Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17]>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature, while stirring. The mixture is heated to the reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours and then cooled and poured onto water. It is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](OC1C=C(O)C=CC=1OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1OCc1ccccc1
Reactant: COc1ccc(OC(=O)c2ccccc2)cc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)c2ccccc2)cc1OCc1ccccc1

Procedure:
The compound 3-hydroxy-4-methoxyphenyl benzoate was made as follows. An amount of 2.00 gms. of 3-benzyloxy-4-methoxyphenol, 1.00 gms. of triethylamine and 0.10 gms of 4-dimethylaminopyridine were dissolved in 100 ml. of methylene chloride at 0° C. and stirred. To the mixture was added 1.22 gms. of benzoyl chloride and the mixture was stirred overnight. The mixture was then washed with equal volumes of 1M hydrochloric acid, saturated sodium bicarbonate and water. The mixture was then dried over magnesium sulfate and the solvent evaporated to yield 3-benzyloxy-4-methoxyphenyl benzoate.
Reaction SMILES: C(N(CC)C(C)C)C.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][N:17]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([NH2:38])[CH:33]=[CH:32]2)(=[O:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([NH:38][C:22]([C:19]1[CH:20]=[N:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=3)=[N:17][CH:18]=1)=[O:24])[CH:33]=[CH:32]2)(=[O:28])=[O:27]
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2NC(=O)c2cnc(-c3ccccn3)nc2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
Diethyl-iso-propylamine (3.54 mmol) is added a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid HCl (1.18 mmol), 5-methanesulfonyl-indol-1-ylamine (1.18 mmol) and TBTU (1.77 mmol) in anhydrous DMF (16 mL) at rt. The reaction mixture is stirred at 90° C. overnight and then concentrated in vacuo. The residue is dissolved in EtOAc (50 mL) and water (50 mL). The organic layer is separated, washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc and DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (125 mg, 27%) as a solid. MS: 394 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.14 (s, 3H), 6.82 (m, H) 7.50-7.72 (m, 3H), 7.80 (m, H), 8.07 (m, H), 8.30 (m, 2H), 8.70(d, H), 8.80 (s, H), 9.51 (s, 2H).
Reaction SMILES: O[CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:38])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:38][CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Tert-butyl(3S)-3-hydroxymethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (1.70 g, 5.10 mmol) was dissolved in dichloromethane (20 mL). To this solution, toluene (20 mL) was added, and diethylaminosulfur trifluoride (1.68 mL, 12.8 mmol) was added dropwise in an ice bath. After stirring at 60° C. for 8 hours, saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the reaction mixture, and the mixture was extracted by ethyl acetate (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was then purified by silica gel column chromatography (solution by hexane:ethyl acetate, 9:1→2:3) to obtain 0.910 mg (53%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C@H:13]([OH:25])[C:14]([C:16]1([C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][C:45](=[O:65])[C@H:46]([CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:64])[NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45](=[O:65])[C@H:46]([CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:64])[NH:53][C:54]([O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[O:55])[NH:47][C:22]([C:16]1([C:14](=[O:15])[C@@H:13]([OH:25])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])=[O:23])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: N=C(NCCC[C@H](N)C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C(=O)C2(C(=O)O)CCCC2N)cc1
Product: CS(=O)(=O)c1ccc(C[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C(=O)C2(C(=O)N[C@@H](CCCNC(=N)NC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)CCCC2N)cc1
Yield: 30 %

Procedure:
By working in a way similar to that described in example 1 and using 1-[(2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-(4-methylsulfonyl-phenyl)-butanoyl]-amino-1-cyclopentanecarboxylic acid (0.4 g; 0.00077 moles), prepared as described in example 15, and Nω -benzyloxycarbonyl-L-arginine benzyl ester (0.614 g; 0.00154 moles) as starting compounds, Nα -[1-[(2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4(4-methylsulfonyl-phenyl)-butanoyl]-amino-1-cyclopentanecarbonyl]-Nω -benzyloxycarbonyl-L-arginine benzyl ester was obtained (0.207 g; 30% yield).
Reaction SMILES: CCNC1N=C(Cl)N=C(NC(C)C)N=1.C[O-].[Na+].[CH3:18][O:19][C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)[N:23]=[C:22]([NH:30][CH:31](C)[CH3:32])[N:21]=1.ClC1N=C(NC2CC2)N=C(NC(C)C)N=1>CCCCCC>[CH3:18][O:19][C:20]1[N:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22]([NH:30][CH2:31][CH3:32])[N:21]=1
Reactant: COc1nc(NC(C)C)nc(NC2CC2)n1
Agent: CC(C)Nc1nc(Cl)nc(NC2CC2)n1
Agent: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: C[O-]
Solvent: CCCCCC
Product: CCNc1nc(NC(C)C)nc(OC)n1

