Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[Cl-].[NH4+]>CN(C=O)C.CCOCC>[Si:21]([O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
To a round bottom flask charged with (+/−)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (2 g, 9.21 mmol) in DMF (2 mL) was added imidazole and TBS-Cl (1.387 g, 9.21 mmol). The reaction mixture was stirred at room temperature 2 d. The reaction mixture was poured into a separatory funnel containing half-saturated aqueous ammonium chloride and ether. The aqueous layer was extracted with ether (2×). The combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. (+/−)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate (3.039 g) was isolated as a white pasty solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cccc(C(=O)O)c2)cc1

Procedure:
A mixture of 3-bromo-benzoic acid (4.02 g) and 4-ethoxycarbonyl-phenyl boronic acid (3.88 g) in DME (100 ml) containing cesium carbonate (6.5 g) and tetrakis(triphenylphosphine) palladium (0) (1.15 g) was heated to reflux for 24 h. The cooled mixture was then filtered through celite and evaporated giving the crude title compound as a white solid which was used without purification in the next synthetic step.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1-BOC-homopiperazine (0.8 ml) was added methane sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane and water. The combined organic extracts were then washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 1.23 g of crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]([CH3:30])[CH:20]=1>C(C(CC)=O)C>[CH3:30][N:21]1[C:22]2[C:27](=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:19]([CH2:18][CH2:17][N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:20]1
Reactant: O=C(CC1CCNC1)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)c(CCBr)cn2C
Solvent: CCC(=O)CC
Product: COc1ccc2c(c1)c(CCN1CCC(CC(=O)c3ccc(F)cc3)C1)cn2C

Procedure:
Alkylation of 3-(4-fluorobenzoylmethyl)pyrrolidine by the brominated compound obtained in Stage 3 is carded out in diethyl ketone by following the procedure described in Stage 3 of Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.N1C=CC=CC=1.O>O1CCCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([NH:15][S:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:17]=3)[NH:21][N:20]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc2[nH]nc(-c3ccc(Cl)cc3)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc(Cl)cc3)c2c1
Yield: 92.6 %

