Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccccc1C1CCCc2cncn21
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: COCCOC
Product: c1csc(-c2ccccc2C2CCCc3cncn32)c1

Procedure:
To a solution of 5-(2-bromophenyl)-5,6,7,8,-tetrahydro-imidazo[1,5-a]pyridine, Example 12D (120 mg, 0.43 mmol) in DME (2 mL) is added thiophene-2-boronic acid (166 mg, 1.3 mmol), aqueous Na2CO3 (2M, 1.0 mL, 2.0 mmol), and Pd(PPh3)4 (20 mg). The reaction mixture is refluxed overnight. The mixture is partitioned between EtOAc and 1M NaOH. The organic layer is washed by sat. NaHCO3, dried and concentrated to give an oil. The crude reaction mixture is subjected to flash chromatography (silica gel) eluting with acetone:hexane to yield the desired compound. MS (ESI) m/z 280 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.74 (m, 1H), 1.85-2.01 (m, 2H), 2.14-2.27 (m, 1H), 2.74-2.94 (m, 2H), 5.45 (dd, J=8.6, 5.1 Hz, 1H), 6.81 (s, 1H), 7.00-7.05 (m, 2H), 7.06 (s, 1H), 7.10 (dd, J=5.3, 3.5 Hz, 1H), 7.31-7.37 (m, 2H), 7.39 (dd, J=5.2, 1.1 Hz, 1H), 7.41-7.46 (m, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:33])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([N:21]([CH3:28])C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:31])[F:32])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][CH3:28])[CH2:16][CH2:15]1)=[O:33]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1
Product: CN[C@@H]1CCCN(c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2CC(F)F)CC1

Procedure:
Following the procedure for Example 108, reacting (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (200 mg, 0.29 mmol) and 2-fluoro-5-methylbenzeneboronic acid (63 mg, 0.41 mmol) gave 109 as the mono formate salt as a pale brown solid (67 mg, 45% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 8.07 (dd, J=7.3, 2.2 Hz, 1H), 7.61 (s, 1H), 7.26-7.20 (m, 1H), 7.12 (dd, J=11.4, 8.4 Hz, 1H), 6.25 (tt, J=55.6, 4.2 Hz, 1H), 4.48 (td, J=13.9, 4.2 Hz, 2H), 3.41-3.33 (m, 3H), 3.30-3.13 (m, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.23-1.72 (m, 6H). LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CNC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CNC
Product: COc1cc(C#C[Si](C)(C)C)ccc1F

Procedure:
4-Bromo-2-methoxyfluorobenzene (obtainable from 5-bromo-2-fluorophenol by reaction with dimethyl sulfate under basic conditions) is reacted with trimethylsilylacetylene with catalysis by bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in dimethylamine at 20° C. to give 1-(4-fluoro-3-methoxyphenyl)-2-(trimethylsilyl)ethyne; after filtration chromatography (SiO2/dichloromethane), the crude product is stirred in methanol for 1 hour at 20° C. with addition of 1 N aqueous NaOH solution. Removal of the solvent by distillation and chromatography (SiO2/dichloromethane) gives 4-ethynyl-3-methoxyfluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1/[CH:33]=[CH:34]/[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1/[CH:33]=[CH:34]/[CH2:35][N:19]1[CH2:20][CH2:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: O=C/C=C/c1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C/C=C/c2ccco2)CC1
Reaction time: 0.67 h
Yield: 93.4 %

Procedure:
To 2 mL of a dichloromethane solution containing 50 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 18 mg of (2E)-3-(2-furyl)acrolein and 20 μL of acetic acid were added, and stirred for 40 min. To the reaction mixture, 43 mg of sodium triacetoxyborohydride was added, stirred for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 60 mg of ethyl 1-((2E)-3-(2-furyl)-2-propen-1-yl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6]>CC1CCNCC1>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:30]5[CH2:29][CH2:28][CH:4]([CH3:5])[CH2:3][CH2:2]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: CC1CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCC(C)CC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 134.7 %