Procedure:
2-methoxy-4-(1-methylethylamino)-6-ethylamino-1,3,5-triazine (14A) (Atraton) was prepared as a white solid (recrystallized from hexane), m.p.: 95°-96° C., by treating atrazine (Examples 5-8) with sodium methoxide according to the procedure described for preparing 13A from 9B, Example 13.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[CH:21]=[O:22])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=Cc1cccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)c1
Yield: 69 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-formylbenzeneboronic acid according to the procedure described in example 8 gave 3-(9-Hydroxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)benzaldehyde (507) (I; Ar=3-formylphenyl) in a 69% yield; mp (THF/CH2Cl2/pentane) 280–286° C. (dec). 1H NMR [(CD3)2SO] δ 11.82 (br s, 1H), 11.07 (br s, 1H), 10.11 (s, 1H), 9.27 (br s, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.14 (t, J=1.4 Hz, 1H), 7.97 (m, 2H), 7.70 (t, J=7.7 Hz, 2H), 7.65 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.08 (dd, J=8.7, 2.5 Hz, 1H). FABMS found [M+H]+: 357.0857. C21H13N2O4 requires 357.0875.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][CH3:19])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH3:9])=[C:13]([CH2:18][CH3:19])[CH:12]=1
Reactant: CCI
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1CC
Reaction time: 20 h
Yield: 71.8 %

Procedure:
Potassium carbonate (3.3 g, 23.6 mmol) followed by iodoethane (0.63 mL, 7.9 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.6 g, 7.9 mmol) in DMF (10 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (hexanes) to give the desired product (1.3 g, 72%). 1H NMR (400 MHz, CDCl3): δ 1.18 (t, J=7.3 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H), 2.60 (q, J=7.6 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 6.68 (d, J=8.1 Hz, 1H), 7.24 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[N:22]=[CH:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:17]3[CH2:18][CH2:19][CH:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[O:8][C:7](=[O:12])[CH:6]=4)[CH2:15][CH2:16]3)=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: O=Cc1ccc2ocnc2c1
Product: O=c1cc(NC2CCN(Cc3ccc4ocnc4c3)CC2)c2cc(Cl)ccc2o1

Procedure:
6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and benzooxazole-5-carbaldehyde were allowed to react in a manner analogous to that previously described to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.66 (m, 2H) 1.91 (m, 2H) 2.14 (m, J=10.29 Hz, 2H) 2.85 (m, 2H) 3.50 (m, 1H) 3.63 (s, 2H) 5.28 (s, 1H) 7.29 (m, 1H) 7.33 (m, 1H) 7.41 (m, 1H) 7.62 (m, 1H) 7.71 (m, 2H) 8.32 (m, 1H) 8.71 (s, 1H); MS (DCI/NH3) m/z 410 [M+H9 +.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[OH:24])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1.Br[CH2:26][CH2:27][Cl:28]>C(OCC)(=O)C.CCCCCC>[Cl:28][CH2:27][CH2:26][O:24][C:14]1[CH:15]=[C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:18][C:13]=1[N:10]1[C:11]([CH3:12])=[C:7]([C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])[N:8]=[N:9]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(O)c1
Reactant: ClCCBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCCCl)c1

