Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].C[CH2:13][N:14]=C=NCCCN(C)C.Cl.CN.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
The solution of 4-amino-3-chlorobenzoic acid (1 equiv), EDCI (1.2 equiv), methylamine hydrochloride (1.2 equiv) in DMF (1.5 M) was added sodium bicarbonate (1 equiv). The reaction was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 10% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions afforded the title compound (89% yield) as colorless oil; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (d, J=4.29 Hz, 3H) 5.81 (s, 2H) 6.72 (d, J=8.59 Hz, 1H) 7.49 (dd, J=8.39, 2.15 Hz, 1H) 7.67 (d, J=1.95 Hz, 1H) 8.08 (d, J=4.29 Hz, 1H); MS (ESI) m/z 185.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)cc1
Yield: 105.3 %

Procedure:
A mixture of 15.0 g. (0.09 mole) of trans-4-fluorocinnamic acid (Compound LXXVI) and 30 ml. (0.41 mole) of thionyl chloride in 100 ml. of toluene is stirred at 70° C. for 18 hours, and the solvent is evaporated at reduced pressure to obtain the crude product (17.5 g. (>100%)).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.[K+].Cl[CH2:14][CH2:15][CH2:16]Cl.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+]>CS(C)=O.CN1CCCC1=O.CN(C)C=O>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:14][CH2:15][CH2:16][O:25][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([NH2:18])=[CH:20][CH:21]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)[O-])cc1
Reactant: ClCCCCl
Agent: [K+]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Nc1ccc(C(=O)OCCCOC(=O)c2ccc(N)cc2)cc1
Yield: 91.5 %

Procedure:
Japanese Kokai 58059949 A2 discloses the preparation of 1,3-propanediol-bis(p-aminobenzoate) by heating Cl(CH2)3R (R=Cl, Br) with sodium or potassium p-aminobenzoate in an aprotic dipolar solvent, e.g., dimethyl formamide, dimethyl sulfoxide, or N-methylpyrrolidone. Thus, 0.15 mol of Cl(CH2)3Cl was heated with 0.3 mol sodium p-aminobenzoate in dimethyl sulfoxide at 100° for three hours to give 91.5 percent 1,3-propanediol bis(p-aminobenzoate) of 97.4 percent purity as opposed to a 3 percent yield with ethylene glycol as solvent. Cl(CH2)nCl(n=2, 4, 5, 8), instead of Cl(CH2)3Cl, gave the corresponding alkylene bis(p-aminobenzoates) in much lower yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)s2)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)s2)n1
Yield: 85.6 %

Procedure:
The title compound was prepared from 11f (6.8 mg, 0.016 mmol) following general procedure A. Flash chromatography (SiO2, 0.5×6 cm, 0-2% AcOH-EtOAc) afforded the title compound (5.4 mg, 86%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 10.51 (s, 1H(—OH)), 8.46 (s, 1H), 8.23 (dd, 1H, J=0.9, 7.6 Hz), 8.07 (t, 1H, J=7.8 Hz), 8.00 (dd, 1H, J=0.9, 7.9 Hz), 7.27 (m, 2H), 7.17 (m, 3H), 3.16 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.79 (m, 2H), 1.65 (m, 2H), 1.42 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 194.3, 175.8, 168.6, 149.0, 146.7, 144.1, 142.8, 142.6, 139.9, 128.5, 128.4, 125.8, 124.7, 123.8, 38.4, 36.0, 31.4, 29.23, 29.17, 24.1; HRMS-ESI-TOF m/z 395.1436 ([M+H]+, C22H22N2O3S requires 395.1424). 1,3,4-Thiadiazoles (5a-5c, 12a-12, 25):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20](Cl)=[N:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20]([N:35]4[CH2:36][CH2:37][C@H:33]([N:29]5[CH2:30][CH2:31][CH2:32][C@@H:28]5[CH3:27])[CH2:34]4)=[N:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cnc(Cl)nc1)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C[C@H]1CCCN1[C@H]1CCN(c2ncc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cn2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 2-(2-chloro-pyrimidin-5-yl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (102 mg, 0.28 mmol) in DMSO (2 mL) was added (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl hydrochloride (350 mg, 1.23 mmol), and K2CO3 (920 mg, 6.65 mmol). The reaction mixture was heated to 90° C. with stirring for 18 hours. The reaction was cooled to rt and was added NaHCO3 (aq) (10 mL), extracted with EtOAc (2×10 mL), washed organics with brine (5 mL), concentrated and purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 18.9 mg (15% yield) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[C:19]([OH:26])[CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:2]=1.[F:27][C@H:28]1[C@@H:33](OS(C)(=O)=O)[CH2:32][CH2:31][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>O.CCOC(C)=O>[F:27][C@H:28]1[C@H:33]([O:26][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[C:16]([C:13]2[N:10]4[CH:11]=[CH:12][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:8][C:9]4=[N:15][CH:14]=2)[CH:25]=[CH:24]3)[CH2:32][CH2:31][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:29]1
