Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].O[NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:19][C:18]3([O:37][C:22]4=[CH:23][N:24]=[C:25]([C:27]5[CH2:28][CH2:29][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:31][CH:32]=5)[CH:26]=[C:21]4[CH2:20]3)[CH2:17]2)[CH2:13][CH2:12]1)=[NH:10].C(N(CC)CC)C>O1CCCC1.CO>[CH:2]([C:1]1[O:5][N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:17][C:18]4([O:37][C:22]5=[CH:23][N:24]=[C:25]([C:27]6[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH2:29][CH:28]=6)[CH:26]=[C:21]5[CH2:20]4)[CH2:19]3)[CH2:13][CH2:12]2)[N:8]=1)([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C(=N)NO)CC3)C2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)c1nc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)no1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Isobutyryl chloride (10 μL) is added to a solution of 1″-(hydroxycarbamimidoyl)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (40 mg) and triethylamine (41 μL) in tetrahydrofuran (3 mL) at room temperature. The solution is stirred at room temperature for 1 h and at 45° C. overnight. The solution is diluted with methanol and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:7→1:9) to give the title compound. LC (method 4): tR=1.13 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[C:13]#[N:14].C[O-].[Na+]>[Ni].C(Cl)Cl.CO>[C:15]([N:5]1[C:6]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=2[CH2:13][NH:14][C:3](=[O:2])[CH2:4]1)(=[O:17])[CH3:16]
Reactant: COC(=O)CN(C(C)=O)c1cc(N)ccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CC(=O)NCc2ccc(N)cc21
Reaction time: 12 h
Yield: 34.4 %

Procedure:
A mixture of [acetyl-(5-amino-2-cyano-phenyl)-amino]-acetic acid methyl ester (0.4 g, 1.6 mmol), sodium methoxide (87 mg, 1.6 mmol) and Raney nickel (50 mg) was shaken for 12 hours under a 50 psi H2 atmosphere. The catalyst was removed by filtration and the filtrate was concentrated. Silica gel chromatography (DCM/MeOH 9:1) gave 1-acetyl-8-amino-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one (120 mg, 0.55 mmol, 34%): 1H NMR (300 MHz, CD3OD) δ 7.12 (d, 1H), 6.7 (m, 2H), 5.35 (d, 1H), 4.37 (d, 1H), 3.80 (d, 1H), 3.49 (d, 1H), 1.93 (s, 3H);); MS (m/e) 220 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:7]2[S:6][C:5]([CH2:4][CH2:3][CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][C:5]4[S:6][C:7]5[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=5[N:9]=4)[CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Product: COc1cc2nc(CCCN3CCN(CCCc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-(3-Bromopropyl)-5,6,7-trimethoxybenzothiazole (328 mg) and piperazine (39 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]C)=[O:13])[C:8]=2[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Yield: 20.9 %

Procedure:
A solution of methyl 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylate (25 mg, 0.084 mmol) and 1N aqueous sodium hydroxide (125 μL, 0.125 mmol) in methanol (1 mL) was heated at 23° C. for 2 h. To the reaction mixture was added acetic acid until the pH was ˜5. The mixture was purified by preparative HPLC to afford 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylic acid (5 mg). The compound had an HPLC ret. time=3.16 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=286+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[C:16]([CH3:18])[S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][C:16]([CH3:18])=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:30]=1
Reactant: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 57.3 %

Procedure:
Following General Procedure B A, 9-bromo-8-methoxy-2-methylthieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.31 mmol) was reacted with 4-[(tert-butoxycarbonylamino)methyl]phenylboronic acid (120 mg, 0.40 mmol) to afford desired product (80 mg, 55%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:30]([NH2:32])=[O:31])[CH2:5][N:4]([C:6]2[N:11]3[N:12]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:10]3[N:9]=[C:8]([CH3:29])[N:7]=2)[CH2:3]1.CO[C:35](OC)([CH3:37])[CH3:36]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:13]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:10]2[N:9]=[C:8]([CH3:29])[N:7]=[C:6]([N:4]3[CH2:3][C:2]4([C:30](=[O:31])[NH:32][C:35]([CH3:37])([CH3:36])[NH:1]4)[CH2:5]3)[N:11]2[N:12]=1
Reactant: COC(C)(C)OC
Reactant: Cc1nc(N2CC(N)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nc(N2CC3(C2)NC(C)(C)NC3=O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1

