Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:27]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:26])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:25])[F:24])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)[N:6]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1B(O)O>>[NH2:27][C:4]1[S:3][C:2]([C:37]2[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:36]=2[F:35])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:22][CH:23]([F:24])[F:25])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(CC(F)F)c3N3CCCC(O)CC3)c(N)s2)c1
Yield: 49.2 %

Procedure:
Following the procedure for Example 105 starting with tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.13 g, 0.23 mmol) and 2-fluoro-5-methylbenzeneboronic acid (53 mg, 0.35 mmol) gave 111 as a black solid (56 mg, 50% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.93 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.66 (s, 1H), 7.42 (s, 2H), 7.24 (d, J=8.7 Hz, 2H), 6.39 (tt, J=55.3, 4.2 Hz, 1H), 4.55 (d, J=3.8 Hz, 1H), 4.42 (td, J=14.5, 4.2 Hz, 2H), 3.86-3.80 (m, 1H), 3.29-3.03 (m, 4H), 2.37 (s, 3H), 1.94-1.84 (m, 3H), 1.77-1.55 (m, 3H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43](O)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30].[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1>C(Cl)Cl>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51]2)[C:43]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (110 mg, 1.18 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (117 mg, 49%) as a pale yellow foam: mp 107-110° C.; EI-HRMS m/e calcd for C21H26N2O5S2 (M+) 450.1283, found 450.1282.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH:11]=[O:12])=[CH:8][C:7]=2[CH:13]=1.[BH4-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1
Reactant: COc1cc(OC)c2oc(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(OC)c2oc(CO)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Compound 4 (460 mg, 2.23 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). NaBH4 (102 mg, 2.68 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1 h. Solvents were evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (1:1) to give 5 (388 mg, 82%) as an oil. m/z=209.08 (M+H). 1H NMR (500 MHz, CDCl3): δ: 6.62 (1H, s, H-3), 6.60 (1H, s, H-6), 6.46 (1H, s, H-4), 4.76 (2H, s, 2-CH2), 3.99 (3H, s, OMe), 3.85 (3H, s, OMe). 13C NMR (500 MHz, CDCl3): δ: 157.23 (C-5), 156.72 (C-1), 145.36 (C-7), 139.50 (C-1a), 129.38 (C-4a), 104.62 (C-3), 96.96 (C-6), 94.58 (C-4), 57.98 (2-CH2), 55.95 (OMe), 55.83 (OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(CC)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.82–1.33, 1.58–1.71, 2.68–2.76, 3.06–3.19, 3.41–3.51, 3.65–3.75, 4.32–4.36, 5.52–5.54, 5.71–5.76, 7.23–7.52; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:6]=1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(NS(C)(=O)=O)cc1
Solvent: O
Product: CCOC(=O)c1ccc(NS(C)(=O)=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Ethyl 4-[(methylsulfonyl)amino]benzoate (Lumma, W. C. et al. J. Med. Chem. 1987, 30, 758-763) (2.0 g, 0.0082 mol) was added portionwise to fuming nitric acid (10 mL) at 5°-10° C. over 0.25 h. The mixture was further stirred for 0.5 h at 10°-15° C. and then poured into cold water (50 mL). The yellow precipitate was separated by filtration and washed several times with cold water. The cake was recrystallized from ethyl acetate to give 1.7 g (72%) of ethyl 3-nitro-4-[(methylsulfonyl)amino]benzoate as yellow crystals, mp 124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12].CO>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:14]([CH:11]([CH3:13])[CH3:12])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)N1CCc2cc(Br)ccc21
Temperature: 100 °C
Yield: 32.9 %

Procedure:
5-Bromoindoline (0.59 g, 3 mmol) was dissolved in isopropylsulfonyl chloride (1.08 g, 7.5 mmol) and heated to 100° C. for 3 hours. The mixture was cooled and treated with methanol (10 mL) then diluted with ethyl acetate. The mixture was washed with NaHCO3, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-30% ethyl acetate in hexane) afforded 5-bromo-1-(isopropylsulfonyl)indoline (0.3 g) as a white solid. MS (EI) m/z 303.7; HPLC purity 95.8% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.OS([O-])(=O)=O.[K+]>>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: C1CNCCN1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: O=C(O)c1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 96.8 %