Procedure:
In the same manner as in Example 145, a product was obtained from N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-methyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 141 and 1-bromo-2-chloroethane (0.05 ml), and the title compound was obtained as a white powder (0.06 g, 31%) by recrystallization from ethyl acetate-hexane.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2].II.[Cl:15][C:16]1[C:17]([NH:23][NH2:24])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1.O.OO>C(O)(=O)C.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:23]=[N:24][C:9]2[CH:10]=[CH:11][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=2[OH:12])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCN(CC)c1cccc(O)c1
Agent: II
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2ncc(Cl)cc2Cl)c(O)c1

Procedure:
Next, a flask was loaded with 3-(N,N-diethylamino)phenol (1.7 g), dimethylformamide (14 ml), acetic acid (5 ml) and iodine (0.24 g), and they were mixed, followed by addition of 3,5-dichloro-2-hydrazinopyridine (1.6 g) to the flask with stirring. Then, to this, a 30% hydrogen peroxide water (2.4 g) was dropwise added in 90 minutes and the mixture was stirred overnight. The reaction mixture was filtrated, and ether and water were added to the filtrate, followed by stirring. After stirring, the ether layer was collected and condensed to precipitate crystals. The crystals were filtrated for collection and dried to give intended crystals (0.54 g).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N:6]=1)C.[ClH:21]>O>[OH2:3].[ClH:21].[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2cccc(C)n2)nn1C
Agent: Cl
Solvent: O
Product: Cc1cccc(-c2nc(C=O)n(C)n2)n1
Yield: 189.6 %

Procedure:
A mixture of 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]-6-methylpyridine (38 g, 0.1377 mol), water (92 mL) and concentrated HCl (23 mL, 0.276 mol) was heated at 70–80° C. for 2 h. The resulting solution was co-evaporated with water four times using a water aspirator vacuum, then dried in vacuo at 60° C. to give 33.5 g (94.5%) of the title product as a covalently-bound hydrate. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, D2O+TFA): δ 2.90 (s, 3H), 4.13 (s, 3H), 6.38 (s, 1H), 7.94 (d, J=8 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 8.56 (t, J=8 Hz, 1H). LC-MS (API-ES) calcd for C10H10N4O: 202.09, found (M+H+): 203.1; (M+18+H+) 221.1 m/z.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>O>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Cc2ccccc2)n1
Agent: Br
Solvent: O
Product: Oc1cccc(Cc2ccccc2)n1
Reaction time: 7 h
Yield: 70.9 %

Procedure:
A mixture of 59 g of 2-benzyl-6-methoxypyridine and 200 ml of 47% hydrobromic acid was heated under stirring for 7 hours in an oil bath kept at 100° C. After cooling as it was, 250 ml of water was added thereto, and the resulting crystals were collected by filtration, washed with water and vacuum-dried, to give 38.9 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1F.[CH3:10][S-:11].[Na+]>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:11][CH3:10]
Reactant: Cc1ccc(F)c(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1ccc(C)cc1Br
Temperature: 125 °C
Reaction time: 8 h

Procedure:
The 2-bromo-1-fluoro-4-methylbenzene (2.00 g, 11.0 mmol) was dissolved in dimethylacetamide (5.3 mL) followed by the addition of sodium thiomethoxide (0.82 g, 12.0 mmol). The reaction was heated at 125° C. for 5.5 h. The reaction was then cooled to rt and stirred overnight. The reaction was then diluted with water (200 mL) and the mixture was extracted with EtOAc (3×125 mL). The combined organic layers were washed with water (1×150 mL) and brine (1×100 mL) and dried over MgSO4. The crude product was purified by column chromatography (silica gel, 0 to 40% EtOAc:hexanes) to give (2-bromo-4-methylphenyl)-(methyl)sulfane. 1H NMR (400 MHz, chloroform-d) δ ppm 7.38 (1H, d, J=0.8 Hz), 7.09-7.13 (1H, m), 7.06 (1H, d), 2.47 (3H, s), 2.31 (3H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: C1=COCCC1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(OC2CCCCO2)cc1
Yield: 62 %

