Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][NH:7][O:6]1>C1(C)C=CC=CC=1>[CH2:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][N:7]([C:1]([Cl:4])=[O:2])[O:6]1
Reactant: O=C(Cl)Cl
Reactant: c1ccc2c(c1)CCNOC2
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCc2ccccc2CO1
Yield: 81.5 %

Procedure:
To a solution of 15.9 g. of phosgene in anhydrous toluene a solution of 19.8 g. (0.135 mole) of 1,3,4,5-tetrahydro-2,3-benzoxazepine in the same solvent was added at 0° - 15°C with stirring. After 6 hours it was washed with H2O, dried over Na2SO4 and the solvent evaporated. Recrystallization from EtOH yielded 22.85 g. (81.5%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Phenyl chloroformate (0.256 mL, 2.04 mmol) was added dropwise to 4-[4-[(4-chlorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (850 mg, 1.85 mmol) and sodium hydrogen carbonate (233 mg, 2.78 mmol) in dioxane (20 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (955 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(Cl)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-pyridine (example E.19) (1.35 g, 3.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.792 g, 3.6 mmol) according to the general procedure VI. Obtained as a light yellow solid. (0.750 g, 60%). MS (ISP) 416.3 [(M+H)+] and 418 [(M+2+H)+]; mp 196° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1[CH:21]=NC2N(O)N=[N:24][C:18]=2[CH:17]=1.C(Cl)CCl.C1(N)CCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:24][CH:18]1[CH2:17][CH2:16][CH2:21]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: On1nnc2cccnc21
Agent: NC1CCC1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 30 ml of DMF, 948 mg of HOAT, 1.3 g of EDC and 495 mg of cyclobutylamine was added and the reaction mixture was stirred for 16 h at RT. Then, water was added and the reaction mixture was extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([Zn]CC)[CH3:13].O.Cl>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: COC(=O)c1ccncc1Br
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cnccc1C(=O)OC
Temperature: 70 °C
Yield: 21.2 %

Procedure:
Methyl 3-bromopyridine-4-carboxylate (5 g, 23.1 mmol) was dissolved in anhydrous dioxane (150 mL). A solution of diethyl zinc (18.9 mL, 20.8 mmol, 1.1 M in toluene) was added dropwise and then was added catalyst ((1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (254 mg, 347 μmol). The mixture was heated at 70° C. for 3.5 hours and then water followed with 1 N HCl was added. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-20% hexane/ethyl acetate to afford methyl 3-ethylpyridine-4-carboxylate (730 mg, 19% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol) in acetonitrile (2 ml) was added potassium carbonate (0.02 g, 0.14 mmol) and iodomethane (0.0047 ml, 0.078 mmol). The mixture was stirred at ambient temperature for 1 h. MS m/z (relative intensity, 70 eV) 271 (M+, 66), 270 (bp), 192 (9), 133 (13) 97 (32).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C.ClCCl>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCOCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethoxy)ethanol (30.3 g, 288 mmol) in a minimal amount of dichloromethane was added dropwise to a stirred mixture of 4-chloro-3-nitroquinoline (50.0 g, 240 mmol), potassium carbonate (33.1 g, 240 mmol), and triethylamine (36.4 g mL, 360 mmol) in DMF (200 mL) at 0° C. A yellow precipitate formed and more dichloromethane (several mL) was added. The mixture was allowed to warm to room temperature and stir overnight. A yellow solid was isolated by filtration, washed with water and dichloromethane, and dried. The filtrate was washed twice with brine, dried over magnesium sulfate, and filtered. Additional orange solid was isolated from the filtrate after concentration under reduced pressure. The solids were dried in a vacuum oven to afford 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethanol.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:33]2[C:34]([CH2:39]CCC)=[N:35]OC=2C)=NC=1>>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH:34]([CH3:39])[CH3:33])=[O:21])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Product: CCCCc1nocc1COc1ccc(C(=O)NC(C)C)cn1
Yield: 91 %

Procedure:
As described for example 5d, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.69 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (200 mg, 91%) which was obtained as a light brown solid after purification by chromatography (silica, 40 to 60% ethyl acetate in heptane). MS: m/e=318.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][C:14]([CH3:16])([S:17]([NH:20][C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:9])(=[O:19])=[O:18])[CH3:15]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.1 %

