Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([CH2:17][CH:18]=O)[C:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH3:8])[CH3:7])C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:6]([CH:5]1[CH2:17][CH2:18][N:21]([C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:4]1=[O:20])([CH3:7])[CH3:8]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C(CC=O)C(C)(C)c1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(c1ccc(Cl)cc1Cl)C1CCN([C@H]2CC[C@H](O)CC2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-(2,4-Dichloro-phenyl)-3-methyl-2-(2-oxo-ethyl)-butyric acid ethyl ester (Preparation 61) in THF and treat with trans-4-Amino-cyclohexan-1-ol (2.0 eq), acetic acid (6.0 eq) and NaBH(OAc)3 (4.0 eq). Allow reaction to stir at room temperature for 17 h and heat to 60° C. for six hours. Cool to room temperature, filter, dilute filtrate with EtOAc, wash with 0.1 N HCl, brine, dry over sodium sulfate and filter. Chromatography (silica, 1:1 to 3:7 hexanes/EtoAc) yields the titled compound in 53% yield: Mass spectrum (API-ES positive) m/z=372.0 (M+H).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[F:32][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: Fc1cc(F)cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]nc(CCc2cc(F)cc(F)c2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 10% palladium-carbon (280 mg), ethanol (25 mL) and 3,4-bis(benzyloxy)-6-[(E)-2-(3,5-difluorophenyl)vinyl]pyridazine (710 mg) was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added diethyl ether and the obtained solid was dried under reduced pressure to give 6-[2-(3,5-difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one (140 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[CH3:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: O
Product: Cc1cccc2c(=O)[nH]cnc12

Procedure:
6 g of 2-amino 3 methyl benzoic acid and 8 ml formamide were heated at 170° C. for 1.5 hours. Water was added and solid filtered to provide 4.6 g of 8-methyl 4-quinazolinone as a white solid, mp-260° C. NMR acetone d6 δ 8.14 (1H, br, S), 8.06 (1H, m), 7.66 (1H, m), 7.38 (1H, m), 2.58 (3H, S).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=S)[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1.[OH2:29].CI>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:29])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:3]=1
Reactant: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=S)cc(C(=O)OCC)oc12
Reactant: O
Solvent: CC(C)=O
Solvent: CI
Product: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 6-chloro-8-methoxycarbonyl-10-propyl-4-thioxo-4H-pyrano[3,2-g]quinoline-2-carboxylate (0.030 g) in acetone (10 ml) containing water (0.2 ml) and methyliodide (0.1 ml) was stirred in the dark at room temperature for 2 days. Concentration of the reaction mixture gave a light buff solid, which was recrystallised from ethanol to give the title compound (0.015 g), mp 176°-179°.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[N:11]([C:29](=[O:30])[CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (106 mg, 335 μmol) in pyridine (3.35 ml) was added 2-(methylsulfonyl)acetic acid (50.9 mg, 369 μmol) followed by phosphoryl chloride (61.3 μl, 670 μmol), dropwise. The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (137 mg, 94%) as a white solid. MS m/z 459 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:34])=[CH:18][CH:17]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 298.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield 1-[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 1H NMR (400 MHz, CDCl3): 8.65 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) for C25H22N4O4S: 475 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]2[C@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[CH2:44][C@@H:43]([C:52](Cl)=[O:53])[O:42][C:39]2=[CH:40][CH:41]=1>>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:52]([C@@H:43]2[CH2:44][C@@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[C:38]3[C:39](=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=3)[O:42]2)=[O:53])[CH2:5][CH2:6]1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Reactant: NCCN1CCN(CC=Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(CC=Cc4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a chilled mixture (less than -5° C.) of 4-(2-aminoethyl)-1-cinnamylpiperazine (10.0 g, 40.8 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (6.20 g, 40.8 mmol) and N,N-dimethylformamide (55.0 ml, 710 mmol) was added over 30 minutes a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 11.1 g, 37.1 mmol) in N,N-dimethylformamide (100.1 ml, 1.29 mol). After stirring the mixture for 15 hours at 25° C., the solvent was evaporated. The residue was chromatographed on silica gel, eluted with a mixture of AcOEtAcOEt/MeOH (9:1), and evaporated in vacuo to dryness to give a colorless oil of the desired compound (17.5 g, 92.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])(O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2F)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.69 mmol) in DCM (20 mL) was cooled to −78° C. Diethylaminosulphur trifluoride (2 mmol) was added and the mixture stirred for 0.5 hour and allowed to warm to room temperature. The mixture was diluted with DCM and washed with water then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a brown oil which was used without further purification. LCMS m/z 298.3 [M+H]+. R.T.=4.97 min (Analytical Method 4).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:27][CH2:26][CH2:25][CH2:24][C:19]54OCC[O:20]5)[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCOCC1.Cl>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:27][CH2:26][CH2:25][CH2:24][C:19]4=[O:20])[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C2CCCCC23OCCO3)Nc2n[nH]cc2C1c1cccc2nonc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#CC1=C(C2CCCCC2=O)Nc2n[nH]cc2C1c1cccc2nonc12
Temperature: 60 °C
Yield: 2.2 %

Procedure:
To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in methanol (30 mL) was added 4N HCl dioxane solution (6.0 mL) at room temperature and the mixture was heated at 60° C. for two hours. After alkalification with sodium bicarbonate, the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (20 mg) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12](Cl)=[O:13])[CH:9]=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)=[O:13])[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1cncc(-n2cccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 65 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to 5.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours, 0.029 mL of triethylamine and 22 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. 0.58 g aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](O)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([Cl:24])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
23 g of 3-chloro-2-(4-chloro-3-hydroxycarbonylphenyl)-5-trifluoromethylpyridine in 23 ml of thionyl chloride were refluxed for 5 hours. The excess thionyl chloride was then removed by distillation. The remaining dark brown oil was used without further purification for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[O:15].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Yield: 34.1 %

