Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([CH:25]([OH:31])[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH:24]=1)[C:18](OC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CCOCC>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:18][OH:19])[CH:22]=[C:23]([CH:25]([CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[OH:31])[CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(C(O)CNC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)NCC(O)c1cc(CO)cc(OCc2ccccc2)c1

Procedure:
To a suspension of LiAlH4 (4.57 g, 120 moles) in anhydrous Et2O (0.5 l.) was added an ethereal solution (0.5 l.) of the methyl 3-benzyloxy-5-[2(isopropylamino)-1-hydroxyethyl]-benzoate (17.5 g, 50.9 mmoles) slowly at room temperature. The resultant mixture was heated at reflux for 4 hrs. The LiAlH4 and complex was hydrolyzed by the slow addition of 40 ml of H2O. The granular precipitate which formed was removed by filtration and an oily product was obtained from the ether filtrate after evaporation; yield 15.2 g. (94.3%). The crude product was crystallized from Et2O-hexane; yield 9.24 g (54.4%) mp. 84°- 89°. The analytical sample was obtained from EtOAc-hexane, mp. 90°-93° .
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:23][CH2:24][N:25]1C(=O)C2=CC=CC=C2C1=O)[CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)#[N:2].NN>CO>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:23][CH2:24][NH2:25])[CH2:10][CH2:11][NH2:12])#[N:2]
Reactant: N#CCCCCCCN(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: N#CCCCCCCN(CCN)CCN
Reaction time: 8 h

Procedure:
A solution of (6-cyanohexyl)bis(2-phthalimidoethyl)amine (13.8g, 0.029 mol) and hydrazine (2.15g, 0.067 mol) in methanol (150 ml) was refluxed for 1.5 hours and allowed to stand overnight. The solvent was removed under reduced pressure and the residue was taken up in water (200 ml) and brought to pH≈2 with HC1. The precipitate was removed by filtration and the filtrate was made basic with solid NaOH. The solution was then concentrated under reduced pressure and extracted with dichloromethane (4×50 ml). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure. Kugelrohr distillation of the residue gave pure (6-cyanohexyl)bis(2-aminoethyl)amine as a water white liquid (4.1g-67%) collected between 120° and 140° C. (pot temp) at 0.07 mm Hg. The ir spectrum was consistent with the assigned structure, as was the elemental analysis.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57][NH2:58])=[CH:55][CH:54]=1>CN(C=O)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([NH:58][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([F:52])=[CH:54][CH:55]=1)=[O:13]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)NCc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid (0.25 g, 0.72 mmol) in DMF (4 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (347 mg, 1.08 mmol) and N-methylmorpholine (0.16 ml, 1.44 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (0.01 ml, 0.86 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 5% acetone/hexane) followed by preparative HPLC affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide (example 15) (0.2 g, 0.42 mmol, 36%). [M+H]+ 455.1.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ccc(Oc2ncccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ncccc2-c2cn[nH]c2)cc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
In a 25 mL sealed tube, was added 4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine (0.150 g, 0.303 mmol), trifluoroacetic acid (0.23 mL, 3.0 mmol), and methanol (1.0 mL). The mixture was stirred at 80° C. for 36 hours. The mixture was concentrated. The residue was extracted into EtOAc, washed 1×NaHCO3, 1×NaCl, and the organic layers were combined and dried over Mg2SO4, filtered through fritted funnel and concentrated to yield 4-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as dark brown waxy solid. MS m/z=253 [M+1]+. Calc'd for C14H12N4O: 252.27.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[N:5]=[C:4]([NH:22]C(=O)C)[CH:3]=1.Cl>C1COCC1>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[N:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: CC(=O)Nc1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(N)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 40 °C
Yield: 73.6 %

