Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:19]1[S:23][C:22]([C:24]2[CH2:28][CH:27]([CH2:29][OH:30])[O:26][N:25]=2)=[CH:21][CH:20]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[C:19]1[S:23][C:22]([C:24]2[CH2:28][CH:27]([CH2:29][OH:30])[O:26][N:25]=2)=[CH:21][CH:20]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)c(F)c1
Temperature: 90 °C
Yield: 26.5 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (195 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (60 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCNC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
4-[2-(Piperidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49A) (311 mg, 0.86 mmol) was dissolved in CH2Cl2 (15 mL) under nitrogen and cooled to 0° C. Benzoyl chloride (0.3 mL, 2.58 mmol) was added followed by dropwise addition of triethylamine (0.48 mL, 3.44 mmol). The mixture was warmed to r.t. and stirred for about 16 hours. Methylene chloride (20 mL) was added, and the solution was washed with saturated NaHCO3 (20 mL)and brine (20 mL), and then dried over magnesium sulfate. The solvents were removed under reduced pressure, and the residue was purified by flash column chromatography on silica to afford the final compound as a white solid (330 mg, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:10]2([NH:13][CH2:12][C:11]2([F:15])[F:14])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.Cl.CO>C(OCC)(=O)C>[F:14][C:11]1([F:15])[C:10]2([CH2:16][CH2:17][NH:8][CH2:9]2)[NH:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)NCC2(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: FC1(F)CNC12CCNC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 129.5 %

Procedure:
To an optically-active compound of 3,3-difluoro-1,6-diazaspiro[3,4]octane-6-carboxylic acid tert-butyl ester (211 mg) were added 4M hydrochloric acid-1,4-dioxane (2.1 ml) and 2M hydrochloric acid-methanol (2.1 ml), and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture was added ethyl acetate, and the mixture was filtered to give the titled compound (163 mg).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[CH:16]N(C)C)[N+:8]=1[CH2:20][CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:33]([N+:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[S:37][C:36]=1[CH3:44])[CH3:34].C(N(CC)CC)C>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[N:8]([CH2:20][CH3:21])[C:9]([CH:16]=[CH:44][C:36]2[S:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:35]=2[CH2:33][CH3:34])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC[N+]1=C(Cl)c2ccccc2C1=CN(C)C
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(Cl)c2ccccc2c1C=Cc1sc2ccccc2[n+]1CC

Procedure:
3-chloro-1-dimethylaminomethylene-2-ethyl-1H-isoindolium perchlorate (0.5 g) and 3-ethyl-2-methylbenzothiazolium p-toluene sulfonate (0.5 g) were dissolved in acetonitrile and triethylamine added. After 30 minutes at room temperature the product was precipitated by the addition of ether and purified by chromatography on silica gel. After recrystalization from ethanol, the purified product melted at 244° C. CH3CN λ max 553 nm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32]CC1C=CC(C2OC3C=CC(C)=CC=3N=2)=CC=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
10 g (15.11 mmol) of (−)-ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[4-(5-methyl-1,3-benzoxazol-2-yl)-benzyl]oxy}-phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 26A) were dissolved in 500 ml of ethanol, and 9.53 g (151.10 mmol) of ammonium formate and 161 mg (1.51 mmol) of 10% palladium on activated carbon were added. The reaction mixture was then heated to 80° C. and stirred at this temperature overnight. The mixture was then cooled to room temperature, another 100 mg of the palladium catalyst were added and the mixture was stirred at 80° C. for a further 6 h. The reaction mixture was then once more cooled to room temperature and filtered, and the filtrate was evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→2:1). This gave 6.55 g (14.87 mmol, 98% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:3]1([N:2]([CH3:1])[C:19](=[O:21])[C:18]2[CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=[CH:25][C:17]=2[O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C=O)ccc1OCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
N-Methylaniline (0.18 mL, 1.68 mmol, 2 eq) was added to a solution of 2-benzyloxy-5-formylbenzoic acid (200 mg, 0.84 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (230 mg, 1.68 mmol, 2 eq), and N-methylmorpholine (0.25 mL, 2.29 mmol, 2.73 eq) in N,N-dimethylformamide (4 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.68 mmol, 2 eq) and the reaction mixture stirred overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a yellow oil (270 mg, 99%). RF (petroleum ether:ethyl acetate 1:1) 0.73. 1H NMR (CDCl3) δ9.79 (s, 1H, O═C—H), 5.01 (s, 2H, CH2Ph), 3.47 (s, 3H, CH3).
Reaction SMILES: C(Cl)Cl.[NH3:4].[CH:5]1[CH:10]=[C:9]2C(C(O)(O)[C:14](=[O:15])[C:8]2=[CH:7][CH:6]=1)=O>CO>[C:14]([NH2:4])(=[O:15])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccccc1

