Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[C:33](=[C:34]([CH:38]=O)[CH:35]=[CH:36][CH:37]=3)[N:29]2[CH2:28][CH2:27][CH2:26]1>O1CCCC1.O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](/[CH:38]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:33]=3[N:29]2[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% in oil, 230 mg, 5.76 mmol) was added to a stirred solution of ethyl (diethoxyphosphoryl)acetate (1.94 g, 8.67 mmol) in tetrahydrofuran (14 mL) at 0° C. After stirring 10 min, 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.88 mmol) in tetrahydrofuran (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (908 mg, 2.18 mmol, 76%).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Yield: 61 %

Procedure:
11.2 g of 60% oily sodium hydride was suspended in 200 ml of dimethylformamide, and a solution of 56.0 g of 4-phenoxyphenylacetone in 100 ml of dimethylformamide, was added under cooling with ice with stirring, followed by stirring at the same temperature for 5 minutes and at room temperature for 30 minutes. Then, the reaction solution was again cooled with ice, and 52.0 g of phenethyl bromide was added. The reaction solution was gradually returned to room temperature and then stirred for 30 minutes, and water was added to the reaction solution, followed by extraction with ethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 50.6 g (yield: 61%) of the above identified compound as a pale yellow oily substance.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[C:26]5[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=5)[N:20]=[CH:19][CH:18]=4)=[CH:15][C:10]=3[O:9][C:8]=2[CH3:28])=[O:6])[CH2:3][CH2:2]1.[Br:29][CH2:30][CH2:31]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:29][CH2:30][CH2:31][O:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:14]3[CH:13]=[CH:12][C:11]4[C:7]([C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[C:8]([CH3:28])[O:9][C:10]=4[CH:15]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)NC1CC1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc2c1C(=O)NC1CC1
Yield: 61.8 %

Procedure:
A solution of 90-G (1.4 g, 3.7 mmol), Br(CH2)2Br 90-H (2.1 g, 11.2 mmol) and K2CO3 (1.5 g, 11.2 mmol) in DMF (40 ml) was heated to 50° C. overnight. The reaction mixture was extracted with EtOAc. The concentrated residue was purified by silica gel column chromatography using 5% MeOH/CH2Cl2 to yield 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-N-cyclopropyl-2-methyl-1-benzofuran-3-carboxamide 90-1 (1.1 g, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Cl:14][C:15]1[C:16]([CH3:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O.O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([CH3:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:5]=[C:4]([CH3:3])[C:12]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 58.6 %

Procedure:
At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to a suspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 25 minutes during which time the suspension became a nearly clear solution. To the resultant mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.35 g, 3.61 mmol, from Example 1, step 5) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 1.03 g (59%) of the desired product as a yellow gum. The racemic products were applied on a Phenomenex Lux-Cellulose 2 column (21.1×250 mm, 5 micron particle size), eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 4 mg/injection, to provide two enantiomers. The retention time of the first peak was 8.34 min and the retention time for the second peak was 10.92 min. Peak 1 (463 mg), LCMS calculated for C24H32ClN6O3 (M+H)+: m/z=487.2; Found: 487.1. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.37 (s, 1H), 6.30, (q, 1H), 5.40 (s, 2H), 4.23 (m, 2H), 4.17-4.00 (m, 3H), 3.57 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.76 (d, 3H), 1.37 (s, 9H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C:7]2[N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]=[CH:13][C:6]1=2)=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:32][C:33]1[NH:37][N:36]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:34]=1>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:7]3[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:37]4[C:33]([CH3:32])=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36]4)[C:6]=3[CH:13]=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 75 °C
Yield: 66.9 %