Reactant: Oc1cccc2ccc(-c3cnc4cc(-c5cccnc5)ccn34)nc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(-c6cccnc6)ccn45)nc23)[C@H](F)C1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
A mixture of 2-(7-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (30.2 mg, 0.089 mmol), tert-butyl cis-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (39.8 mg, 0.134 mmol) and Cs2CO3 (43.6 mg, 0.134 mmol) in DMA (7.78 mg, 0.089 mmol) was heated to 100° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water and EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC, eluting with 10% MeOH 0.5% NH4OH in DCM to provide the desired product (22 mg, 46% yield).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]([CH3:21])([CH3:20])[C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]([CH3:21])([CH3:20])[CH:9]([OH:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:22][CH:23]=1)#[N:2]
Reactant: Cc1cccc(CC(=O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(CC(O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Reaction time: 0.5 h

Procedure:
7.3 q of 2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]-6-methylpyridine N-oxide in 160 ml of ethanol were treated with 0.96 g of sodium borohydride and the mixture was stirred for 30 minutes. The solvent was removed by evaporation and the residue was taken up in water and dichloromethane. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was crystallized from diethyl ether to give 7.1 g of 2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]-6-methylpyridine N-oxide of melting point 89°-92° C.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2occc2c(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1O)CCO2
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
4,6-Di-tert-butyl-5-hydroxybenzofuran (6.0 g) was dissolved in acetic acid (50 ml). After addition of 10% Pd on carbon (5.0 g), the solution was stirred under a hydrogen atmosphere (4 atm.) for 15 min. After filtering off the Pd on carbon, the filtrate was concentrated under vacuum. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [4.4 g (yield, 73%)] as a colorless, fine-grained crystal.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH2:8][CH2:7][O:6][CH2:5]2.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:26]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH2:8][CH2:7][O:6][CH2:5]2)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cc2n(c1)CCOC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2n(c1)CCOC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) mixture of 7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (300 mg, 1.205 mmol) and THF (10 mL) was added n-butyllithium (0.530 mL, 1.325 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 60 minutes, after which tributylchlorostannane (0.392 mL, 1.445 mmol) was added. The reaction mixture was stirred at −78° C. 60 minutes, then warmed to room temperature and stirred for 1 hour. The reaction was quenched with brine (10 mL) and extracted with EtOAc (2×25 mL). The organic phase was separated, dried over sodium sulfate, concentrated, and purified via flash column chromatography to give the title compound as an oil, which was used without further purification (300 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[F:26])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[F:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6.0 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methyl-2H-pyridazin-3-one and 30 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 6.15 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methylpyridazine (hereinafter, referred to as compound (ix) of the present invention).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:27]([O:30][CH2:31][C:32]([NH:34][NH2:35])=O)[CH2:28][CH3:29]>C(O)CCC>[F:26][C:2]([F:25])([F:1])[C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:32]([CH2:31][O:30][CH2:27][CH2:28][CH3:29])=[N:34][N:35]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCCOCC(=O)NN