Procedure:
RF 0.8 in 100:30:5/CH2Cl2:MeOH: 880 Ammonia, visualised with ninhydrin.
Reaction SMILES: C(Cl)[Cl:2].C(OC([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])[C:13]([CH3:32])([CH3:31])[CH2:12]1)=O)(C)(C)C.Cl>C(O)C>[ClH:2].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1([CH3:32])[CH3:31])(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C(C)(C)C1
Reactant: ClCCl
Agent: Cl
Solvent: CCO
Product: CC1(C)CNCCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a methylene chloride solution (0.5 ml) of 4-(tert-butoxycarbonyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazine (140 mg) was added a saturated solution (0.5 ml) of hydrochloride in ethanol. The resulting mixture was stirred at room temperature for 14 hours. Ethanol was added to the reaction mixture. After the sufficient removal of hydrochloric acid by azeotropy, the residue was dried using a vacuum pump, whereby the title compound (119 mg) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:29]3[CH2:30][CH2:31][CH:27]([NH2:26])[CH2:28]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)C1
Yield: 11.8 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (100 mg, 0.22 mmol) and 3-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) were reacted according to GP8 to give 8.1 mg of the title compound (166JO64). MS (ESI) 313 (MH+). Purity for MH+ (UV/MS) 100/94.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.CCOCC>[C:7]1([S:13][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: C#CC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C=CSc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 2.45 g (24.54 mmol) methyl propiolate and 20 ml ether is treated with 2.7 g (24.54 mmol) benzenethiol with 4 drops triethylamine in 25 ml ether over 15 min at 20°. After stirring for 24 hr, the reaction mixture is rotoevaporated to yield methyl 3-phenylthio-2-propenoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1>>[Cl:19][C:20]1[N:21]=[C:22]([NH2:27])[N:23]=[C:24]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:25]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1

Procedure:
Analogously to example 8, the title compound is synthesized from 266 mg (1.09 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 179 mg (1.09 mmol) of 4,6-dichloro-2-pyrimidineamine.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[S:16])[S-:15].C([NH+](CC)CC)C>C(#N)C>[CH3:5][C:2]1([CH3:6])[S:16][C:14](=[S:15])[N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH:3]1[OH:4]
Reactant: CC(C)(Br)CO
Reactant: S=C([S-])Nc1ccccn1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CC1(C)SC(=S)N(c2ccccn2)C1O
Temperature: 2 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-Bromo-2-methylpropanol (39.7 g) is added, at about 5° C., to a suspension of triethylammonium pyrid-2-yl-dithiocarbamate (71.2 g) in anhydrous acetonitrile (330 cc). The reaction is allowed to proceed for 1 hour at 20° C. The insoluble triethylamine hydrobromide is removed by filtration. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 40° C. The residual oil is treated with methylene chloride (300 cc). The organic solution is washed twice with distilled water (100 cc in total), dried over sodium sulphate and evaporated. The resulting product (60 g) is dissolved in methylene chloride (300 cc), and the solution is filtered through silica (0.2-0.5 mm., 850 g) contained in a column of diameter 5 cm. Elution is carried out with methylene chloride (9 liters). After evaporating off the solvent under reduced pressure (20 mm Hg) at 40° C., the resulting product (50 g) is dissolved in boiling methylcyclohexane (150 cc). After cooling for 16 hours at 2° C., the crystals which have appeared are filtered off, washed with methylcyclohexane (50 cc) and dried under reduced pressure (0.1 mm Hg) at 40° C. 5,5-Dimethyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (44.1 g), which melts at 80° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]=1[C:5]([OH:24])=[C:6]([C:19](OCC)=[O:20])[C:7](=[O:18])[C:8]12[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:24][C:5]1[C:4]2[C:14](=[CH:15][CH:16]=[CH:17][C:3]=2[O:2][CH3:1])[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:7](=[O:18])[C:6]=1[C:19]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2c(OC)cccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Temperature: 86 °C
Reaction time: 14 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 5-methoxy-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (44 mg, 132 μmol), tert-butyl 2-aminoacetate hydrochloride (33 mg, 199 μmol) in 2 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (51 mg, 397 μmol). The mixture was warmed to 86° C. and stirred for 14 hours, M+1=418. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 35 mg of the title compound as a yellow oil. MS (m/z) 418 (M+H)+.
Reaction SMILES: C(=O)=O.CC(C)=O.Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2.C([Li])CCC.[F:30][C:31]([F:44])([F:43])[C:32]([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:33]>C1COCC1.[Cl-].[NH4+]>[F:44][C:31]([F:30])([F:43])[C:32]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[OH:33]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: O=C(c1c[nH]c2ncccc12)C(F)(F)F
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ncccc12)C(F)(F)F
Reaction time: 1 h
Yield: 42 %

