Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Fc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cc(F)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 79.6 %

Procedure:
2-(3-Fluoro-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (469 mg, 1.33 mmol) and phenyl pyridin-3-ylcarbamate (273 mg, 1.33 mmol) were dissolved in DMSO (4 mL) and triethylamine (0.53 mL, 3.83 mmol) was added. The reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (35% acetone in hexane) to give the title compound (500 mg, 80%). 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H), 8.45 (s, 1H), 8.27 (d, J=4.5 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.82 (m, 3H), 6.71 (s, 1H), 6.37 (s, 1H), 3.64 (t, J=5.5 Hz, 2H), 3.56 (t, J=5.5 Hz, 2H), 2.63 (m, 2H), 2.49 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 165.15, 163.96, 161.99, 154.67, 153.88, 153.79, 145.40, 143.56, 141.00, 140.15, 140.07, 139.38, 136.97, 136.44, 127.78, 124.64, 123.69, 122.49, 122.23, 121.97, 117.60, 112.87, 112.70, 111.71, 107.56, 107.37, 45.59, 44.54, 35.70, 29.18; m/z (473.4 M+ H+); HPLC: 96.6%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1.Br[CH:18]([CH2:26][CH3:27])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[O:16][CH:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:26][CH3:27])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CSCCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(O/N=C(\C(=O)OCCSC)c1csc(N)n1)C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A mixture of 10 g of 2-methylthioethyl 2-(2-aminothiazol-4-yl)-2(Z)-hydroxyiminoacetate, 10 g of tertbutyl 2-bromobutyrate and 7 g of anhydrous potassium carbonate in 250 ml of acetone is kept at 60°-70° C. for 20 hours with stirring. Insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and the solution is washed with water, then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then evaporated off to give the above-identified compound as a viscous liquid, which, upon standing, solidifies. Yield: 12.6 g.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:44]=[CH:43][C:33]([NH:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:32][C:30]3=[O:31])[C@@H:26]([F:45])[C@@H:25]2[OH:46])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:49](O[C@@H]1[C@@H](CO)O[C@@H](N2C=CC(NC(=O)C3C=CC=CC=3)=NC2=O)C1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Si:49]([O:46][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:44]=[CH:43][C:33]([NH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:32][C:30]2=[O:31])[C@H:26]1[F:45])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H](F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO

Procedure:
This compound is prepared from 1-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N4 -benzoylcytosine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N4 -benzoyl-2'-deoxycytidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([N:14]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:11][CH2:10][C@H:9]1[C:35]1[N:39]=[CH:38][O:37][N:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].SCC(O)=O.O[Li].O.CCOC(C)=O>CN(C=O)C>[CH2:28]([O:27][NH:14][C@H:12]1[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:35]2[N:39]=[CH:38][O:37][N:36]=2)[CH2:10][CH2:11]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncon1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncon1
Temperature: 30 °C
Reaction time: 17 h
Yield: 69.7 %

Procedure:
A mixture of (2S,5R)-tert-butyl5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.5 g, 2.683 mmol), HSCH2COOH (1.48 g, 16.1 mmol), LiOH.H2O (1.13 g, 26.83 mmol) in DMF (50 mL) was stirred at 30° C. for 17 hrs. EtOAc (150 mL) was then added and the mixture was washed with water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜50% petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (700 mg, 63%) as a pale yellow solid. ESI-MS (EI+, m/z): 375.0 [M+H]+.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrBr.[OH-].[Na+]>>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC#CCCCCCCCCO
Temperature: 15 °C
Yield: 81.1 %

Procedure:
Oleyl alcohol (9.80 g, 36.5 mmoles, Sigma) was placed in a 25 ml 3-neck roundbottom flask equipped with a thermometer, an overhead mechanical stirrer, and a reflux condenser. The contents of the flask were cooled to 15° C. and bromine (5.83 g, 36.5 mmole) was added slowly with stirring at such a rate as to keep the reaction temperature below 30° C. After addition of the bromine, the reaction was stirred at room temperature for 10 minutes. Polyethylene glycol 300 (1.0 g, Fluka) was added followed by powdered sodium hydroxide (3.65 g, 91.3 mmoles). A large exotherm was noted which brought the reaction temperature to 150° C. The reaction was stirred vigorously with heating to maintain a temperature of 125° C. for 2.5 hours. The reaction was cooled and filtered to remove the solid sodium bromide. The filtered salts were washed with 25 ml of hexanes and the solvent removed. The crude product was kugelrohr distilled (ca. 200° C./ 0.20 torr) to yield 9-octadecyn-l-ol (7.89 g, 81% yield) as a clear colorless liquid which solidified upon standing. 1H NMR (CDCl3): 3.61 (q, 2H), 2.12 (m, 4H), 1.02-1.87 (m, 25H), 0.88 (t, 3H) 13C NMR(CDCl3): 79.94, 79.84, 62.33, 32.48, 31.65, 29.19, 29.04, 28.96, 28.66, 28.61, 25.58, 22.45, 18.52, 13.84.
Reaction SMILES: [NH2:1][C@@:2]1([C:22]#[N:23])[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][C@@H:5]2[C@H:3]1[C@@:4]2([F:21])[C:18](N)=[O:19].C(O)(=[O:26])C.Cl>O>[NH2:1][C@@:2]1([C:22]#[N:23])[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][C@@H:5]2[C@H:3]1[C@@:4]2([F:21])[C:18]([OH:26])=[O:19]
Reactant: CC(=O)O
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Agent: Cl
Solvent: O
Product: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 75 °C