Procedure:
N-[3-(4-Chlorophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a solution of 0.515 g 2-methylsulfonylbenzenesulfonyl chloride in 3 ml of tetrahydrofuran is added dropwise to a solution, cooled to 0° C., of 0.45 g of 5-amino-3-(4-chlorophenyl)-1H-indazole, of 15 ml of tetrahydrofuran and of 0.165 ml of pyridine. After reacting for 30 minutes at a temperature in the region of 0° C. and 2 hours at a temperature in the region of 20° C., 50 ml of distilled water are added to the reaction medium. The medium is extracted with 30 ml of ethyl acetate. The organic phase is then washed with 3 times 20 ml of distilled water and the aqueous phase is extracted again with 30 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered and concentrated to dryness by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/ethyl acetate (99/1 by volume) mixture as eluent. 0.79 g of N-[3-(4-chlorophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a white powder melting at 242° C. (analysis C20H16ClN3O4S2.0.65CH3OH % calculated C, 52.01; H, 3.49; Cl, 7.67; N, 9.10; O, 13.85; S, 13.88. % found C, 52.02; H, 3.78; Cl, 7.91; N, 9.21; S, 13.45).
Reaction SMILES: [CH2:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C:8]2[C:13]([C:14]#[N:15])=[C:12]([O:16]C)[CH:11]=[C:10]([C@:18]3([O:36][C@H:35]([CH2:37][O:38]C(=O)C)[C@@H:30]([O:31]C(=O)C)[C@H:25]([O:26]C(=O)C)[C@H:20]3[O:21]C(=O)C)[OH:19])[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[NH+]1C=CC=CC=1.[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:13]([C:14]#[N:15])=[C:12]([OH:16])[CH:11]=[C:10]([C@:18]3([O:36][C@H:35]([CH2:37][OH:38])[C@@H:30]([OH:31])[C@H:25]([OH:26])[C@H:20]3[OH:21])[OH:19])[CH:9]=2)=[CH:42][CH:43]=1)[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(O)c2C#N)cc1
Temperature: 215 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(4-ethylbenzyl)-2-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.36 g) and pyridinium hydrochloride (0.72 g) is heated at 215° C. for 1.5 h. After cooling to ambient temperature, the mixture is dissolved in methanol (8 mL) and treated with 4 M aqueous NaOH solution (2.5 mL). The solution is stirred at room temperature for 1 h and then acidified using hydrochloric acid (4 mol/L). After removal of the organic solvents, the residue is extracted with ethyl acetate, the combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by HPLC on reversed phase (YMC C18, acetonitrile/water).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:21]1CCOCC1.ClC(OCC)=O.[OH-].[NH4+]>O1CCCC1>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:10]([NH2:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of Boc-Phe-OH (30.1 g, 113 mmol, 1 eq.) in tetrahydrofuran (378 mL, 0.3 M) cooled to −10° C. were added N-methylmorpholine (13.6 mL, 124 mmol, 1.09 eq.), and ethyl chloroformate (11.8 mL, 124 mmol, 1.09 eq.). After 20 minutes, a 30% aqueous ammonium hydroxide solution (45 mL, 350 mmol, 3.1 eq.) was added. The mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The residue was diluted with ethyl acetate and washed sequentially with 1 N aqueous potassium bisulfate solution, water and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The white solid was dissolved (this required heating with stirring) in ethyl acetate (about 400 mL); the solution was then allowed to cool to room temperature before adding hexane (1000 mL). After a few minutes, a white material started to precipitate from the reaction mixture. The solid was collected by filtration, washed with heptane (2×˜150 mL), and dried under vacuum for 18 hours to give #12 (24.50 g, 82%) as a solid. LC-MS: m/z 263.2 [M−H+], 309.2 [M+HCO2−], retention time=1.85 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 7.35 (br s, 1H), 7.22-7.30 (m, 5H), 7.00 (br s, 1H), 6.78 (d, J=8.6 Hz, 1H), 4.09 (ddd, J=10, 9, 4.5 Hz, 1H), 2.95 (dd, J=13.8, 4.4 Hz, 1H), 2.72 (dd, J=13.7, 10.1 Hz, 1H), 1.30 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: CN1CCC(NC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=543.96 (M+H+); retention time=0.51 minutes.
Reaction SMILES: [C:1]([CH:3]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:21][CH:20]=1)[N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)#[N:2].C([NH+](CC)CC)C.C(=O)([O-])[O-]>ClCCl.FC(F)(F)C(O)=O>[NH2:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH:3]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH:20]=2)[C:1]#[N:2])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(C#N)c2cnc(-c3ccccn3)s2)CC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC(c1cnc(-c2ccccn2)s1)N1CCC(CN)CC1
Reaction time: 1 h

