Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(C(=O)c2ccccc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride and benzoyl chloride are processed according to the method described in Example 38 to give (3-methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 7.26-7.40 (m, 5H), 7.45-7.52 (m, 1H), 7.57 (d, J=1.3 Hz, 1H), 7.59 (s, 1H), 7.63 (dd, J=7.1, 1.3 Hz, 1H), 7.68-7.73 (m, 1H), 7.75 (dt, J=7.8, 1.9 Hz, 1H), 8.33 (dd, J=5.1, 1.5 Hz, 1H), 8.47 (d, J=1.3 Hz, 2H). HRMS (ESI) m/z 313.1337 [(M+H)+ Calcd for C21H17N2O: 313.1341].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=c1[nH]c2cc(F)cc(Br)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
The method of Cheeseman, supra. was adapted. 5-Bromo-7-fluoro-1,4-dihydroquinoxaline-2,3-dione (77 mg, 0.30 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 min, and KNO3 (35 mg, 0.346 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. The mixture was poured into ice water (10 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (10 mL), then was acidified to pH=2 with 4N HCl to give cream precipitate, which was collected by filtration, and was dried in the air at 50° C. for 4 h affording pure (by NMR) 5-bromo-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 90%), as a white amorphous solid; mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3416, 3071, 2952, 1721, 1609, 1546. NMR (1H, DMSO-d6): δ7.146 (d, J=10.2 Hz, 1H), 11.432 (s, 1H), 12.340 (s, 1H). HRMS: calcd. for C8H3N3O4BrF (M+) m/z: 302.9290, found: 302.9290.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-fluorobenzaldehyde (5 g, 24.75 mmol) in anhydrous tetrahydrofuran (100 mL) was added methyl magnesium bromide (3 M solution in tetrahydrofuran, 8.21 mL) at −45° C. under the atmosphere of nitrogen then stirred at room temperature. After 2 hours, LC-MS showed the desired product has received. The aqueous of ammonium chloride (15 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL), combined and concentrated the organic layers. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give 1-(4-bromo-3-fluorophenyl)ethanol (4 g, 78%). LCMS (M+H+) m/z: calcd 217.97. found 218. 1H NMR (300 MHz, CD3OD): δ 7.92-7.87 (m, 1H), 7.23-7.19 (m, 1H), 7.07-7.10 (m, 1H), 4.80 (d, J=6.3 Hz, 1H), 1.41 (t, J=2.7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)=[O:15])(=[O:9])=[O:8])=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:25].[Na+].C(OO)=O>C(O)=O.O>[CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:16]2[N:20]([CH3:21])[N:19]=[N:18][N:17]=2)(=[O:25])=[O:15])(=[O:8])=[O:9])=[N:5][N:4]=[N:3]1
Reactant: O=S([O-])O
Reactant: Cn1nnnc1S(=O)CCCCS(=O)(=O)c1nnnn1C
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)(=O)CCCCS(=O)(=O)c1nnnn1C
Reaction time: 5 h

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (3.2 g) is dissolved in formic acid (30 ml), and thereto is added with stirring 30% hydrogen peroxide (2.3 g) at room temperature, and the mixture is stirred for 5 hours. Sodium hydrogensulfite is added to the mixture under ice-cooling in order to decompose excess performic acid. Water is added to the mixture and the precipitated crystals are collected by filtration and recrystallized from N,N-dimethylformamide to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfonylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (2.1 g) as colorless prisms, m.p. 192°-194° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.CN1CCN(C)CC1.ClN1C(=O)CCC1=O.[Cl:30][CH2:31][CH2:32][CH2:33][OH:34].ClC(Cl)(Cl)C(O)=O>ClCCl>[Cl:30][CH2:31][CH2:32][CH2:33][O:34][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OCCCCl
Agent: CN1CCN(C)CC1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of methyl indole-3-carboxylate and dichloromethane is cooled to 0° C. 1,4-dimethylpiperazine (0.55 eq.) and N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir for two hours to give a slurry containing the compound of formula (C) above. The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining the temperature below 0° C. The reaction mixture is left to stir for half an hour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water. The organic solution is dried over sodium sulphate, filtered and the solvent evaporated. Toluene is added and the mixture stirred at 0-5° C. for one hour. The product is then filtered, washed with toluene and dried to give the title product in 83% yield.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH2:16]([N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH2:2].[C:28]1([CH2:27][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25][NH:26][C:3](=[O:15])[C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:8][CH:9]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1.[C:17]1([CH2:16][N:23]([CH2:24][CH2:25][NH:26][C:3](=[O:15])[C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:8][CH:9]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: COC(=O)c1ccc(-n2ccnc2)cc1