Procedure:
To a mixture of 3-amino-1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-azetidine-3-carboxylic acid amide (3A-6; 27 mg, 0.057 mmol) and 2,2-dimethoxypropane (0.75 ml, 6.1 mmol) in toluene (1.3 ml) was added acetic acid (5 drops). After stirring at reflux for 18 hours, the reaction was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12S column using 0-5% methanol in methylene chloride as eluant to afford after drying, in vacuo, 4A-1 (16 mg, 55%) as an off-white solid: +ESI MS (M+1) 508.1; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.56-7.42 (m, 4H), 7.34-7.30 (m, 4H), 4.92 (d, J=10.4 Hz, 1H), 4.73 (d, J=10.4 Hz, 1H), 4.43 (d, J=10.4 Hz, 1H), 4.19 (d, J=10.4 Hz, 1H), 2.40 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:8]2([CH2:7][CH2:6][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:12][CH2:11][N:10]([C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1

Procedure:
2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]ethyl methanesulfonate (191 mg, 0.43 mmol) was treated with the 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (144 mg, 0.599 mmol) and NaHCO3 (90 mg, 1.07 mmol, 2.5 eq.) in THF/H20 (5 mL/1 mL) at reflux for 21 hours. The solution was concentrated in vacuo and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with 6% methanol in dichloromethane to give 146 mg (44%).
Reaction SMILES: Br.[N:2]1[CH:3]=[CH:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH2:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:2]1[CH:3]=[CH:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc2ccccc2c2nccn12
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccccc2c2nccn12)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a mixture of imidazo[1,2-c]quinazolin-5-amine hydrobromide (93 mg, 0.35 mmol) and nicotinic acid (124 mg, 1.01 mmol) and DMF (2.5 ml) at room temperature was added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (525 mg, 1.01 mmol) followed by N,N-diisopropylethyl amine (0.264 ml, 1.51 mmol), and the mixture was stirred at 80. for 6 hours. After cooling to room temperature, the reaction mixture was poured into aqueous saturated NaHCO3 solution. The resulting precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to give N-imidazo[1,2-c]quinazolin-5-ylnicotinamide (40 mg, 39% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([NH:8][C:9](=[O:11])[CH:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([C:5]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9](=[O:11])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCCC1=CC(=O)NC1=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1(Nc2ccccc2)CC(=O)NC1=O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
Maleic anhydride is reacted with n-butylamine under the conditions reported by L. E. Coleman et al., in J. Org. Chem., 24: 135, (1959). A mixture containing the thus-formed n-butylmaleamic acid (12.0 g, 0.07 mol), anhydrous sodium acetate (2.7 g) and acetic anhydride (29 mL) is heated at 85° C. to 90° C. for 30 minutes. The solution is cooled to 40° C. and poured into 55 mL of water. The layers are stirred at room temperature for 15 minutes, the diluted to 275 mL. A dark oil precipitates. Extraction with 100 mL of CH2Cl2, then another 25 mL of CH2Cl2, and evaporation of solvent gives 9.9 g of n-butylmaleimide as an oil, ir, 1735 (sh) and 1700 cm-1. A solution of 9.9 g (0.065 mol) of the n-butylmaleimide and 35 mL of acetic acid is treated with 6.51 g (0.07 mol) of aniline, with the resulting solution heated at 120° C. for 30 minutes. The solution is cooled and poured into 280 mL of water. The amorphous material is collected and recrystallized from isopropyl alcohol to give 9.3 g of n-butyl anilinosuccinimide as off-white crystals, m.p. 97°-100° C., ir, 3350, 1720 (sh), 1680, 1600 cm-1; mass spec, (ci) m/e 247. Anal. Calcd. for C14H18N202: C, 68.29; H, 7.32; N, 11.38. Found: C, 68.46; H, 7.28; N, 11.25.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:33])([F:32])[F:31].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:31])([F:33])[F:32])=[O:8])=[O:5]
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 95 mg of 3-(4-amino-3-trifluoromethoxyphenyl)-4H-[1,2,4]-oxadiazol-5-one hydrochloride and 0.054 ml of Hünig's base in 4 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].C1COCC1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.[BH4-].[Na+]>CO>[CH2:17]([NH:6][C@@H:5]([C@@H:7]([CH3:8])[CH2:9][CH3:10])[C:4]([O:3][CH3:2])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NCc1ccccc1)C(=O)OC
Yield: 68 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-isoleucine methyl ester hydrochloride (1 gm, 5.5 mmol), THF (20 mL) MgSO4 (1.12 gm, 9.35 mmol), benzaldehyde (1.12 mL, 11.0 mmol), Et3N (767 μL, 5.5 mmol), sodium borohydride (416 mg, 11.0 mmol), and methanol (30 mL) to give 11a (880 mg, 68%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.88-0.943 (6H, m), 1.16-1.3 (1H, m), 1.55-1.64 (1H, m), 1.68-1.88 (2H, m), 3.13 (1H, d, J=6.10 Hz), 3.62 (1H, d, J=12.93 Hz), 3.74 (3H, s), 3.84 (1H, d, J=12.93 Hz), 7.24-7.29 (1H, m), 7.31-7.39 (4H, m). ESI-MS: 258.0 (M+23).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:16]=3)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CCOCC>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22]([C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:13]([C:9]4[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=4[CH3:12])[NH:14]3)=[CH:19][CH:18]=2)=[O:34])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1cc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Temperature: 50 °C