Procedure:
The compound prepared in Example 235 (0.14 g) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL). The reaction was stirred for 1 hour and then concentrated and pumped to dryness. The amine salt was dissolved in tetrahydrofuran (5 mL) and Macroporous triethylammonium methylpolystyrene carbonate (MP-carbonate: Argonaut Technologies catalog number 80,026-9; 0.65 g) (2.5-3.5 mmol/g) 1.6-2.2 mmol was added. After 2 hours of stirring the reaction was filtered, washed with tetrahydrofuran, concentrated and used without further purification.
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=1.[Cl-].[Li+].[OH-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:19]1[CH:18]=[C:17]([CH:1]=[CH2:2])[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=1
Reactant: Fc1cc(Br)cc(OC(F)F)c1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1cc(F)cc(OC(F)F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
Tri(butyl)vinylstannane (7.0 g, 22.2 mmol) was added to a suspension of 1-bromo-3-fluoro-5-difluoromethoxybenzene (4.9 g, 20.2 mmol; see step (iii) above), dichlorobis(triphenylphosphine)palladium(II) (1.42 g, 2.02 mmol) and anhydrous lithium chloride (0.90 g, 20.2 mmol) in THF (40 mL) under nitrogen at 65° C. and the mixture was stirred for 5 h. The reaction mixture was cooled to 0° C. and 1N NaOH (90 mL) was added. The biphasic mixture was vigorously stirred for 1 h then the layers were separated. The aqueous layer was extracted with Et2O (3×70 mL). The combined organic layers were washed with 2N NaOH (2×40 mL) and H2O (40 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexane afforded the sub-title compound (2.2 g, 57%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][S:27]([CH3:26])(=[O:29])=[O:28])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(NS(C)(=O)=O)c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (26 mg, 0.11 mmol) in dry dichloromethane (2 mL) at 0° C. were added triethylamine (22 mg, 0.22 mmol) and methanesulfonyl chloride (20 mg, 0.17 mmol). The reaction was slowly warmed to room temperature and stirred overnight. Reaction was treated water (10 mL) and diluted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated to afford 3-amino-N-methyl-6-{3-[(methylsulfonyl)amino]phenyl}pyrazine-2-carboxamide (15 mg, 45% yield) as yellow solid. 1H NMR (400 MHz, CDCl3): 8.62 (s, 1H), 7.94 (br s, 1H), 7.75 (br s, 1H), 7.68 (br d, 1H), 7.45 (t, 1H), 7.30 (br d, 1H), 7.25 (br s, 1H), 3.02 (m, 6H); MS (EI) for C13H15N5O3S: 322 (MH+).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:25][Mn](=O)(=O)=O.[K+].Cl.S(=O)(O)[O-].[Na+]>CC#N.O>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Yield: 886.4 %

Procedure:
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.15 g, 0.44 mmoles) and KMnO4 (0.03 g, 0.29 moles) was stirred in CH3CN/H2O (4:1) for 1 hour. Reaction mixture was acidified with 2N HCl, stirred with saturated sodium bisulfite for 10 minutes, then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.13 g, 3.9 mmoles).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:16][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]=[C:4]([C:12]([F:14])([F:15])[F:13])[N:3]=[C:2]([Cl:1])[C:11]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2Br
Yield: 58.3 %

Procedure:
To a solution of 17.63 g of 4-chloro-5,6,7,8,-tetrahydro-2-trifluoromethylquinazoline in 220 mL of chloroform was added 14.6 g of N-bromosuccinimide and 0.85 g of AIBN. The resulting reaction mixture was heated to reflux overnight under a nitrogen atmosphere. The reaction was cooled, filtered and all solvents were removed by evaporation. The residue was purified on a silica column (5% ethyl acetate in hexane) to yield 13.7 g (58%) of the required compound. This material was carried to the next step with no further purification.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[NH2:28])[CH:17]=[CH:18][C:19]=1[Cl:20]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(Cl)c2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
5.6 g (0.029 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 10.4 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 5 minutes, 7.8 g (0.030 mol, approx. 92% pure) of 3′,4′-dichloro-5-fluorobiphenyl-2-ylamine, dissolved in 28 g of toluene, were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 25° C. overnight, the mixture was cooled further to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 8.1 g (71%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(COc2nn(Cc3cccnc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (0.71 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.08 g) at 0° C. and the mixture was stirred at room temperature for 2 hrs. Sodium sulfate decahydrate (0.65 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give [3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]methanol as colorless crystals (0.34 g, yield 52%) from a fraction eluted with ethyl acetate-methanol (10:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C(=O)C(F)(F)F)[CH2:7]2.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: O=C(Nc1cc(Cl)c2c(c1)CN(C(=O)C(F)(F)F)CC2)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1cc(Cl)c2c(c1)CNCC2)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
A suspension of the compound of Procedure 2 (148 mg, 0.35 mmol) and potassium carbonate (800 mg, 5.8 mmol) in 20% aqueous methanol (50 ml) was stirred at 25° C. for 18 h. Work-up similar to Description 3 gave the title compound as a white solid (68 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(F)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-fluorobenzyl bromide in the same manner as in Example 32.