Product: O
Product: O=C(NCCN(Cc1ccccc1)Cc1ccccc1)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
Heat 4.23 g (21.0 mmol) of 4-(1H-imidazol-1-yl)benzoic acid methyl ester and 5.00 g (21.0 mmol) of N,N-dibenzylethylenediamine in 10 mL of xylenes at reflux for about 48 hr. Cool the solution to room temperature. Filter to obtain crystals of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)ccc1Cl
Temperature: 110 °C
Yield: 40.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 4-chloro-3-methoxyphenylboronic acid (56.2 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (42.3 mg, 40%). 1H NMR (DMSO-d6) δ: 11.15 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.50-7.59 (m, 3H), 6.34 (s, 1H), 3.88 (s, 3H), 2.34 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 451.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C:63](O)=[O:64])[CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:4][C:3]([C:6]1[NH:10][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)=[C:8]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])[CH2:2][NH:1][C:63]([CH:60]1[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:62][CH2:61]1)=[O:64]
Reactant: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Reactant: COCCN1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCN1CCC(C(=O)NCC(C)(C)c2nc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol), 1-hydroxybenzotriazole (0.06 g, 0.44 mmol) and polymer bound 1,3-dicyclohexylcarbodiimide (0.4 g, 0.6 mmol, 1.52 mmol/g) in a 1:1 mixture of dichloromethane and DMF (4 ml) was stirred at room temperature for 30 min. A solution of 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO 97/25309] (0.098 g, 0.44 mmol) in DMF (2 ml) was then added and the mixture stirred at room temperature overnight. The reaction mixture was then filtered, the solvent removed in vacuo and the crude residue purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.88 ammonia solution:methanol:dichloromethane to give the title compound (0.12 g, 80%) as a yellow oil; MS(AP+) m/e 516 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].I(O)(=O)(=O)=[O:14].C(Cl)Cl.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:14])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
428 mg (2.64 mmol) of iron(III) chloride was added to a mixture of 16.86 g (92.02 mmol) of 1-ethylsulfanyl-4-nitrobenzene in 75 ml acetonitrile and it was stirred for 10 minutes at room temperature. Then 22.44 g (98.44 mmol) of periodic acid was added in portions, so that the temperature did not exceed 30° C. The mixture was stirred for 50 minutes and was then added, with stirring, to a mixture of 170 ml DCM, 500 ml ice water and 100 g sodium thiosulfate pentahydrate. It was extracted with DCM (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was recrystallized from ethyl acetate/hexane. 12.49 g (62.69 mmol; yield: 68%) of the product was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 720.5 [(M+H)+]
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:25]>CO.C(O)(=O)C.[Pd]>[ClH:25].[C:15]1(=[O:24])[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C1CCNCC1

Procedure:
16.0 Grams of 1-benzyl-4-phthalimido-piperidine were dissolved in 200 milliliters of 50% methanol/acetic acid and 25 milliliters of ethereal hydrogen chloride, and were hydrogenated at 60° C. and 60 psi in the presence of 2.0 grams of 10% palladium-on-charcoal catalyst. After 4 hours the reaction mixture was filtered while still hot and addition of ether gave 8.7 grams of 4-phthalimido-piperidine mono-hydrochloride. Melting point: 300° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH2:27])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].[CH2:29]=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH2:7][O:8][CH3:9])[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:12][C:11]=2[CH2:29][NH:27]1)=[O:28])[CH3:2]
Reactant: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(Cc3ccccc3Cl)c12