Procedure:
A mixture of 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-indol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester and 1N NaOH (500 μL) in THF (5 mL) was heated at 50° C. for 18 h. The mixture was cooled and was neutralized with one equivalent of 1N HCl and partitioned between water and ethyl acetate. The ethyl acetate layer was dried, filtered, and the solvent removed under reduced pressure to leave an oil, which was twice taken up in ether and solvent removed under reduced pressure to give 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-indol-2-yl]-3,5-dimethylphenyl}-propionic acid. 1H NMR (Acetonitrile-d3, 400 MHz): δ 9.62 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.63 (m, 4H), 7.40 (d, J=8.7 Hz, 2H), 7.03 (s, 2H), 6.40 (s, 1H), 2.87 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.11 (s, 6H), 1.32 (s, 9H). MS (m/z) 469.3 (M+1); Retention time=1.50 min (Method 10).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:12]2[C:13](=O)[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(OCC)C>[CH:7]1[C:12]2[CH2:13][NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc2c(c1)CNc1ccccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
In a dry 250 ml three-necked flask equipped with reflux condenser and thermometer, lithium aluminum hydride (1.8 g, 0.047 mol) was suspended in dry diethyl ether (75 ml) under a nitrogen atmosphere. Cautiously, 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (5.0 g, 0.024 mol) was added in portions. The mixture was heated at reflux temperature for 5 hours, cooled to room temperature and left stirring overnight. The reaction mixture was quenched by cautious addition of water (1.8 ml), 4N sodium hydroxide (1.8 ml) and finally water (5.4 ml). Diethyl ether and toluene were added and the mixture was filtered. The filtercake was washed with diethyl ether, toluene and ethyl acetate, successively. The filtrate was evaporated until dryness, affording 4.55 g (96%) of 10,11-dihydrodibenz[b,f][1,4]oxazepine.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][CH2:7][NH2:8].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1>CC(O)C>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][NH:8][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=[CH:4]1
Reactant: NCCc1cnc[nH]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1NCCc1c[nH]cn1
Yield: 65 %