Procedure:
A solution of N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (692 mg, 2.051 mmol) in THF (25 mL) was treated with HCl (3 M, 3.4 mL, 10.2 mmol) and warmed at 40° C. for 17 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (446 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.7 Hz, 1 H), 8.23 (s, 1 H), 7.93 (d, J=0.7 Hz, 1 H), 7.10 (d, J=2.4 Hz, 1 H), 6.44 (dd, J=5.7, 2.4 Hz, 1 H), 6.22 (s, 1 H), 5.81 (s, 2 H), 3.84 (s, 3 H), 2.02 (s, 3 H), 1.92 (s, 3 H); MS (ESI) m/z: 296.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]([N:11]2[CH2:10][CH:9]([N:13]([C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)[CH3:28])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12]2)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown foam. MS m/e: 624.3 [M]+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.[CH3:13]CCCCC>CN(C)C=O>[CH3:13][C:4]1[N:5]=[C:6]2[C:10]([NH:9][CH:8]=[N:7]2)=[C:11]([NH2:12])[N:3]=1
Reactant: CCCCCC
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 114 mg (2.85 mmol) of 60% sodium hydride (previously washed with hexane) in 18 ml of anhydrous dimethylformamide 386 mg (2.85 mmol) of adenine was added, and the mixture was stirred for 20 minutes at room temperature. Then, 1.18 g (2.38 mmol) of (Z)-[1,2-bis(benzoyloxymethyl)] cyclopropylmethyl p-toluenesulfonate obtained in Example 1 in 6 ml of anhydrous dimethylformamide was added and the mixture was stirred for 3 hours at 60° C. The solvent was distilled off, and dichloromethane and a saturated aqueous solution of sodium bicarbonate was added to the residue. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The resulting residue was subjected to silica gel chromatography (4-10% methanol/dichloromethane) to get 844 mg (1.84 mmol, 77%) of (±)9-[1'α, 2'β-bis-(benzoyloxy methyl) cyclopropan-1'β-yl] methyladenine and 52.8 mg (0.115 mmol), 5 %) of (±)7-[1'α2'β-bis-(benzoyloxymethyl) cyclopropan-1'β-yl] methyladenine.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: C=CCC(C#N)C#N
Reactant: FC(F)(F)c1ccn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1ccc(C(F)(F)F)n1
Yield: 31.3 %

Procedure:
1.33 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole and 0.76 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.99 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.57 g of allyl {[3-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}malononitrile (referred as the compound of the present invention (7), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[C:26]1([C@H:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(N(CC)CC)C>[C:26]1([C@H:32]([NH:34][C:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]2)=[O:17])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (5 g, 20.5 mmol) was dissolved in THF, to which triethylamine (3 mL) was added. The reaction mixture was cooled to 0° C. and a solution of isobutyl chloroformate (2.8 g, 20.7 mmol) in THF was added dropwise. The resulting white suspension was stirred at room temperature for 30 min, after which a solution of (R)-1-phenylethanamine (2.9 g, 20.5 mmol) in THF was added dropwise. The reaction mixture was then stirred at room temperature for 4 h, after which LC-MS showed one major peak corresponding to desired product. The reaction mixture was concentrated, and the residue was diluted with water (250 mL). The resulting white precipitate was filtered, washing with ether, to afford a dry white solid tert-butyl trans-4-((R)-1-phenylethylcarbamoyl)cyclohexylcarbamate (5.2 g).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][S:6][CH2:5][CH2:4]2)[CH2:2]1.[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:3]1([CH2:2][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=3)=[C:12]([CH3:25])[CH:11]=2)[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1
Reactant: C1CC2(CCS1)CO2
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(C=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a solution of 1-oxa-6-thiaspiro[2.5]octane (6.33 g, 48.6 mmol) and 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (10.0 g, 44.2 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (6.11 g, 44.2 mmol) at room temperature, and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (12.3 g, yield 78%) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:25]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)C=Cc1ccccc1F
Yield: 88.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-leucinate hydrochloride (3.0 g), triethylamine (2.5 mL), 2-fluorocinnamic acid (3.0 g), WSC.HCl (3.5 g), and methylene chloride (100 mL), to give the captioned compound (4.3 g, 88%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH2:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH3:30]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([CH3:23])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:34][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])=[N:9][CH:10]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cc(C)c(=O)n(C)c2)n1