Procedure:
13.62 g (100 mmol) of 4-hydroxyacetophenone and 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were suspended in 100 ml of anhydrous methylene chloride. At 0° C., 190 mg (1 mmol) of p-toluenesulfonic acid were added with stirring and the mixture was stirred at 0° C. for 3 hours. 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were added again and the mixture was stirred at room temperature for a further 3 hours. The batch was poured into 150 ml of water, the phases were separated and the organic phase was extracted with saturated NaHCO3 solution, saturated NaCl solution and with water. The organic phase was dried over sodium sulfate, concentrated and, for purification, chromatographed on silica gel (70-200 μm) using methylene chloride as an eluent. 13.65 g (62%) of 10.1 were obtained.
Reaction SMILES: OCC[NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)=[N:16][C:15]=2[CH3:26])[CH:9]=1)(=[O:7])=[O:6].N>>[CH3:26][C:15]1[N:16]=[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[S:18][C:14]=1[C:10]1[CH:9]=[C:8]([S:5]([NH2:4])(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(=O)(=O)NCCO)c1
Agent: N
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(N)(=O)=O)c1

Procedure:
The titled compound is prepared by an analogous procedure to N-(2-hydroxy-ethyl)-3-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (Example 42 using ammonia in place of ethanolamine in the final step.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(O)C>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium ethoxide was generated by the addition of sodium (9.45 g) to ethanol (370 ml). The resulting solution was cooled to 5° C. and diethyl 2-methylmalonate (68.8 ml) added over 2 minutes. The reaction mixture was stirred at 5° C. for 20 minutes and then 4-bromobenzyl bromide (97.0 g) was added over 20 minutes. The reaction mixture was then heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth and evaporated. The residue was partitioned between water (500 ml) and diethyl ether (1000 ml). The diethyl ether was separated and the aqueous layer was extracted with diethyl ether (2×500 ml). The combined organic layers were dried (MgSO4) and evaporated to give an amber oil. This was purified by vacuum distillation, affording diethyl 2-(4-bromobenzyl)-2-methylmalonate (84.4 g), b.p.122-125° C./0.1-0.2 mm Hg; mass spectrum (+ve CI): 343 (M+H)+.
Reaction SMILES: C([Li])(CC)C.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[C:23]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH2:35]([N:42]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C@@H:43]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:44]=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C.C(O)(=O)C>[C:26]([O:25][C:23]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:34]1[C@@H:44]([OH:45])[C@@H:43]([N:42]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
Add sec-butyllithium (1.29 mL, 1.8 mmol) dropwise to a solution of (−)-sparteine (0.44 mL, 1.36 mmol) in diethyl ether (10 mL) over 3 min at −78° C. Add N-Boc-pyrrolidine (0.245 mL, 1.4 mmol) in diethyl ether (2 mL) dropwise over 10 min. Stir 2 h, add 2-(S)-dibenzylamino-3-phenylpropionaldehyde (0.69 g, 2.1 mmol) in diethyl ether (1.8 mL) over 5 min and stir 20 min. Add acetic acid (0.16 mL) and warn to room temperature. Add saturated aqueous sodium chloride (20 mL), separate layers, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (0.421 g, 60%).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20]([O:23][CH:24](C)[CH2:25][CH2:26][CH2:27]I)(=[O:22])[CH3:21].Cl>O1CCCC1>[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)CCCI
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCOC(C)=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Diisopropylamine (2.4 g, 23.8 mmole) was dissolved in anhydrous tetrahydrofuran (50 ml) under argon, and the solution was cooled at -70° C. 1.6M n-butyllithium-hexane solution (14.8 ml, 23.7 mmole) was added dropwise to the solution, followed by stirring at -70° C. for 10 minutes. Tetrahydrofuran (10 ml) solution containing ethyl phenylacetate (3.24 g, 20 mmole) was added, while maintaining the reaction solution at not higher than -60° C. After stirring was continued for 30 minutes under the same conditions, a solution of 4-acetoxypentyl iodide (4.8 g, 20 mmole) in hexamethylphosphortriamide (4 ml) was added dropwise to the reaction solution. Following the dropwise addition, stirring was continued at -70° C. for another 1 hour, and the reaction temperature was allowed to rise to room temperature. 2N hydrochloric acid (30 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel, and development was effected with isopropyl ether:hexane (1:1) to yield ethyl 6-acetoxy-2-phenylhexanoate (5 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccc(F)cc2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-fluoro-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.