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 4-methylpiperidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(4-methylpiperidin-1-yl)isonicotinamide (39 mg). NMR; δH [2H6]—DMSO 10.28,(1H, s), 8.62,(1H, t), 8.22,(11, d), 7.93,(2H, d), 7.71,(1H, d), 7.64,(1H, s), 7.44,(2H, d), 7.30,(1H, d), 7.21,(1H, s), 7.00,(1H, d), 4.35,(2H, m), 3.16,(2H, t), 2.83,(2H, m), 2.20,(3H, s), 1.69-1.60,(3H, m), 1.07,(3H, m), 0.92,(3H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.55 min, MH+483.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C@@H:28]([CH2:34][CH3:35])[CH2:29][C:30](OC)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C@@H:28]([OH:27])[CH2:34][CH3:35])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC[C@H](O)CC(=O)OC
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (99 mg, 93%), MS (ISP) m/z=427.3 [(M+H)+], mp 140° C., was prepared in accordance with the general method of example 46 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (S)-methyl 3-hydroxypentanoate.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=4[F:45])=[C:33]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:32]=3)S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.SCC(O)=O.O.[OH-].[Li+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=4[F:45])=[C:33]([CH2:46][C:47]([CH3:48])([CH3:50])[CH3:49])[CH:32]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CN(c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1)C1CC1
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-((N-(2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)-2-nitrophenylsulfonamido)methyl)phenyl)propanoate (1.22 g) in DMF (35 mL) were added mercaptoacetic acid (617 μL) and lithium hydroxide monohydrate (728 mg) at room temperature, and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (801 mg) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH3:38][O:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH3:38][O:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:42][CH2:41]1
Reactant: COC1CCNCC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CCC(OC)CC3)cc2)cc1
Yield: 72.1 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.15 g) as obtained in Example 16-(1) and 4-methoxypiperidine hydrochloride (60 mg), there was obtained (2S)-2-{[4-({4-[(4-methoxypiperidin-1-yl)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.13 g, 74%) in the same manner as in Example 16-1-(3).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH:15]1[CH2:16][C:17](=[O:18])[NH:13][C:14]1=[O:19])=[O:8])=[O:4]
Reactant: O=C(O)CNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CC(OC(=O)CNC(=O)C(F)(F)F)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Trifluoroacetylglycine (684 mg) and N-hydroxysuccinimide (480 mg) in 5 ml of dry CH2Cl2 at 50° C. are treated with a solution of 915 mg dicyclohexylcarbodiimide (4.43 mmol) in 5 ml of CH2Cl2. The mixture is stirred at room temperature overnight, is then filtered and evaporated to produce the named compound which can be used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:48])[NH:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]([CH3:44])[C:28]([CH2:31][N:32]([CH2:40][CH2:41][O:42][CH3:43])C(=O)OC(C)(C)C)=[CH:29][N:30]=4)[S:25][C:18]=23)=[C:14]([F:47])[CH:13]=1.Cl.O1CCOCC1.CCOC(C)=O>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]([CH3:44])[C:28]([CH2:31][NH:32][CH2:40][CH2:41][O:42][CH3:43])=[CH:29][N:30]=4)[S:25][C:18]=23)=[C:14]([F:47])[CH:13]=1)=[O:48]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of 350 (600 mg, 0.879 mmol) in DCM (15 ml) was added HCl in dioxane (2 ml, 7.17 eq, 8 mmol, 4M in dioxane) and the reaction mixture was stirred at RT for 3 hours. The mixture wad diluted with water and solid NaHCO3 was added. The reaction mixture was extracted with EtOAc then the organic phase was collected, dried over Na2SO4, filtered and concentrated. Trituration of the residue with EtOAc afforded the desired compound 351 as an off-white solid (314 mg, 61% yield). 1H NMR (d6-DMSO): 10.90 (s, 1H), 8.89 (s, 1H), 8.50 (d, J=5.48 Hz, 1H), 7.98 (m, 1H), 7.95 (s, 1H), 7.72 (m, 1H), 7.41 (m, 1H), 7.28-7.20 (m, 3H), 7.04 (m, 1H), 6.68 (d, J=5.28 Hz, 1H) 4.28 (s, 2H), 3.92 (s, 3H), 3.61 (m, 2H), 3.27 (s, 3H), 3.13 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH2:11].C(N(CC)CC)C.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N[C@H]1c2ccccc2C[C@H]1O

