), 1.45-1.55 (m, 2H), 1.5 (s, 3H), 1.55-1.7 (m, 2H), 1.75-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.1-2.4 (m, 2H), 2.4-2.5 (m, 2H), 2.6-2.7 (m, 2H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.3-3.4 (m, 1H), 3.6-3.7 (m, 1H), 3.9 (d, J=11.6 Hz, 1H), 4.05 (s, 3H), 4.6 (t, J=8.0 Hz, 1H), 5.2 (t, J=10.6 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 (br s, 1H), 7.1 (s, 1H), 7.2 (d, J=9.3 Hz, 1H), 7.53 (s, 1H), 7.95 (d, J=9.3 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][CH:34]=[C:35]3[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][CH:34]=[C:35]4[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.053 g, 58%). 1H NMR (DMSO-d6): 8.99 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.74 (d, J=8 Hz, 2H), 7.59-7.56 (m, 1H), 7.41 (d, J=8 Hz, 2H), 7.26-7.24 (m, 1H), 7.16 (d, J=8 Hz, 2H), 4.99 (s, 2H), 3.94 (s, 3H), 3.39-3.20 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19](CCl)=[CH:18][CH:17]=1.[C:24]([O-])([O-])=[O:25].[K+].[K+]>CC(C)=O>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]3)=[C:4]([O:25][CH3:24])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: Cc1c(C)c2ccc(O)cc2oc1=O
Reactant: ClCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2ccc(Br)cc2)cc2oc(=O)c(C)c(C)c12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5.0 g of 7-hydroxy-3,4-dimethylcoumarin, 5.4 g of 4-bromobenzyl chloride, 5.4 g of K2CO3 and 100 ml of acetone was stirred for 4 days at room temperature and evaporated down, and the residue was partitioned in H2O/methylene chloride. After the organic phase had been separated off, extraction was carried out twice with methylene chloride, the combined organic phases were evaporated down and the residue was recrystallized from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 5-nitroindole (10 g, 61.6 mmol) and acetyl chloride (5.8 g, 74 mmol) in methylene chloride at 0° C. is treated with tin tetrachloride (1M in CH2Cl2, 68 mL), stirred under N2 for 6 h, treated with saturated NaHCO3 to pH 9 and filtered. The filtrate is concentrated in vacuo to give a residue. The residue is dissolved in DMF and filtered. This filtrate is concentrated in vacuo to give the title product, 12.6 g (99% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[C:15]([C:25]([F:28])([F:26])[F:27])=[CH:14][C:10]=2[C:11]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 53; 112 mg, 0.29 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.10 ml, 0.57 mmol), 3-aminopyridine (40.2 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (50.4 mg, 0.37 mmol) and EDC (109 mg, 0.57 mmol). The reaction was stirred for 3 hours, then the solvent removed in vacuo to give a yellow oil. Purification by MDAP gave the title compound as a white solid. 69 mg.
Reaction SMILES: [NH:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27](O)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27]([N:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of N-Me-Tyr(Bzl)-NH2(329 mg, 1.16 mmol) in THF (15 ml), Fmoc-N-Me-Val-OH (533 mg, 1.51 mmol), CMPI (415 mg, 1.62 mmol) and TEA (0.323 ml, 2.32 mmol) were added under cooling with ice, followed by stirring for 4 hours at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (680 mg, 95%).
Reaction SMILES: [NH:1]([C:3]1[C:4]2N=CC=C[C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1)[NH2:2].[C:15](=[S:17])=S.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC.C(N(CC)CC)C.O1CCOCC1>[CH2:18]([S:17][C:15]1[N:8]2[C:7]([S:9][CH3:10])=[N:6][C:5]3[N:1]=[CH:3][CH:4]=[CH:5][C:4]=3[C:3]2=[N:1][N:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=C=S
Reactant: ClCc1ccccc1
Reactant: CSc1nc(NN)c2ncccc2n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1COCCO1
Product: CSc1nc2ncccc2c2nnc(SCc3ccccc3)n12
Yield: 158.2 %

Procedure:
4-Hydrazino-2-methylthiopyrido[3,2-d]pyrimidine (14.5 g, 70 mmol) was combined with 200 mL of dioxane, 12.6 mL (16.0 g, 210 mmol) of carbon disulfide, and 29 mL (21.2 g, 210 mmol) of triethylamine and the mixture was heated at reflux with stirring for 4 hours during which time another 50 mL of dioxane was added to facilitate stirring. The mixture was allowed to cool, 13.3 g (105 mmol) of benzyl chloride was added, and the resulting mixture was allowed to stir overnight. Another 6 g of benzyl chloride and 25 mL of triethylamine were added and the mixture was heated to reflux with stirring for a short period. The volatile components were removed by evaporation under reduced pressure and the residue was diluted with dichloromethane and water. The resultant emulsion was filtered to obtain separable phases and the organic phase was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with hexane and the resulting black solid was recovered by filtration. This solid was diluted with dichloromethane and the solution obtained was filtered through silica gel. Evaporation of the filtrate under reduced pressure gave a black solid that was diluted with ether and recovered by filtration to obtain 18.8 g the title compound melting at 157°-158° C. The proton NMR spectrum was compatible with the assigned structure. Work up of the filtrate gave an additional 6 g of impure title compound as a black oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]Cl)[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1.CN1C(=[O:46])CCC1>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:46])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:35]4[CH2:38][CH:37]([OH:39])[CH2:36]4)[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: CN1C=C(C(=O)NCc2ccc(Cl)cc2)Cc2cc(CCl)ccc21