Procedure:
A mixture containing 22.5 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 0.1 mL of acetic acid, 0.1 mL of water, and 0.2 mL of concentrated hydrochloric acid was stirred for 6 hrs approximately under heating at 75° C. (external temperature). The reaction mixture was concentrated under reduced pressure to obtain 24.6 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid (6f) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[CH2:11][N:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].COC1N=CN=CC=1.Cl[C:66]1[CH:71]=[C:70]([O:72][CH3:73])[N:69]=[C:68]([S:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([F:82])[C:77]=2[F:83])[N:67]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:83][C:77]1[C:78]([F:82])=[CH:79][CH:80]=[CH:81][C:76]=1[CH2:75][S:74][C:68]1[N:67]=[C:66]([NH:15][S:12]([N:10]2[CH2:11][CH:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]2)(=[O:13])=[O:14])[CH:71]=[C:70]([O:72][CH3:73])[N:69]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)NC1CN(S(N)(=O)=O)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: COc1ccncn1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CC(NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl[1-(aminosulfonyl)azetidin-3-yl]carbamate (0.50 g), tris(dibenzylideneacetone)-dipalladium (0) (0.12 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (63 mg), cesium carbonate (0.65 g) and 4-chloro-2-[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.400 g) in anhydrous dioxane (17 ml) was heated to reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 3:7 mixture of EtOAc and iso-hexane as eluent to give the subtitle compound as a yellow oil. Yield: 0.48 g
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Reaction time: 72 h
Yield: 20.5 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO was added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 4-fluorophenylboronic acid (0.60 g, 4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture was stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture was concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 0.28 g of 1-(4-Fluoro-phenyl)-5-(5-nitro-pyridin-2-yloxy)-1H-indazole as a colorless syrup. 1H NMR (CD3OD, 400 MHz): δ 8.17 (s, 1H), 7.7-7.8 (m, 3H), 7.61 (d, 1H, J=2.8 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.30 (m, 2H), 7.22 (m, 2H), 6.77 (1H, d, J=8.8 Hz) ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)([O-:21])=[O:20].[BH4-].[Na+]>CO>[C:13]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]2[CH2:5][CH:2]([NH:1][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[N+:19]([O-:21])=[O:20])[CH2:3]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccccc1CNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 45.0 g (0.189 mol) of 3-amino-1-(diphenylmethyl)-azetidine, 28.7 g (0.190 mol) of 2-nitrobenzaldehyde and 280 ml of methanol was stirred for 3 hours at ambient temperature. Then 7.4 g (0.196 mol) of sodium borohydride were added followed, after a further 2 hours, by another 6.0 g of sodium borohydride and 300 ml of methanol and after a further 16 hours by 4.0 g of sodium borohydride, and the mixture was stirred for a further 4 hours at ambient temperature. The mixture was concentrated by evaporation in vacuo and the residue was treated with 200 ml dichloromethane and 200 ml of water. It was filtered, the methylene chloride phase was dried over sodium sulphate and freed from solvent. The residue was purified by chromatography on silica gel (30–60 μm) using dichloromethane/EE/MeOH/cyclohexane/conc. ammonia (59/25/7.5/7.5/1 v/v/v/v/v) as eluant, then on silica gel using dichloromethane/EE (1/1 v/v) as eluant. After the appropriate fractions had been worked up, 20.0 g (28% of theoretical) of the desired compound were obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[OH:19].[O:20]1[CH2:25][CH2:24][N:23]([CH:26](Cl)[CH3:27])[CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[O:19][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: CC(Cl)N1CCOCC1
Reactant: Cc1ccc2oc(=O)c(-c3ccccc3)c(O)c2c1
Product: Cc1ccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c2c1
Yield: 77 %

Procedure:
This compound is prepared as described in Example 8 from 19.4 g. (0.077 mol) of 6-methyl-4-hydroxy-3-phenyl-coumarin and 16.1 g. (0.1 mol) of 2-morpholino-2-chlorethane. Weight 21.7 g.; yield 77% (theoretical yield 28.2 g.). M.P. 96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>>[Cl:10][C:11]1[CH:18]=[C:17]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COc1ccccc1S
Product: COc1ccccc1Sc1ccc(C=O)c(Cl)c1