Procedure:
To a cold (0° C.) solution of methylene chloride (30 ml) containing 2(R)-hydroxy-1(S)-aminoindane (750 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) was added a solution of hydrocinnamoyl chloride (843 mg, 5.0 mmol) in 5 ml of methylene chloride. After 2 hr the reaction was poured into a separatory funnel containing 50 ml of methylene chloride and washed with 10% citric acid solution (2×30 ml). The organic layer was dried, filtered and concentrated to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH2:17])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 2 ml (0.02 mole) of 57% ammonium hydroxide. The slightly exothermic reaction mixture was stirred for 3 hr as it cooled to ambient temperature then diluted with 200 ml of water. The precipitated product was collected by filtration (2.4 g) and recrystallized from absolute ethanol to yield 2 g (83.3%) of fine white crystals, m.p. 210°-212° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[C:3]1[CH3:25].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1>C(OC(=O)C)(=O)C>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:11]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:25])[C:13]2[C:14](=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: Cc1c(C(=O)c2ccc(N(C)C)cc2C(=O)O)c2ccccc2n1C
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)c2ccccc2n1C

Procedure:
A mixture of 0.34 g (0.001 mole) of 2-[(1,2-dimethyl-3-indolyl)carbonyl]-5-dimethylaminobenzoic acid prepared as described in Example 1 of U.S. Pat. No. 3,540,910 was interacted with 0.16 g (0.001 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 5 ml of acetic anhydride in a similar manner to the procedure described in Example 1, part C hereinabove to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1,2-dimethyl-3-indolyl)-6-dimethylaminophthalide (Formula III: R0 =R1 =R3 =Y1 =H; R2 =N(CH3)2 ; R=R5 =R6 =CH3 ; R4 =N(CH3)2) which melts over the range of 146°-152° C. A significant infrared absorption maximum appeared at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([S:13]([C:16]3[CH:24]=[CH:23][C:22]4[N:21]([CH3:25])[C:20]5[CH2:26][CH:27]6[NH:31][CH:30]([C:19]=5[C:18]=4[C:17]=3C(OCCCC)=O)[CH2:29][CH2:28]6)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39]>C(O)C>[ClH:39].[C:1]1([C:7]2[CH:8]=[C:9]([S:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]5[NH:31][CH:30]([C:19]4=3)[CH2:29][CH2:28]5)(=[O:14])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCOC(=O)c1c(S(=O)(=O)c2cccc(-c3ccccc3)c2)ccc2c1c1c(n2C)CC2CCC1N2
Agent: Cl
Solvent: CCO
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(-c5ccccc5)c4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of step A (0.30 g, 0.56 mmol) in ethanol (20 mL) was added concentrated HCl (8.0 mL). The reaction mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by semi-preparative HPLC. The free base was dissolved in methanol and treated with concentrated HCl then concentrated to dryness in vacuo to give 2-[(3-phenyl)-phenyl]sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (98 mg, 38%, AUC HPLC 97.7%) as a light brown solid: mp 230-235° C. dec; 1H NMR (CDCl3, 300 MHz) δ 9.71 (s, 1H), 9.12 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 8.15 (t, J=1.2 Hz, 1H), 7.89-7.94 (m, 2H), 7.75 (dd, J=6.6, 1.2 Hz, 1H), 7.63-7.71 (m, 4H), 7.48-7.53 (m, 2H), 7.40-7.46 (m, 1H), 5.36 (d, J=3.0 Hz, 1H), 4.45 (br s, 1H), 3.67 (s, 3H), 3.37 (dd, J=12.9, 3.3 Hz, 1H), 2.99 (d, J=12.9 Hz, 1H), 2.23-2.31 (m, 2H), 1.99-2.11 (m, 1H), 1.74-1.81 (m, 1H); ESI MS m/z 429 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[O:21])[C:8]2([N:20]=1)[CH2:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=1)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:7](=[O:21])[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:20]1)[CH2:16]2
Reactant: CC(C)(C)C1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C1=NC2(Cc3ccc(N)cc3C2)C(=O)N1