Procedure:
5-Chloro-2-nitro-benzoic acid (44 g) and piperizine (90 g, 4.8 eq.) were mixed without solvent and heated at 110° C. for 6 hours and then stirred at room temperature over night. At this time, the mixture had solidified. To this solid was added 10% KHSO4 (wt/vol, pH 4 to 5) aqueous solution and the mixture was sonicated. The supernatant was decanted and fresh 10% KHSO4 (wt/vol) aqueous solution was added. A total of 1.8 liters of 10% KHSO4 (wt/vol) aqueous solution was added and decanted in this manner. After stirring at room temperature, the solid was filtered and rinsed with water. The remaining solid was dried in a vacuum oven, leaving a yellow-orange solid (53.1 g). This material was carried forward to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH2:35]O)=[C:32]([CH3:34])[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][C:31]2[S:30][C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:24][CH:25]=3)=[N:33][C:32]=2[CH3:34])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(C)(C)C)cc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with [2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-yl]-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)=[O:40].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:53]([C:50]1[CH:51]=[CH:52][C:47]([CH:44]3[CH2:45][CH2:46][N:41]([C:39](=[O:40])[C:38]([F:58])([F:37])[F:57])[CH2:42][CH2:43]3)=[CH:48][CH:49]=1)(=[O:54])=[O:55])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 77.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethy)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.51 mmol), 4-[1-(2,2,2-trifluoroacetyl)-4-pipendinyl]benzenesulfonyl chloride (preparation 20) (157 mg, 0.48 mmol) and triethylamine (155 mg, 1.53 mmol) in tetrahydrofuran (25 ml). This gave the title compound as a solid (300 mg). MS: 811 (MH+)
Reaction SMILES: [CH3:1][N:2]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:19])[CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O.O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=[C:45]=[O:46])[CH:41]=[CH:42][CH:43]=1>>[CH3:1][N:2]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:19])[CH2:7][NH:8][C:45]([NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=1)=[O:46]
Reactant: Cc1ccc(N(C)C(=O)CN(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc2)cc1
Reactant: Cc1cccc(N=C=O)c1
Agent: NN
Solvent: O
Product: Cc1ccc(N(C)C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 69.9 %

Procedure:
The procedure is analogous to that described in Example 23, but 1.6 g of N-methyl-N-(4-methylphenyl)-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.36 g of hydrazine hydrate and 0.3 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 80 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride], collecting 20 cm3 fractions. Fractions 10 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a mixture of ethyl acetate and diethyl ether (40-60 by volume), 0.7 g of N-methyl-N-(4-methylphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 162° C. is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[N:7][C:6]=1[CH3:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COCCc1scnc1C
Product: COCCc1sc(C(=O)C(F)(F)F)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl trifluoroacetate, following the procedure of Preparation 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:12][CH:11]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccn3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 mg (1.41 mmol) of [4-(2-pyridyl)phenyl]acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene, and the solvent is again removed in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol and then filtered off, and the filtrate is back-extracted with 20 ml of dichloromethane. Solid and dichloromethane phase are combined, and the solvent is removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2B (3.637 g, 13.3 mmol) in methanol was added dropwise at 0° C. a solution of NaBH4 added to 3.9 g NaOH dissolved in 7.8 mL H2O. The solution was allowed to stir at room temperature overnight. Water was added and the product was extracted with ether (2×) and washed with brine (2×). The combined ether extracts were dried over MgSO4. The solvent was removed and the product was purified using flash chromatography with a hexanes and then ethyl acetate. The ethyl acetate fraction was collected and the solvent removed to reveal 2.667 g (74%) of a honey yellow crystal solid. 1H NMR (CDCl3): δ4.63 (d, 2H), δ6.97–7.06 (m, 6H), δ7.09 (m, 2H), δ7.20–7.28 (m, 6H); m/z 298.1 (M++Na), 276.1 (M++H), 258.1 (M+−H2O).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:18][C:19]=1[CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:18][C:19]=1[CH2:20][CH2:21][O:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][NH:6]2)=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: CCCc1c[nH]c2cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c[nH]c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
In analogy to the procedure described in example 3 c], 3-propyl-1H-indol-6-ol was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield 6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-1H-indole as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(O)cc1
Solvent: ClCCl
Product: COc1ccc(O)c([N+](=O)[O-])c1
Yield: 58 %