Procedure:
To a mixture of 3-nitrobenzoic acid (0.37 g, 2.2 mmol), 1,1-dimethylethylsulphonamide (0.3 g, 2.2 mmol) and 4-dimethylaminopyridine (0.27 g, 2.2 mmol) in anhydrous dichloromethane (20 ml), under an atmosphere of nitrogen, was added. 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.42 g, 2.2 mmol). The mixture was stirred at ambient temperature for 22 h. The mixture was extracted with 1M NaOH (50 ml) and the separated aqueous phase acidified using 5M HCl. This was extracted with dichloromethane (5×20 ml), then the combined organic extracts were dried (Na2SO4) and evaporated to dryness. The residue was chromatographed on silica gel using 1% methanol in dichloromethane as the eluant. The title compound (0.53 g, 85%) was isolated as a colourless solid. mp 220° C. 1H NMR (360 MHz, D6-DMSO) δ 1.27 (9H, s), 6.59 (1H, brs), 7.65 (1H, t, J=7.9 Hz), 8.24-8.30 (1H, m), 8.34-8.38 (1H, m), 8.68-8.72 (1H, m).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:30][CH3:31])[C:25]=1[O:26][CH2:27][C:28]#[CH:29])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:20](=[O:21])[C:19]1[CH:23]=[C:24]([O:30][CH3:31])[C:25]([O:26][CH2:27][C:28]#[CH:29])=[C:17]([F:16])[CH:18]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
To a mixture of 1 ml of ethyl acetate and 0.2 g of 2-methylcyclopentylamine hydrochloride was added 0.48 ml of triethylamine and then, a mixture of 0.24 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of ethyl acetate was added dropwise thereto under ice cooling. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain 0.21 g of N-(2-methylcyclopentyl)-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 70 of the present invention) represented by the formula:
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:5]1[CH2:4][CH:3]=[CH:2][CH:1]=1
Reactant: [H][H]
Agent: [Pd]
Agent: C1=CCC=C1
Product: C1=CCCC1
Yield: 90 %

Procedure:
reacting the purified cyclopentadiene of step (B) with hydrogen gas in the ratio of 1 to 1.5 mol hydrogen to 1 mol cyclopentadiene, in the presence of a palladium catalyst on a carrier and at a temperature of 50° to 200° C and at substantially ordinary atmospheric pressure thereby to produce a conversion ratio of 90 to 98% cyclopentene, remainder unreacted cyclopentadiene;
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]([CH3:13])[C:8](=[O:14])[C@@H:7]([CH2:15][CH3:16])[N:6]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:5]=2[N:4]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=1[O:36][CH3:37]>C(O)C.O>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([N:6]2[C:5]3[N:4]=[C:3]([NH:24][C:25]4[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=4[O:36][CH3:37])[N:12]=[CH:11][C:10]=3[N:9]([CH3:13])[C:8](=[O:14])[C@H:7]2[CH2:15][CH3:16])[CH2:18]1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)C(=O)N3C)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
Concentrated hydrochloric acid (42 μl) was added to a mixture of (R)-2-chloro-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (80 mg, 0.24 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (70.47 mg, 0.36 mmol) in ethanol (1.2 mL) and water (4.8 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with dichloromethane, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (89 mg, 75% yield).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9]([C:11]1[C:12](=O)[NH:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH3:7].N>O>[CH2:6]([O:8][C:9]([C:11]1[C:12]([Cl:3])=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Agent: N
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
POCl3 (15 ml) was added to 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (3 g, 9.15 mmol) and refluxed for 1 h. Then the reaction mixture was cooled to room temperature and diluted with cold water and the pH was adjusted to 7 with ammonia solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 5-10% ethyl acetate in hexane) to afford pure 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (2 g, 63%) as pale yellow solid. LC-MS: 346 (M+H)+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[C:1]1([C:7]2[CH:16]=[C:15]([OH:17])[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccnc1C#Cc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(-c2ccccc2)cc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
30 mg 1-(2-(Phenylethynyl)pyridin-3-yl)ethanone were suspended in 350 μL 1N sulfuric acid and 2.147 mg mercuric chloride and stirred for 30 min at 60° C. Then 1 mL of NaOH was added and the mixture stirred for additional 1 h at 25° C. Water was added and a neutral pH adjusted with NaHCO3 solution. The precipitate was filtered off and washed with water and dried to yield 30 mg 7-phenylquinolin-5-ol 6.1 as solid. Analysis: HPLC-MS: Rt=1.18 min (method D), M+H=240.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[CH:21]2>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[CH:21]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]ncc2c1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 5-aminoindazole (Aldrich), the title compound was obtained as a pink solid after trituration in DCM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[BH4-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[O:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2cccc(F)c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccc(Oc2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-fluoro-phenoxy)-furan-2-carbaldehyde described in Preparation Example 50 (1.5 g, 7.3 mmol) in tetrahydrofuran (20 mL) was added sodium borohydride (280 mg, 7.3 mmol), and the solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, and the organic layer was filtered through a glass filter lined with silica gel. The solvent was evaporated in vacuo, and the title compound (1.5 g, 7.2 mmol) was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[NH2:45][CH:46]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([NH:45][CH:46]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47]3)[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(NC3CCN(C(=O)OC(C)(C)C)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (100 mg, 0.142 mmol, prepared in Example 63, step A), tert-butyl 3-aminopyrrolidine-1-carboxylate (132 mg, 0.708 mmol), copper(I)iodide (5.39 mg, 0.0283 mmol), (S)-pyrrolidine-2-carboxylic acid (6.52 mg, 0.0566 mmol), K2CO3 (97.8 mg, 0.708 mmol) and DMSO (10 mL). The reaction mixture was stirred at 80° C. overnight. The reaction was cooled to ambient temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (61.3 mg, 56.6%). LRMS (APCI pos): m/e 765 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=2)=[N:6]1.[S:26]([Cl:30])(=O)(=[O:28])[OH:27]>C(OCC)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:20]=[C:19]([OH:21])[C:18]([S:26]([Cl:30])(=[O:28])=[O:27])=[CH:17][N:16]=2)=[N:6]1
Reactant: Oc1ccnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)n1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1O