Procedure:
To a chilled (−78° C.) (dry ice-acetone) solution of 291 mg (1.0 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in 5 mL of anhydrous THF was added rapidly 0.4 mL (1.0 mmol) of a 2.5 M solution of n-butyllithium (n-BuLi) in hexanes. Immediately after, a chilled (dry ice-acetone bath) solution of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (prepared according to the procedure described in J. Org. Chem. 2002, 76, 6226) in 3 mL of THF was added rapidly. The mixture stirred for 1 hour, TLC [ethyl acetate-hexanes (1:1)] indicated a new more polar product than both starting materials. The mixture was diluted with 10 mL of saturated aqueous ammonium chloride and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using dichloromethane to load the sample and then eluting with ethyl acetate-CH2Cl2 (0-30% gradient). The material from the column was solidified from ether-hexanes (1:1), dried under house vacuum at 90° C. for 3 hours, to afford 91 mg (42%) of the title compound. MS m/z 427.18 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:24])[CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[OH:23])(=[O:5])[CH3:4].Cl[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27].C(O)(=O)C>CN1CCCC1=O.C(OCC)(=O)C>[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:24])[CH:11]=[C:12]2[C:17]=1[N:16]([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]2=[O:23])(=[O:5])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(COC(C)=O)cc(C)cc2c1O
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Sodium hydride (3.1 g, 60% dispersion) is added at 0° C. to a stirred solution of ethyl 8-((acetyloxy)methyl)-4-hydroxy-6-methyl-3-quinolinecarboxylate (Preparation 25, 29.6 g) in N-methylpyrrolidinone (250 ml). The solution is allowed to warm to room temperature over 10 min and isobutyl chloroformate (25.5 g) is then added. After 30 min, acetic acid (3.6 g) is added. The solvent is evaporated under reduced pressure, and the residual oil is partitioned between ethyl acetate and water. The ethyl acetate layer is concentrated to give an oil. The crude product is dissolved in ethyl acetate (50 ml) and is chromatographed on silica gel with 10% ethyl acetate/hexane as the initial eluant to give 19.5 g of the title compound. A sample is recrystallized from ethyl acetate/hexane for analysis. Physical characteristics: M.p. 101-103° C.; 1H NMR (CDCl3) δ1.05, 1.44, 2.12, 2.18, 2.59, 4.15, 4.45, 5.82, 7.74, 7.88, 9.40. Anal. Found: C, 62.42; H, 6.34; N, 3.45.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].O.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[N:20]=[CH:31][O:22][N:21]=2)[C:3]=1[S:23]([C:26]([F:28])([F:29])[F:27])(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Solvent: O
Solvent: COC(OC)OC
Product: Nc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 658.2 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime (0.51 g, 1.87 mmol) was dissolved in 12 ml of trimethyl orthoformate and p-toluenesulfonic acid monohydrate (0.05 g) was added, and then the mixture was heated under reflux for 1 hour. Trimethyl orthoformate was distilled off and 80 ml of ethyl acetate was added to the residue. The ethyl acetate layer was washed twice with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, and then washed once with 50 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless crystal. This crystal was washed with a hexane-chloroform mixed solvent (volume ratio=2:1) to obtain 0.86 g (1.73 mmol) of the title compound as a colorless crystal. Yield 93%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([O:39][CH3:40])[CH2:9]1)=O)(C)(C)C.C=O>>[CH:35]1([O:34][C:20]2[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH:10]4[O:39][CH3:40])[CH:18]=3)=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][C@H:24]([CH3:33])[N:25]3[C:29]([O:31][CH3:32])=[O:30])[CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C

Procedure:
(2S)-Methyl 5-cyclobutoxy-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (2S)-methyl 6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and formaldehyde according to the procedure outlined above for Example 40. 1H NMR (300 MHz, CD3OD) δ ppm 1.19 (d, J=6.00 Hz, 3H), 1.20-1.50 (m, 2H), 1.55-1.85 (m, 1H), 2.01-2.22 (m, 4H), 2.22-2.68 (m, 4H), 2.88-3.08 (m, 5H), 3.10-3.22 (m, 2H), 3.50-3.60 (m, 1H), 3.80 (s, 3H), 3.81-4.01 (m, 1H), 4.05-4.25 (m, 1H), 4.30-4.45 (m, 1H), 4.48-4.70 (m, 1H), 7.20-7.40 (m, 2H), 7.85-8.10 (m, 2H). MS (ESI, pos. ion) m/z 469 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:39]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][C:3]=2[N:12]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[S:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:41][CH2:40]1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2Br)cc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C2CC2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 76.5 %

Procedure:
A mixture of ethyl 4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (65.0 mg, 0.107 mmol) prepared in Example 153, cyclopropylboronic acid (27.0 mg, 0.321 mmol), palladium acetate (2.5 mg, 0.011 mmol), tricyclohexylphosphine (5.9 mg, 0.021 mmol) and tripotassium phosphate (79.0 mg, 0.375 mmol) in water (0.027 mL) and toluene (0.54 mL) was stirred under argon atmosphere at 100° C. for 5 hours. After cooling, the reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→65:35) to give ethyl 4-({(4-cyclopropylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (46.7 mg, 78%) as a white powder.