Reactant: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1NCc2[nH]c3cccc(Cc4ccccc4Cl)c3c2C1COC
Yield: 18.6 %

Procedure:
5.2 g (0.013 mol) of 2-amino-3-[4-(2-chlorobenzyl)-indol-3-yl]-4-methoxybutyric acid ethyl ester is refluxed for one hour with 0.44 g of paraformaldehyde in 500 ml of toluene under argon on a water separator. Then it is filtered off from a turbidity. The evaporation residue is chromatographed on silica gel with equal parts of acetone and dichloromethane and yields 1 g (19% of theory) of 1,2,3,4-tetrahydro-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26](Cl)=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.C1COCC1>[C:12]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(C(=O)O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: Br[C@H:2]1[C@H:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[O:4][CH2:3]1.[OH-:14].[NH4+:15]>O1CCCC1.C(O)C>[NH2:15][C@H:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[O:4][CH2:3][C@@H:2]1[OH:14]
Reactant: [NH4+]
Reactant: O[C@@H]1c2cc(Br)ccc2OC[C@H]1Br
Reactant: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N[C@H]1c2cc(Br)ccc2OC[C@@H]1O
Temperature: 43 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of racemic-trans-3,6-dibromochroman-4-ol (5.10 kg, 16.6 mol) in tetrahydrofuran (5.0 L) and ethanol (5.0 L) at room temperature, add ammonium hydroxide (13.0 L) in one portion and slowly heat to 43° C. over 2 hr. and continue heating for 14 hr. Concentrate the mixture under reduced pressure to remove about 9 L of solvent. Add methyl tert-butyl ether (10 L) to the residual slurry and stir the mixture for 3 hr. at 25° C. Collect the precipitate by filtration, wash with water (2×2 L) and then methyl tert-butyl ether (3×1.5 L) to obtain a wet solid. Dry in air at room temperature overnight to obtain the title compound as a pale yellow solid (2.78 kg, 69%). LC-ES/MS m/z (79Br) 244 [M+H]+. Separate the enantiomers by purifying in 100 g portions on a 11×33 cm CHIRALPAK® AD, 20 μm column eluting with 100% methanol with 0.2% dimethylethylamine (steady state recycle purification) to obtain the 3S,4R enantiomer (isomer 1, 1362.5 g, 97.4% ee) and the title compound (isomer 2, 1323.7 g, 97.5% ee). Conditions for analytical chiral HPLC analysis: 4.6×150 mm CHIRALPAK® AD-H 5 μm column, 100% methanol with 0.2% dimethylethylamine, flow rate 0.5 mL/min., isomer 1 TR=4.69 min, isomer 2 TR=6.27 min.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17]/[C:18](/SC)=[CH:19]/[N+:20]([O-:22])=[O:21])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:35].[ClH:36].O1CCOCC1>C(O)C.CO>[ClH:36].[NH2:35]/[C:18](/[NH:17][CH2:16][C:13]1([OH:15])[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[O:10])[CH2:12]1)=[CH:19]\[N+:20]([O-:22])=[O:21]
Reactant: [NH4+]
Reactant: CS/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: N/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of (0.05 g 0.08 mmol) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol in ethanol (2 mL) was added ammonium hydroxide (0.1 mL, 0.8 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (40 μL, 0.16 mmol) was added to the solution. A white precipitate formed and was collected by vacuum filtration. The solid was washed with hexane, and dried to afford 42 mg (87%) 3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride. 1H NMR (400 MHz, d4-MeOH): 7.58 (t, 0.5H), 7.44 (t, 0.5H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.63 (m, 1H), 3.90-4.30 (m, 4H) 3.72 (s, 2H); MS (EI) for C19H17F3IN5O4: 564 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:23])([F:24])[F:22])[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.414 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.22 g, 40%). MS (ISN) 550.2 [(M−H)−]; mp 197.5° C.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9](Br)=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: Brc1cnc(-c2ccc(-c3ccccc3)cc2)s1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2ccc(-c3ncc(-c4ccccc4)s3)cc2)cc1
Yield: 97.7 %

Procedure:
The compound of the title was prepared in a similar way to example 3 from 2-(biphenyl-4-yl)-5-bromothiazole (311 mg, 0.98 mmol) and phenylboronic acid (955 mg, 1.27 mmol) for 4 h at 100° C. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 8:2) afforded 300 mg of 2-(biphenyl-4-yl)-5-phenylthiazole as a white solid (98% yield). EM (IE): m/z (%): 313; (M+, 100). HRMS (ESI): (M+H)+: calculated for C21H15NS: 314.0925. found: 314.0995.