Procedure:
A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol Compound I-160 (56 mg, 1 equiv) and sulfurochloridic acid (552 μl) in a sealed vial was heated to 100° C. for 30 min. The mixture was diluted in ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give 79 mg of crude 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-4-hydroxypyrimidine-5-sulfonyl chloride as a white solid. The solid was combined with morpholine (47.4 μl, 3.3 equiv) and stirred at 25° C. for 30 min. The mixture was diluted in ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give crude oil. Purification by column chromatography (0 to 10% methanol in dichloromethane) gave 40 mg of the desired product (45%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 9.11 (d, 1H), 8.01 (bs, 1H), 7.74-7.67 (m, 1H), 7.66 (s, 1H), 7.51 (t, 1H), 7.35-7.30 (m, 1H) 7.22 (s, 1H), 6.33 (bs, 1H), 5.97 (s, 2H), 3.52-3.46 (m, 4H), 2.67-2.59 (m, 4H).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:38])[C:11]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:15]([C:26](=O)[CH2:27][S:28](=[O:34])(=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:14]([CH3:36])[NH:13][C:12]=2[CH3:37])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)(C)C.CN(C)C=O>[C:1]1([C@H:7]([O:9][C:10](=[O:38])[C:11]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:15](/[CH:26]=[CH:27]/[S:28](=[O:34])(=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[C:14]([CH3:36])[NH:13][C:12]=2[CH3:37])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(C(=O)CS(=O)(=O)NC(C)C)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@H](C)c2ccccc2)=C(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC1=C(/C=C/S(=O)(=O)NC(C)C)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@H](C)c2ccccc2)=C(C)N1
Yield: 78.2 %

Procedure:
Analogously to Example 18, 1.08 g of (S)-1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid (R)-1-phenylethyl ester were treated with 0.08 g of sodium borohydride in a mixture of 10 ml of isopropanol and 2 ml of dimethylformamide. The product was chromatographed with methylene chloride/ethyl acetate (4:1) as the elution agent and then recrystallized from ethanol. There was obtained 0.82 g of (S)-1,4-dihydro-5-[(E)-2-(isopropylsulfamoyl)vinyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid (R)-1-phenylethyl ester in the form of yellow crystals, m.p. 198°-201°, specific rotation: [α]54620 =-290° (c=1.0% w/v, chloroform).