Procedure:
2-Chloro-1-(1-(4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (118 mg, 0.4 mmol) was diluted in 1.2 mL of 2:1 THF:DMF and treated with K2CO3 (111 mg, 0.8 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole (60 mg, 0.4 mmol). The slurry was heated to 75° C. for 2 hours. The reaction slurry was purified by normal phase flash chromatography (24 g column, eluting with 10-80% EtOAc in hexanes) to provide 109 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 0.8H), 7.59 (s, 0.2H), 7.42-7.47 (m, 2H), 7.12-7.25 (m, 2H), 5.25 (s, 0.4H), 5.14 (s, 1.6H), 3.92 (m, 0.4H), 3.86 (m, 1.6H), 2.86 (t, J=6.2 Hz, 2H), 2.37 (s, 2.4H), 2.36 (m, 0.6H), 2.11 (m, 1.6H), 2.04 (m, 0.4H); MS: (ES) m/z calculated for C19H18F4N5O [M+H]+ 408.1, found 408.1.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(OCC)C>C(N(CC)CC)C>[F:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzaldehyde (6 g) in triethylamine (60 ml) was added trimethylsilylacetylene (4.6 ml), bis-triphenylphosphinepalladium dichloride (331 mg) and cuprous iodide (130 mg). The resulting mixture was allowed to stir overnight at room temperature under a nitrogen atmosphere. After this time, diethyl ether was added and the mixture was filtered. The filtrate was washed with water and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. The resulting oil was crystallised from cold hexane to give 3-fluoro-4-trimethylsilylethynylbenzaldehyde as a light brown solid (4 g).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:38]([C:36]2[N:37]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[S:34][CH:35]=2)=[O:39])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: O=C(O)c1csc(-c2ccccc2F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-fluorophenyl)thiazole-4-carboxylic acid (see Bioorg. Med. Chem. Lett. 2010, 20, 1758) gave 318. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.53 (s, 1H), 8.35-8.28 (m, 1H), 7.81 (s, 1H), 7.66-7.58 (m, 1H), 7.53-7.41 (m, 2H), 5.02-4.81 (m, 2H), 4.24-4.09 (m, 1H), 4.09-3.92 (m, 1H), 3.77 (s, 3H), 2.20-2.09 (m, 1H), 2.07-1.92 (m, 1H), 1.87-1.74 (m, 2H), 1.66 (d, J=13.1 Hz, 1H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [CH:1]1([NH:5][CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[CH:39][CH:38]=3)[C:28](=[O:36])[C:29]3[CH:35]=[CH:34][CH:33]=[N:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[C:49](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH:1]1([N:5]([CH3:49])[CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=3)[C:28](=[O:36])[C:29]3[CH:35]=[CH:34][CH:33]=[N:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:21])([F:20])[F:22])[CH:13]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)NC3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)N(C)C3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1

Procedure:
E4 (31 mg, 0.048 mmol), formaldehyde (37% in water, 5.4 μL, 0.073 mmol), and sodium triacetoxyborohydride (31 mg, 0.15 mmol) was stirred in dichloroethane at room temperature for 45 min. The reaction mixture was diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. 33 mg of E5 was recovered.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3nccs3)c(=O)n12
Temperature: 120 °C
Yield: 71.7 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol), and 2-(tributylstannyl)-1,3-thiazole (143 mg, 0.382 mmol) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The reaction mixture was heated at 120° C. overnight. After cooling to room temperature, the mixture concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (73 mg, 72%). LCMS calculated for C12H11N6OS2 (M+H)+: m/z=319.0. Found: 319.0.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11]/[C:12](=[CH:22]\[F:23])/[CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.[ClH:34]>C(Cl)Cl>[ClH:34].[NH2:14][CH2:13]/[C:12](=[CH:22]/[F:23])/[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:1])[CH3:26])(=[O:5])=[O:4])=[CH:25][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccc(OC/C(=C\F)CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc(OC/C(=C\F)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirring solution of (Z)-tert-butyl 2-((4-(N,N-dimethylsulfamoyl)phenoxy)methyl)-3-fluoroallylcarbamate (279.0 mg, 0.72 mmol) in CH2Cl2 (4.0 mL) at room temperature was added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at room temperature for 30 min. All volatiles were removed in vacuo and the residue was co-evaporated with CH2Cl2 (2×20 mL). The resulting oil was taken up in ethyl acetate/MeOH (5:1; 3.0 mL) and then ethereal HCl (2.0 M in diethyl ether; 0.5 mL, 1.0 mmol) was added. The precipitate formed was isolated and dried under reduced pressure to afford (Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)-N,N-dimethylbenzenesulfonamide hydrochloride (196.0 mg, 84%) as a white solid; m.p. 185-187° C.; 1H-NMR (300 MHz; d6-DMSO) δ ppm: 3.39 (6H, br s), 3.54 (2H, br s), 4.81 (2H, d, J 2.3 Hz), 7.16 (2H, d, J 9.0 Hz), 7.24 (1H, d, J 82.3 Hz), 7.25 (2H, br s), 7.77 (2H, d, J 9.0 Hz).
Reaction SMILES: [CH3:1][CH:2]([OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10])=[O:11]
Reactant: CC(O)c1cccc(Cl)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC(=O)c1cccc(Cl)c1Cl
Temperature: 20 °C
Yield: 65.1 %