Procedure:
To a stirred solution of 124 mg of 4-methoxyphenol in dichloromethane were added 1 g of silica gel and 0.077 ml of concentrated nitric acid at room temperature. After the completion of the reaction was detected by thin layer chromatography, the reaction mixture was filtered using Cerite. The filtrate was evaporated, and the residue was purified by silica gel chromatography (dichloromethane) to give 98.5 mg (58%) of 4-methoxy-2-nitrophenol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:20][O:19][CH2:18]2)[CH2:13][CH2:12]1)([O-])=O.CCOC(C)=O>CO.[Ni]>[O:19]1[CH2:20][CH:17]([N:14]2[CH2:13][CH2:12][N:11]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH2:16][CH2:15]2)[CH2:18]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCN(C2COC2)CC1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccncc1N1CCN(C2COC2)CC1
Yield: 99.9 %

Procedure:
1-(4-nitro-1-oxido-pyridin-1-ium-3-yl)-4-(oxetan-3-yl)piperazine (553 mg, 1.973 mmol) in MeOH (15 mL)/EtOAc (25 mL) was passed through the H-cube apparatus to hydrogenate over raney nickel at 20° C. and full H2 mode, flow rate 1 ml/min. The solvent was removed in vacuo to give the title compound 7l as an orange solid (462 mg, 100% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[NH:14][C:13](=O)[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:17][NH2:18]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[CH2:10][O:11][CH2:12][C:13]([CH2:17][NH2:18])=[N:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)COCC(=O)N2)cc1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(C)COCC(CN)=N2)cc1
Temperature: 0 °C

Procedure:
A solution of 69.5 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-one in 200 ml of tetrahydrofuran and 25 ml of benzene is cooled to 0° C. and saturated with methylamine. A solution of 19 g of titanium tetrachloride in 25 ml of benzene is added dropwise over the course of 15 minutes. After addition is complete, the reaction mixture is heated to reflux for 3 hours. The reaction mixture is then cooled to 0° C. and cautiously quenched with 60 ml of water. It is filtered through Hyflo, and the filter cake is washed several times with tetrahydrofuran. The phases of the filtrate are separated, and the organic phase is dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(C)=O)cc1
Temperature: 60 °C
Yield: 86.3 %

Procedure:
To a solution of the 4-hydroxyacetophenone (1.0 g, 7.3 mmol) in 5 mL DMF under Ar was added K2CO3 (1.0 g, 7.3 mmol) and 1-bromopentane (1.1 mL, 8.7 mmol) and heated at 60° C. overnight. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated to afford a residue which upon purification by combiflash, eluting with 5% EtOAc in Hexane afforded 1.3 g product (86%). 1H NMR (500 MHz, CDCl3): δ 0.98 (t, 3H, J=7.0 Hz), 1.41-1.49 (m, 4H), 1.83-1.86 (m, 2H), 2.59 (s, 3H), 4.09 (t, 2H, J=6.5 Hz), 6.98 (d, 2H, J=7.0 Hz), 7.98 (d, 2H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1cc(S(=O)(=O)Cl)c([N+](=O)[O-])cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])cc1F
Yield: 29.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-fluoro-5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 452) (1.6 g, 6.3 mmol), 8-aminoquinoline (700 mg, 4.86 mmol), DMAP (cat.), pyridine (5 ml) and DCM (5 ml) gave the title compound (520 mg, 52%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]=[O:17]>[OH-]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Reactant: C=O
Agent: [OH-]
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethylquinoline (30.0 g.), 40% aqueous formaldehyde solution (36 ml.) and 1 M aqueous solution hydroxide solution (250 ml.) was stirred at 40°-50° for 8 hours. The solid product was collected and dried to give the novel 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline, m.p. 302-304°.