Reactant: CS(=O)(=O)c1cccc(C2=NCC(=S)Nc3cccc(C(F)(F)F)c32)c1
Solvent: CCCCO
Product: CCCOCc1nnc2n1-c1cccc(C(F)(F)F)c1C(c1cccc(S(C)(=O)=O)c1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-trifluoromethyl-5-[m-(methylsulfonyl)phenyl]-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with propoxyacetic acid hydrazide to give 7-trifluoromethyl-1-(propoxymethyl)-6-[m-(methylsulfonyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17].[CH2:23]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([NH:31][S:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:16])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Reactant: CCCCCS(N)(=O)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-2-methyl-3H-benzimidazole-5-carboxylic acid (34.1 g, 102 mmol), N,N′-carbonyldiimidazole (21.4 g) and N,N-dimethylformamide (122.7 g) was stirred for one hour at 35° C., into which 1-pentanesulfonamide (20.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (20.1 g) were then added, and stirred for 6 hours at 40° C. After the reaction, a portion of N,N-dimethylformamide (62.9 g) was distilled off in vacuo, and, to the residue were added methanol (227.8 g) and water (227.8 g). This solution contained 1,8-diazabicyclo[5.4.0]-7-undecene and imidazole generated from N,N′-carbonyldiimidazole as the bases. This solution was filtered to remove insoluble materials, and the filtrate was heated to 50° C., and conc. hydrochloric acid (20.4 g) was added drop-wise thereto over one hour. After the dropping, crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (119 mg) was added as seed crystal, and the mixture was allowed to be ripen for 2 hours. After the ripening, conc. hydrochloric acid (15.5 g) was further added drop-wise thereto over 2 hours. The slurry was ripened for one hour at 50° C. and cooled down to 30° C., and then the crystals were collected by filtration. The crystals were washed with a mixed solvent of methanol (120 g) and water (120 g), and vacuum-dried to obtain crystal form B of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[CH:4][C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[C:14]=1[Cl:15].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c3c(sc2c(Cl)c1Cl)CCCC3
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2c3c(sc2c(Cl)c1Cl)CCCC3
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of 4.2 g of 3,4-dichloro-6,7,8,9-tetrahydro-2-methoxydibenzothiophene and 40 g of pyridine hydrochloride is stirred at 190°-195° under nitrogen for 2 hours. The cooled mixture is triturated with water and the solid product is collected. Recrystallization from ether-pentane after decolorization with charcoal gave 3.6 g of 3,4-dichloro-6,7,8,9-tetrahydro-2-hydroxydibenzothiophene as off-white crystals, mp 103°-105°.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8]O)=[C:6]([CH2:10][CH3:11])[N:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[OH:33][CH2:34][CH:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>C(Cl)Cl.C(#N)C.CN(C)C=O.O>[CH2:1]([C:3]1[C:7]([CH2:8][N:36]2[C@@H:35]([CH2:34][OH:33])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[C:6]([CH2:10][CH3:11])[N:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2]
Reactant: OCC1Cc2ccccc2CN1
Reactant: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1CN1Cc2ccccc2C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a solution of 272 mg (1,0 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole-4-methanol in 5 mL of methylene chloride cooled to 0° C. under dry nitrogen in a 25 mL 3-neck flask, was added to 0.2 mL (2.5 mmol) of triethylamine and 0.092 mL (2.0 mmol) of methanesulfonyl chloride. This mixture was stirred for 15 minutes at 0° C. and then 0.648 g (4.0 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 1 mL of 50:50 dimethylformamide acetonitrile was added. The reaction mixture was heated at reflux overnight whereupon no starting material was seen by TLC. The cooled reaction mixture was diluted with water and the product was extracted with ethyl acetate. After drying (brine wash, magnesium sulfate) and evaporation, the crude product was chromatographed on silica gel, eluting with 10:1 and 5:1 hexane/ethyl acetate to give 184 mg (44%) of the desired product. 1H-NMR (CDCl3):0.80 (3H, t, J=7), 1.18 (3H, t, J=7), 1.92 (6H, s), 2.21 (2H, q, J=7), 2.28 (3H, s), 2.55 (2H, q, J=7), 2.97 (2H, d of d, J=7), 3.25 (1H, m), 3.50-3.66 (5H, m), 3.80 (2H, d, J=12), 6.82-7.16 (6H, m).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1C(=O)C2C(=CC=CC=2)C1=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.CO.O.NN>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccc(Cl)c(F)c1