Procedure:
To a solution of (±)-2-tert-butyl-5′-nitro-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one from Step B (22.0 mg, 0.077 mmol) in degassed MeOH (5 mL) was added 10% palladium on carbon (10 mg). The suspension was placed under a hydrogen balloon for 1 h, then filtered through a pad of Celite, concentrated, and dried under high vacuum to give the title compound. MS: m/z=258 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 0.33 h

Procedure:
To Ethyl 3-(4-(benzyloxy)phenyl)isoxazole-5-carboxylate (900 mg) in THF (18 ml), 1M aqueous solution of NaOH (13.9 ml) was added and the reaction mixture was stirred for 20 minutes. It was acidified with 1 Molar hydrochloric acid and extracted with ethyl acetate. Organic layer was collected and dried over Na2SO4 and concentrated to obtain pale yellow solid, which was crystallized using EtOAc—petroleum ether to obtain the title compound as off white solid. Yield: 765 mg (93%); MS (ES+): m/z 296 (M+1); 1H NMR (DMSO-d6; 300 MHz): δ 7.91 (d, 2H), 7.73 (s, 1H), 7:34-7.48 (m, 5H), 7.17 (d, 2H), 5.19 (s, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([CH:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:11]#[N:12])[CH:7]=[CH:6][C:5]=1[N+:22]([O-])=O)[CH3:2].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:22][C:5]1[CH:6]=[CH:7][C:8]([CH:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:11]#[N:12])=[N:9][C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CCSc1nc(C(C#N)C(=O)c2ccccc2F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1nc(C(C#N)C(=O)c2ccccc2F)ccc1N
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A solution of 2-(6-(ethylthio)-5-nitropyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile (0.40 g, 1.16 mmol, 1.0 eq.) and SnCl2.2H2O (1.35 g, 5.98 mmol, 5.2 eq.) in EtOAc (30 mL) was refluxed for 0.75 hr and cooled to room temperature. At 0° C., aqueous NaOH (1N, 15 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (10:0.2) as eluent afforded 2-(5-amino-6-(ethylthio)pyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile as a light brown solid (0.1933 g, 53%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[NH:49][N:48]=[N:47][N:46]=1>C(Cl)Cl>[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[N:49]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:48]=[N:47][N:46]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2oc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.89 g of triethylamine, 8.14 g of triphenylchloromethane and 0.10 g of 4-N,N-dimethylaminopyridine are added in succession to a suspension of 10.37 g of 3-bromo-2-[2'-(1H-tetrazol-5-yl)-phenyl]-5-methylbenzofuran in 300 ml of CH2Cl2 and the batch is stirred for 3 hours at room temperature. The reaction solution is washed with 150 ml of water and 150 ml of brine, concentrated in vacuo to a volume of 50 ml and chromatographed on silica gel 60 (40-63 μm) using CH2Cl2 as eluant. The product, of Rf =0.82 (CH2Cl2 /CH3OH (95:5)), yields crystalline 3-bromo-2-[2-(1-trityltetrazol-5-yl)-phenyl]-5-methylbenzofuran, m.p. 199-200°, from ether.