Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[NH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[O:9])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2c[nH]c(=O)o2)CC1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (step 1) and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate analogously to Example 20 step 4;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:8]([CH2:23]O)=[CH:7]2.C(Cl)(Cl)[Cl:26].S(Cl)(Cl)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:8]([CH2:23][Cl:26])=[CH:7]2
Reactant: OCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cl
Product: Fc1ccc(C(F)(F)F)c(-c2nc3c(Cl)cccc3cc2CCl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinolin-3-yl)-methanol (0.3016 g, 0.8479 mmol) in chloroform (2.826 mL, 0.8479 mmol) was treated with thionyl chloride (0.3085 mL, 4.239 mmol) dropwise, and the reaction mixture was stirred at room temperature. After 3 h, the mixture was concentrated under reduced pressure and co-evaporated three times with CH2Cl2 to give 8-chloro-3-(chloromethyl)-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline hydrochloride as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (1 H, s), 8.11 (1 H, dd, J=8.2, 1.2 Hz), 7.99-8.07 (2 H, m), 7.60-7.75 (3 H, m), 4.63-4.90 (2 H, m); LC-MS (ESI) m/z [M+H]+ (Exact Mass of neutal form: 373.005). The yellow syrup was carried on crude without purification for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Temperature: 80 °C
Yield: 49.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (2.49 g, 10 mmol) in DMF (20 mL) was added 3-amino-phenyl boronic acid (1.51 g, 11 mmol), Pd(PPh3)4 (90 mg, 0.30 mmol), potassium carbonate (1.52 g, 11 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (50 mL×3). The combined organics were concentrated under reduced pressure to give crude product, which was washed with EtOAc to give pure 3′-amino-N-methylbiphenyl-4-sulfonamide (C-3) (1.3 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.95-7.01 (m, 2H), 6.73-6.77 (m, 1H), 2.54 (s, 3H). MS (ESI) m/e (M+H+) 263.0.
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][C:24]1([O:30]C(=O)C)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].C(C(CC#CC(OC(=O)C)CCCCC)(CCCCCCC(OCC)=O)C(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:21][C:22]#[C:23][C:24]1([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)(C(C)=O)C(=O)OCC
Agent: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Product: CC(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the same procedure described in Example 35, Step B, except that diethyl 2-acetyl-2-[3-(1-acetoxycyclohexyl)-2-propyn-1-yl]azelate is substituted for diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate. The chromatographically purified product is a yellowish viscous oil; pmr (CDCl3) δ 2.14 (3H, s CH3CO), 6.50 (2H,s OH and COOH).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:12][CH2:11]1)=[O:28]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
The compound (100 mg, 0.215 mmol) obtained in Example 4g was dissolved in ethanol (6 mL), tert-butyl 3-aminobenzoate (54 mg, 0.279 mmol) and sodium triacetoxyborohydride (59 mg, 0.279 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (80.0 mg; yield, 58%) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[CH2:21](I)[CH3:22].[CH2:24]1COC[CH2:25]1>CN(C=O)C>[CH2:24]([C:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)([CH2:21][CH3:22])[C:16]#[N:17])[CH3:25]
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: C1CCOC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C#N)(CC)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (2.0 g, 8.23 mmol) in DMF (40 mL) was cooled to 0° C. and sodium hydride (60 wt %, 1.2 g, 32.9 mmol) added portion wise. The mixture was stirred for 10 min and ethyl iodide (0.74 mL, 9.05 mmol) in THF (10 mL) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (950 mg, 38%) as a brown solid: ESI MS m/z 300 [C18H26BNO2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH2:24][CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:27]([CH3:26])=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)c1ccccc1C1CCNCC1
Reactant: CCCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CCCN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 46.5 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-propyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.235 g) was treated with 4-(2-methylsulfinylphenyl)piperidine (0.236 g) as described in Example 8. The resulting material was purified by chromatography and was transformed into the hydrochloride to afford the title compound (0.09 g); mp 78-85° C. (dec); MS: m/z=583(M+1); NMR(CD3OD): 0.92 (m,3), 1.5-4.3 (m,21), 4.98-5.04 (m,1), 7.27 (m,1l). Analysis for C32H36Cl2N2O2S.1.0 HCl.0.5 H2O: Calculated: C, 61.09; H, 6.08; N, 4.45; Found: C, 60.78; H, 5.68; N, 4.67.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].[CH3:30][C:31]1[N:32]=[C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[S:34]C=1C(=O)C>C1(C)C=CC=CC=1>[CH3:2][O:3][CH:24]=[C:25]([C:28]1[S:34][C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:41][CH:40]=2)=[N:32][C:31]=1[CH3:30])[CH3:26]
Reactant: CC(C)(C)[O-]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of (methoxymethyl)triphenyl phosphonium chloride (15.5 g, 45.2 mmole) in toluene (330 mL) is added potassium t-butoxide (5.07 g, 45.2 mmole) in one portion and stirred for 30 minutes, then a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (8.6 g, 30.1 mmole) in toluene (20 mL) is added. The reaction is stirred for 4 hours, quenched by NH4Cl aqueous solution, extracted with ethyl acetate and then concentrated on rota vapor. The residue is purified on a silica gel column, eluting with 0–10% ethyl acetate in hexane and concentrated to provide the title compound (7.0 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([O:31][CH3:32])[C:23]([CH2:33][CH3:34])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([CH2:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([O:31][CH3:32])[C:23]([CH2:33][CH3:34])=[CH:22][CH:21]=2)=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(CC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Yield: 67.6 %