Procedure:
α-Methyl-2,3-dichlorobenzyl alcohol (5.0 g, 0.026 mol) was dissolved in acetic acid (24 ml) and 12% w/v sodium hypochlorite solution (23.26 ml, 0.0314 mol) was added slowly dropwise, with stirring, at a temperature of 15-25° C. When the addition was complete the reaction mixture was stirred at ambient temperature for approximately 1% hours until a starch/iodide test gave a positive result. Saturated sodium bisulphite solution was added to the reaction mixture until the starch/iodide test was negative. The mixture was poured onto ice/brine (100 ml) and extracted with diethyl ether (3×75 ml). The ether phases were combined and washed with 2N sodium hydroxide solution (3×75 ml) until the aqueous washes were alkaline. The ether phase was dried over anhydrous magnesium sulphate, filtered and evaporated down. 2,3-Dichloroacetophenone (3.2 g, 65% yield) was afforded as a pale-yellow oil. T.l.c. (SiO2 ;CHCl3) and nmr showed this material to contain no impurities.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([F:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[O:20][Si](CC)(CC)CC.[ClH:40].O1CCOCC1>O1CCCC1>[ClH:40].[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([F:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=1)[OH:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CNCCOc1ccc2c(c1)[nH]c1ccccc12)c1ccc(F)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 102 (243 mg) was dissolved in anhydrous tetrahydrofuran (15 ml), whereto 4 N hydrogenchloride/1,4-dioxane (1 ml) was added and the mixture was agitated at room temperature for 1 hour. The deposited precipitate was taken out and washed with tetrahydrofuran, whereupon it was dried under a reduced pressure at 40° C., whereby the above-identified compound was obtained (96.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C=CC#N
Solvent: CO
Product: COc1ccc(CCNCCC#N)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
54.5 gm of 2-(3,4-dimethoxy-phenyl)-ethylamine were dissolved in 100 ml of methanol, a solution of 16.2 gm of acrylonitrile in 50 ml of methanol was added dropwise at 50° C, and the mixture was stirred for 1 hour at 50° C. After evaporation of the methanol, the raw reaction product thus obtained was used without further purification in the next step.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1>CCOCC>[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: CN1CCCc2ccccc21
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Product: CN1CCCc2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
A solution of H2SO4 (6 g, 60.00 mmol) in ether (40 mL) was added dropwise to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (9 g, 61.14 mmol) in diethylether (10 mL) at 5° C. The resulting solution was maintained at room temperature for 30 minutes, then under vacuum, with stirring, for an additional 3 hours at 170° C. The resulting mixture was washed with methanol (1×100 mL) and filtered to afford 5 g (34%) of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:19])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: ONC1CCCCC1
Product: CCOc1ccccc1C=[N+]([O-])C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 89% yield as a solid. m.p. 54.8° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]([OH:57])=O.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][N:7]([CH3:8])[C:55](=[O:57])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH2:2][CH2:3]1
Reactant: COCCOCC(=O)O
Reactant: CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1

Procedure:
A mixture of 194 mg of methyl 4-[2-(4-{[(2-{[3-({cyclopropyl[2-(methylamino)ethyl]amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.050 mL of (2-methoxyethoxy)acetic acid, 84 mg of WSC.hydrochloride, and 5.0 mL of DMF was stirred for 15 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 200 mg of methyl 4-[2-(4-{[(2-{[3-(11-cyclopropyl-8-methyl-7-oxo-2,5-dioxa-8,11-diazadodecan-12-yl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 5 e]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:28])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[H-].C([Al+]CC(C)C)C(C)C.C1COCC1>CO>[F:28][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C

Procedure:
100 mg (0.26 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine and 1.28 ml (1.0M in THF, 1.28 mmol) of diisobutylaluminium hydride/THF solution are stirred for 1 h at -20°. After the addition of 2 ml of methanol, the reaction mixture is heated to RT and the reaction product is isolated by filtration. After concentration under reduced pressure using a rotovapor and chromatography [methylene chloride:methanol:ammonia (conc.)=95:5:]N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-aminomethyl-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 64°-67°, FAB-MS: 394 (M+ +H).