Procedure:
The target product (5.50 g) was obtained as a colorless oil by reacting 2-methoxybenzenethiol (2.80 g) and 2-chloro-4-fluorobenzaldehyde (3.17 g) based on the same experiment operations as in Reference Example 1 of WO 03029205 pamphlet.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(F)(F)F)nc1
Reaction time: 72 h
Yield: 93 %

Procedure:
5-Nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (20.5 g, obtained in example 108, step 1) was dissolved in methanol (160 mL). Palladium on activated charcoal (1.96 g, 10% Pd) was added and an atmosphere of hydrogen was introduced at RT. The mixture was stirred under hydrogen for 72 hours. The reaction mixture was filtered over dicalite speed plus (Acros Organics), washed with ethyl acetate and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a brown liquid (16.49 g, 91%). MS (m/e): 193.1 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 400 mg (1.22 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 290 mg (1.22 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 4 ml DMF was added 90 mg (2.06 mmol) of sodium hydride (55% in oil). The reaction mixture was stirred for 2 h at RT, taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 347 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: N#Cc1cccc(N)c1
Agent: Br
Product: CC(Nc1cccc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 49.3 %

Procedure:
3-aminobenzonitrile (96 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyanophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (44 mg, 48%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:38][CH3:39])=[C:16]([CH:37]=2)[CH2:17][S:18][C:19]2[N:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:22]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=3[N:20]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.ClCCl>>[N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:38][CH3:39])=[C:16]([CH:37]=2)[CH2:17][S:18][C:19]2[N:23]([CH2:24][C:25]([OH:27])=[O:26])[C:22]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=3[N:20]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)N2CCc3ccccc32)cc1CSc1nc2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N2CCc3ccccc32)cc1CSc1nc2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
tert-Butyl {2-[5-(2,3-dihydro-indole-1-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro-benzoimidazol-1-yl}-acetate (Precursor 5-F-H-17b, 26 mg, 0.047 mmol) in a TFA/dichloromethane mixture (1:1, 0.5 ml) is allowed to stir at rt for 4 h. The solvents are removed under a stream of air. The product is precipitated in Et2O, filtered, rinsed with Et2O and dried under high vacuum. This yields the title compound (22 mg) in 99% as a light pink solid: tR=1.04 min (LC-3), ESI-MS (pos.): m/z 492.11 [M+H]+, ESI-MS (neg.): m/z 490.18 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.88 (t, 2H, NCH2CH2Ar), 3.85 (t, 2H, NCH2CH2Ar), 3.89 (s, 3H, OCH3), 4.54 (s, 2H, SCH2), 4.95 (s, 2H, CH2CO2), 6.97 (t, 1Harom), 7.02-7.09 (m, 4Harom), 7.11 (d, 1Harom), 7.21 (d, 1Harom), 7.38-7.57 (m, 3Harom).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[O:19])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH3:33][C:34]([CH3:41])([CH2:38][CH2:39][CH3:40])[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][C:34]([CH3:41])([CH2:38][CH2:39][CH3:40])[C:35]([N:30]1[CH2:31][CH2:32][N:27]([CH:24]2[NH:23][CH2:22][CH:21]([NH:20][C:18]([NH:17][C:7]3[N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)[N:9]=[C:5]([C:2]4([CH3:1])[CH2:3][CH2:4]4)[CH:6]=3)=[O:19])[CH2:26][CH2:25]2)[CH2:28][CH2:29]1)=[O:36]
Reactant: CCCC(C)(C)C(=O)O
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(C)C(=O)N1CCN(C2CCC(NC(=O)Nc3cc(C4(C)CC4)nn3-c3ccc(C)cc3)CN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Treat a solution or slurry of the 1-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (Preparation 5, 1 equiv., 0.1510 g), 2,2-dimethyl pentanoic acid (1.15 equiv., 0.0521 g) and catalytic DMAP (ca. 0.1 equiv., 0.049 g) in dichloromethane (ca. 0.1 M, 5 mL) with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC1.15 equiv., 0.0767 g). Agitate the resulting mixture at ambient temperature for 48 hours then wash with saturated aq. sodium bicarbonate solution. Dry the organic layer over sodium sulfate and concentrate under reduced pressure. Purification A: Purify on silica gel using a gradient 2 M ammonia-methanol in dichloromethane, a gradient of ethyl acetate in dichloromethane or hexanes. Purification B: Purify by reverse phase on an Xterra 30×75 mm 5 micron MS C18 column using a gradient of aqueous 10 mM ammonium bicarbonate in acetonitrile affords the title compound. LCMS(ES+): m/z=544. [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26].Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[OH:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:26])[C:19]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1cccc(O)c1N
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3c(C)cccc3O)c2cc1OC
Yield: 64.5 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.123 g of 2-amino-m-cresol, 20 mg of pyridine hydrochloride, and 1 0 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.216 g of 4-(2-hydroxy-6-methyl-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 245-247° C.; mass spectrum (electrospray, m/e): M+H 336.1363.