Procedure:
1.14 g (10.2 mmol) of histamine base and 1.62 g (10.2 mmol) of 2-chloro-3-nitropyridine are brought to reflux in 5 ml of 2-propanol for 3 h. Evaporation of the solvent under reduced pressure and purification of the solid residue by chromatography on a column of silica gel, eluted with chloroform containing increasing amounts of methanol (5, 10 and 20%), provide the title compound. M.p.: 178°-180° C. (yield 65%; ethanol:water).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[Cl:21][C:22]([C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)(Cl)[C:23]([N:25]([C:32]([O:34][CH:35]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].O>CN(C=O)C>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([C:48]([C:22]([S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)([Cl:21])[C:23]([N:25]([C:32]([O:34][CH:35]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[O:57])=[CH:54][CH:53]=1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nc2ccc(C(=O)O)cc2[nH]1)C(=O)c1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
3.9 g of 2-mercapto-5-carboxybenzimidazole and 3 ml of triethylamine were dissolved in 50 ml of DMF and to the solution was added dropwise 50 ml of a DMF solution containing 11 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide at 15° C. over a period of 30 minutes. The reaction mixture was further stirred at room temperature for 2 hours and then poured into 1 liter of water. The crystals thus deposited were collected by filtration and recrystallized from methanol to obtain 11 g of α-(4-methoxybenzoyl)-α-(5-carboxy-2-benzimidazolylthio)-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 77.6%. Melting Point: 190° to 205° C. 11 g of α-(4-methoxybenzoyl)-α-(5-carboxy-2-benzimidazolylthio)-2-chloro-5-dodecyloxycarbonylacetanilide, 2.6 g of 1-formyl-2-(4-aminophenyl)hydrazine and 0.1 g of 4-dimethylaminopyrimidine were dissolved in 50 ml of DMF and to the solution was added dropwise 5 ml of a DMF solution containing 3.2 g of dicyclohexylcarbodiimide with stirring at room temperature. The mixture was further stirred at room temperature for 2 hours and then at 50° C. for 30 minutes. After cooling with water, dicyclohexylurea formed was removed by filtration and the filtrate was poured into 500 ml of water. The crystals thus deposited were collected by filtration and purified with 50 ml of hot ethanol to obtain 8.5 g of the desired Compound (8). Yield: 65%. Melting Point: 244° to 247° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.C1(C)C=CC=C[C:18]=1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[OH:28][CH:27]([C:26]1[CH:29]=[CH:30][C:23]([CH3:18])=[CH:24][CH:25]=1)[C:7]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: Cc1ccccc1-c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2nccn2S(=O)(=O)N(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of N,N-dimethyl-1H-imidazole-1-sulfonamide (2.02 g) in THF (50 mL) was cooled to −78° C., and thereto was added dropwise n-BuLi (4.77 mL, 2.66 M hexane solution), and the mixture was stirred for 30 minutes. To the mixture was added p-tolyl benzaldehyde (2.08 g), and the mixture was warmed to room temperature over a period of 1 hour, and then stirred for 16 hours. The mixture was extracted with aqueous hydrochloric acid solution, washed with Et2O, and basified with an aqueous NaOH solution. This solution was extracted with Et2O, and the organic layer was dried and filtered. The solvent was evaporated under reduced pressure to give 2-[hydroxy(4-methylphenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]2[C@H:18]1[CH2:19]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29]>C(#N)C>[C@@H:18]12[CH2:19][C@@H:20]1[CH2:21][C@@H:22]([C:23]([O:25][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29])=[O:24])[N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16]
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
DIPEA (2.79 mL, 16.0 mmol) was added to a stirring slurry of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethanone (2.22 g, 8.00 mmol) in acetonitrile (25 mL) (the solution became clear and amber colored) and the reaction mixture was stirred overnight. The reaction was concentrated and purified via BIOTAGE® (80 g SiO2, 10-25% EtOAc/hexanes) to yield (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.37 g, 7.94 mmol) as a viscous light yellow oil. LC-MS retention time 1.853 min; m/z 423 and 425.98 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a waters XTERRA® MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=1.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0, 7.8 Hz, 1H), 5.58-5.10 (m, 2H), 4.23 (br s, 1H), 3.62-3.39 (m, 1H), 2.58 (dt, J=13.3, 6.5 Hz, 1H), 2.46 (dd, J=13.3, 9.5 Hz, 1H), 1.73-1.51 (m, 1H), 1.47 (s, 9H), 0.85 (br s, 1H), 0.51 (s, 1H).