Procedure:
The title compound of Example 149, step 4 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.03-6.97 (m, 1H), 6.91-6.87 (m, 1H), 3.66-3.61 (m, 5H), 2.22 (s, 3H), 1.44 (t, J=7.6 Hz, 3H). LCMS: 437.0 (M+1)+
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(C(C)C)C(C)C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (2.5 g, 4.77 mmol) in N,N-dimethylformamide (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.90 mL, 5.01 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (927 mg, 5.01 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, water (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (2.14 g, 77%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20](=O)[C:19]3[C:18]([C:22](OCC)=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:36][NH2:37]>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:22](=[O:23])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:1])[CH3:34])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of ethyl 3-(4-(dimethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (400 mg, 0.87 mmol) and hydrazine monohydrate (85%, 10 mL) were dissolved in MeOH (20 mL), and stirred at 35° C. for 2 h. The mixture was concentrated under reduced pressure. The resulting mixture was filtered, the solid was washed with water and methanol to obtain a white solid, and the solid was dried in vacuum at 40° C. to obtain the title compound (100 mg, yield 54%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.85 (s, 3H), 2.94 (s, 3H), 4.37-4.40 (d, 1H), 4.80-4.82 (d, 1H), 7.17-7.25 (m, 5H), 7.33-7.36 (m, 2H), 7.39-7.41 (d, 1H), 7.45 (s, 1H), 7.57-7.61 (t, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1.[BH4-].[Na+].[OH-].[Na+]>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH:35][CH2:12][C:10]3[CH:9]=[CH:8][C:5]4[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[N:11]=3)[CH2:32]2)=[N:27]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(n3)NC(=O)CO5)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (153 mg, 0.858 mmol) in DMF (1.36 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (84.4 mg, 0.286 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (37.6 mg, 0.572 mmol) was then added and the suspension was stirred for 1 h at RT. The reaction mixture was diluted with CH3OH and poured into 1 N NaOH. The organic layer was separated, washed with brine (4×), dried (Na2SO4), filtered, and concentrated. The crude material was purified by basic reverse phase HPLC to provide 4.6 mg (3.5%) of the title compound. MS (ESI): exact mass calculated for C24H23N7O3, 457.19; m/z found, 458.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.19 (d, J=8.0, 1H), 7.17 (d, J=9.1, 1H), 6.95 (d, J=8.0, 1H), 4.62 (s, 2H), 4.09 (s, 3H), 3.92 (s, 2H), 3.09-2.98 (m, 3H), 2.83-2.77 (m, 1H), 2.56 (dd, J=14.6, 7.9, 1H), 2.17-2.14 (m, 1H), 1.89-1.82 (m, 1H), 1.24 (s, 1H).
Reaction SMILES: CO[C:3]([O:8][CH3:9])(OC)OC.C(O)(=O)C.[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]3[N:31]=[C:3]([O:8][CH3:9])[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)[C:27]=3[CH:26]=2)=[O:46])(=[O:22])=[O:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Tetramethoxymethane (0.250 g) is added to an acetic acid solution (3 ml) of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide (0.400 g), and the solution is stirred for two hours at 80° C. Methanol is added to the reaction solution, and precipitated crystals are collected. The crystals are washed in a mixture solvent of acetone (1 ml) and methanol (8 ml), separated through filtration, dried and thus, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole (0.280 g) is obtained. 1H-NMR (DMSO-d6, δ): 4.17 (3H, s), 5.33 (2H, s), 7.30 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz), 7.50 (1H, d, J=8.4 Hz), 7.60-7.65 (6H, m), 7.68-7.72 (2H, m), 7.98-8.01 (2H, m), 8.05 (1H, d, J=1.5 Hz), 8.18 (1H, s), 12.50 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccccc4)C3)CC2)cc1
Yield: 117.7 %

Procedure:
The title compound (D145) (225 mg) was prepared according to the experimental procedure described in Description 142 starting from 5-chloro-2-(3-phenoxyazetidin-1-yl)nicotinic acid (D101) (140 mg, 0.46 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (104 mg, 0.40 mmol).