Procedure:
6,7-Dimethoxy-1,4-dihydro-4-quinolinone (4.10 g, 20.0 mmol), 2-bromo-5-nitropyridine (4.46 g, 22.0 mmol) and potassium carbonate (5.53 g, 40.0 mmol) were heated and stirred at 70° C. for 3 hours in N,N-dimethylformamide (20 ml). The reaction solution was diluted with ethyl acetate, the insoluble portion was filtered off, and after washing with water and saturated brine and drying the organic layer over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent: ethyl acetate), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (2.23 g, 6.81 mmol, 34%) as yellow crystals.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.N.[F:10][C:11](I)([F:13])[F:12].C(OCC)C>O>[F:10][C:11]([F:13])([F:12])[S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: FC(F)(F)I
Agent: N
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(SC(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
p-Toluenethiol (8 g.) was added to liquid ammonia (60 ml.) at -30°. Trifluoromethyl iodide (18 g.) was added and the mixture was irradiated with uv light (297nm.) for 30 minutes. Dry diethyl ether (35 ml.) was added and irradiation was continued for 1 hour. The mixture was allowed to warm to 20° C. and water was added. The mixture was extracted with diethyl ether and the ethereal extracts were washed with sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Distillation gave 4-trifluoromethylthiotoluene as a mobile yellow-brown liquid (b.p. 78°-80° C., 16 mm.).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[N:12]2[N:13]=[C:14]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:15]=[C:11]2[C:10]([CH:23]=[O:24])=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:10]1[C:11]2[N:12]([N:13]=[C:14]([C:16]([F:22])([F:21])[C:17]([F:18])([F:19])[F:20])[CH:15]=2)[C:7]([O:6][CH3:5])=[CH:8][CH:9]=1)[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=O)c2cc(C(F)(F)C(F)(F)F)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an argon atmosphere, ethyl magnesium bromide (5.44 mL, 0.91 mol/L tetrahydrofuran solution) was added to a solution of the compound of Example 354 (1.24 g) in tetrahydrofuran (30 mL) at −78° C. The mixture was allowed to gradually warm to room temperature and was stirred at room temperature for 1 hour. Subsequently, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (100 mL). The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was then concentrated and purified by amino-silica gel column chromatography (ethyl acetate) to afford the title compound as a pale yellow oil (1.41 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al](C)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([CH3:20])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Reactant: C[Al](C)C
Solvent: CCCCCC
Product: C[C@@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O

Procedure:
Under argon to a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino -1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (108 mg) in hexane (10 ml) was added a 2 M solution of trimethylaluminum in hexane (0.30 ml), the mixture was heated under reflux for 31/2 hours and was quenched by addition of a 2 M aqueous solution of ammonium chloride adjusted to pH 8 with ammonium hydroxide. The resulting suspension was extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated under vacuum to give a colorless oil which was purified by preparative thin layer chromatography on silica gel (elution with ethyl acetate:cyclohexane, 3:8) to afford the title compound as a solid (32 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH:30]([NH:32][CH2:33][CH2:34][OH:35])[CH2:29][CH2:28][CH2:27][C:26]=2[C:36]=1[O:37][CH3:38]>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH:30]([NH:32][CH2:33][CH2:34][OH:35])[CH2:29][CH2:28][CH2:27][C:26]=3[C:36]=2[O:37][CH3:38])=[N:3][CH:4]=1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.30 mmol) and 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a tan solid. Mp: 92-4° C. LCMS (m/e) 553 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (m, 2H), 7.40 (br s, 1H), 6.89 (d, J=8 Hz, 1H), 5.56 (d, J=8 Hz, 1H), 3.90 (m, 1H), 3.71 (s, 3H), 3.61 (m, 2H), 3.47 (s, 3H), 3.25 (m, 1H), 2.93-2.63 (m, 10H), 2.20 (m, 2H), 2.01 (m, 1H), 1.80 (m, 4H), 1.55 (m, 1H), 1.39 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][CH2:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][CH2:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(CCCCO)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 200 mg, 0.61 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (305 μL, 0.61 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (145 μL, 1.22 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 0.61 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 45 min. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-butyl)-1H-pyrazol-3-yl]-propionamide (35 mg, 12%) as a white foam: ESI-LRMS m/e calcd for C22H30ClN3O4S [M+] 467.2, found 468.0 [M+H+], 450.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.45-1.99 (m, 12H, 6×CH2), 2.17-2.30 (m, 1H, CH), 2.71 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.8 Hz, 1H, CH), 3.69 (t, J=6.2 Hz, 2H, OCH2), 4.09 (t, J=6.6 Hz, 2H, NCH2), 6.70 (s, 1H, Ar), 7.30 (s, 1H, Ar), 7.49 (d, Jo=8.3 Hz, 1H, Ar), 7.62 (s, 1H, Ar), 8.10 (d, Jo=8.6 Hz, 1H, Ar), 8.47 (brs, 1H, NH).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN(C1C=CC=CN=1)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:20]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2ccccc2N1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccccc2CC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a mixture of 2-methylindoline (20.0 g, 0.15 mol) and dimethylaminopyridine (500 mg, 5 mmol) in pyridine (50 mL) at room temperature is added acetic anhydride (20 mL). The mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 26.3 g (100%) of the title compound as an amber oil. MS (ESI+) m/z 176.1 (M+H).