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)C3)ccc21
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-1,4-dihydro-3-quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry NMP (2 mL) containing diisopropylethylamine (0.14 mL) is treated with 3-azetidinol hydrochloride (0.04 gm) (prepared as described in Helv. Chim. Acta 1988, 1035). The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by flash column chromatography eluting with 5% to 20% methanol in dichloromethane and then by recrystallization from methanol-acetonitrile to afford 0.08 gm of the title compound as an off-white solid.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]([C:23]#[N:24])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:5][CH2:4]1)#N.Cl>C(O)(=O)C.O>[C:23]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)#[N:24]
Reactant: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccccc2Sc2ccc(F)cc2)CCNCC1

Procedure:
A solution of 2.0 g of 1,4-dicyano-4-[2-(4-fluorophenylthio)phenyl]piperidine, Example 29, in 12 ml of glacial acetic acid and 21 ml of 3 N hydrochloric acid is stirred at 110°-120° C. for 18 hours. Thereafter, the solution is diluted with 50 ml of water and the diluted solution is rotary evaporated twice to near dryness. The residual material is diluted in 100 ml of water and 2 ml of 58% ammonium hydroxide, giving a milky solution at pH 9. This aqueous suspension is extracted thrice with 150 ml portions of a benzene-ether (1:1) mixture. The combined extracts are washed, first with 50 ml of water and then with 25 ml saturated sodium chloride solution, and dried. The residual material is recrystallized from a benzene-hexane mixture to provide 4-cyano-4-[2-(4-fluorophenylthio)phenyl]piperidine.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:37]4[CH2:38][C:35]([F:39])([F:34])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Reactant: FC1(F)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 2.5 g, 4.45 mmol), and 3,3-difluoroazetidine (1.73 g, 13.34 mmol) in THF (40 mL) was added diisopropylethylamine (3.88 mL, 22.23 mmol). It was stirred at 60° C. for 15 minutes at which time complete conversion by LCMS was noted. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexanes to get the title compound (2.2 g, 86% yield) as a white solid. LCMS (M+H)+: 577.1; 575.2. 1H NMR (CDCl3, 500 MHz): δ 8.38 (s, 1H), 7.93 (s, 1H), 7.81 (s, 2H), 5.82 (d, J=8.5 Hz, 1H), 4.84 (d, J=18.0 Hz, 1H), 4.48 (m, 4H), 4.40 (m, 1H), 4.23 (d, J=18.0 Hz, 1H), 0.83 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]1=[O:10].C(=O)([O-])O.[Na+].Cl.[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:28](Cl)=[O:29])[N:26]=1)=[O:20]>O1CCCC1.O>[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH2:33][CH:34]=[CH2:35])[C:28]([NH:1][C@H:2]2[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]2=[O:10])=[O:29])[N:26]=1)=[O:20]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: C=CCO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 185.5 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylate and under ice-cooling and stirring 469.6 mg of sodium hydrogen carbonate and successively, 600 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-allyloxyiminoacetyl chloride hydrochloride is added. The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue is added 20 ml of water and the insolubles are collected by filtration, washed with aqueous sodium hydrogen carbonate, water, hexane and ether in this order, and dried to give methyl cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-allyloxyiminoacetamido]-2-oxoazetidine-4-carboxylate (syn isomer) as light-yellow granules, m.p. 270°-280° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O.C(#N)C>[C:54]1([NH:53][C:17]([C:15]2[CH:14]=[CH:13][C:5]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:2]([Cl:1])=[N:3][C:4]=3[CH:16]=2)=[O:19])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COCCOCn1c(Cl)nc2cc(C(=O)O)ccc21
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCOCn1c(Cl)nc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a solution of 2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid (0.235 g, 0.825 mmol) and acetonitrile (4 mL) was added HATU (0.408 g, 1.07 mmol). The resulting suspension was stirred at 23° C. for 5 min, treated with DIPEA (0.428 mL, 2.48 mmol) and stirred for an additional 20 minutes. The reaction mixture was then treated with aniline (90.0 μL, 0.990 mmol) and stirred for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-70% EtOAc/hexanes) to yield the titled compound (0.265 g, 89%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. for C18H18ClN3O3, 359.1; m/z found, 360.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.26 (d, J=7.5 Hz, 2H), 8.32 (dd, J=3.6, 1.5 Hz, 2H), 7.99 (dd, J=8.6, 1.6 Hz, 1H), 7.94 (dd, J=8.5, 1.6 Hz, 1H), 7.87-7.73 (m, 6H), 7.41-7.32 (m, 4H), 7.16-7.02 (m, 2H), 5.75 (d, J=8.6 Hz, 4H), 3.67-3.61 (m, 4H), 3.43 (ddd, J=6.3, 4.7, 3.1 Hz, 4H), 3.19 (d, J=1.5 Hz, 6H).