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To a solution of 66 (14.35 g, 33.07 mmol) and THF/MeOH (1:1, 400 mL) was added hydrazine monohydrate (4.138 g, 82.67 mmol) and the reaction was heated to 60° C. for 3 h. The reaction was diluted with THF and filtered. The solid was discarded and the filtrate was concentrated and the residue dissolved in ether (200 mL). The organic layer was washed twice with water (100 mL). The organic layer was then dried, filtered and concentrated. The crude product was purified by SiO2 (Biotage 65) eluting with an EtOAc/hexane gradient (30 to 40% EtOAc) to afford 8.85 g (88.1%) of (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (68).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH2:12]2)=[CH:8][CH:7]=1.C1COCC1>CO>[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH2:12]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(C)C1=CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC=C2C(C)C(=O)O
Temperature: 38 °C
Reaction time: 17 h
Yield: 90.3 %

Procedure:
In a 1 L three-neck flask charged with NaOH (18.57 g, 0.464 mol) and water (216 mL), was slowly added (over 15-20 min) a solution of methyl 2-(6-methoxy-1H-inden-3-yl)propanoate (Example 10) (53.92 g, 0.232 mol) in MeOH (215 mL). During the addition, the reaction temperature increased to 38° C. To this mixture was added THF (108 mL) and then the mixture was heated to 40-45° C. for a period of 8 h and subsequently stirred at rt for 17 h. The solvent was removed under vacuum and the resulting aqueous mixture was extracted with CH2Cl2 (3×100 mL). The aqueous layer was acidified with HCl (38 mL, 37% aqueous solution) to pH˜2.5 and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (4×150 mL) and brine (50 mL), dried over Na2SO4, and filtered. The solvent was evaporated under vacuum, and the resulting oil was dried under vacuum at 40-45° C. for 16-18 h to give 45.71 g (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (1H, d), 7.05 (1H, s), 6.83 (1H, dd), 6.19 (1H, s), 3.73 (3H, s), 3.68 (1H, q), 3.30 (2H, s), 1.39 (3H, d); LC-MS: RT=2.43 min, (M+H)+: 219.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O.Cl>[CH3:18][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH:12]([CH3:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17]
Reactant: CC1C(=O)CC(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)C(C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.0 g of crude 5-methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 25 mL of N,N-dimethylformamide was added 1.2 g (8.7 mmol) of K2CO3, and 1.2 mL (19.3 mmol) of methyl iodide. The mixture was stirred at 80° C. for 20 min, cooled to ambient temperature, then diluted with 125 mL of 0.2M HCl(aq.). This was extracted with diethyl ether (3×20 mL), then the combined ether layers were extracted with water (1×20 mL), and brine (1×20 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 20% ethyl acetate/hexanes to give the 2,5-cis isomer. The 2,5-trans isomer eluted slightly faster than the desired cis isomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J=7.1 Hz, 3 H) 1.40 (m, 9 H) 2.59 (dd, J=19.2, 3.2 Hz, 1 H) 3.12 (dd, J=18.3, 11.2 Hz, 1 H) 3.66 (s, 3 H) 3.92 (q, J=6.8 Hz, 1 H) 4.63 (dd, J=10.7, 3.6 Hz, 1 H), NOE observed between H-2 and H-5, not observed in the corresponding trans isomer; MS (ESI) m/z=256 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(C)=O>CCO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH:17]4[N:13]([CH2:12][CH2:11][C:6]2=3)[CH2:14][CH2:15][CH2:16]4)=[CH:22][CH:23]=1
Reactant: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Fc1ccc(CCBr)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)C2CCCN2CC3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11c-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated at 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), and once with brine, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC. Column: ZORBAX SB C18, 4.6×250 mm, 5μ, retention time (min): 9.71, purity: 95.20%;