Procedure:
3-Chloroperbenzoic acid (0.07 g) was added to a stirred solution of ethyl 6-(phenylthiomethyl)-3-ethyl-2-methoxybenzoate (Intermediate 19, 0.315 g) in DCM (5 ml) and the resultant mixture was stirred at room temperature overnight. The solution was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give ethyl 6-(benzenesulphinylmethyl)-3-ethyl-2-methoxybenzoate (0.095 g) as a clear gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:10][C:9]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:41]CC1.[Li+].[OH-].CO>O>[C:1]([O:5][C:6]([NH:8][C@H:15]1[CH2:16][C@@H:11]([CH2:10][C:9]([OH:41])=[O:37])[CH2:12][CH2:13][C@@H:14]1[N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@H](CC(=O)O)C[C@@H]2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A 500 ml two-necked round-bottomed flask was loaded with 5.25 g of PMBzBoc-A lactam 15f (10.36 mmol) and 200 ml of THF. After cooling to 0° C., a solution of 2.17 g of LiOH×H2O (51.8 mmol) in 50 ml of H2O was added dropwise over a period of 20 min. 30 ml of MeOH were then added, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. An ion-exchange resin (Amberlite IR-120, H+ form) was then added until a pH of 7 was reached. The resin was removed by filtration and the solution was concentrated under reduced pressure to a volume of 100 ml. 200 ml of H2O were then added and a pH of 2 was adjusted by addition of 1 M aqueous HCl. The solution was extracted with EtOAc (3×200 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in 25 ml of hot MeOH. The product was then precipitated by addition of 10 ml of H2O. The precipitate was filtered, washed with H2O and dried over P4O10 to afford 1.95 g of 16. It was possible to obtain a further 0.57 g from the mother solution and the wash solutions to afford a total yield of 46%.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:1][C:4]=2[CH:18]=1
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)NCc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol was hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceased, the catalyst was removed by filtration and the ethanol solvent was evaporated. The residue was then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There was then obtained yellowish-white crystals which were separated by filtration to give 8-(trifluoromethyl)10,11,-dihydrodibenz-[b,f][1,4]oxazepine melting at about 86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([Cl:22])=[CH:14][C:3]=1[NH:4]C1C=CC=CC=1CCO.[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[N:24]1.[C:30]([O-:33])(=O)[CH3:31].[C:34]([O-])(=O)[CH3:35].[C:38]([O-])(=O)[CH3:39].[C:42]([O-])(=O)[CH3:43].[Pb+4].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[Cl:22][C:15]1[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:2]2[N:1]=[C:28]([C:25]3[CH:26]=[CH:27][NH:23][N:24]=3)[N:4]([C:35]3[CH:34]=[CH:39][C:38]([CH2:31][CH2:30][OH:33])=[CH:43][CH:42]=3)[C:3]=2[CH:14]=1
Reactant: O=Cc1cc[nH]n1
Reactant: CC(=O)[O-]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccccc1CCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Pb+4]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCc1ccc(-n2c(-c3cc[nH]n3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Yield: 84.4 %

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of Example 104, 2.28 g, 5.85 mmol) and 1H-pyrazole-3-carbaldehyde (562 mg, 2.85 mmol) in ethanol (35 ml) was stirred under reflux temperature for 1 h. The mixture was concentrated and dissolved in benzene (40 ml). To this solution was added lead tetraacetate (2.85 g, 6.44 mmol) at rt. After stirring at room temperature for 18 h, to the mixture were added saturated aqueous sodium hydrogencarbonate (50 ml) and ethyl acetate. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (20:1 to 10:1), then dichloromethane/2-propanol (5:1) afforded 979 mg (41%) of the title compound as a slight brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH3:15][N:12]1[CH:13]=[CH:14][C:10]([NH:9][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:2]4[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[N:11]1
Reactant: Cn1ccc(N)n1
Reactant: Cc1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cc1cccnc1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1

Procedure:
The compound of Example 121 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-methylpyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29](OCC)=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.O>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: OCCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 65 °C

Procedure:
To a solution of ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate (90 mg, 0.2 mmol) in EtOH (3 mL) was added NaBH4 (76 mg, 2 mmol). The resulting mixture was heated at 65° C. for 2 h and then poured into CH2Cl2/H2O (50 mL/50 mL). The aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by silica gel column using EtOAc to 2% MeOH/EtOAc as the eluent to yield 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)ethanol.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22]([C:28](OCC)=O)[C:23](OCC)=O)[CH3:21]>C1COCC1.CCOCC>[CH3:19][N:20]([CH3:21])[CH:22]1[CH2:28][C:7]2[C:11]3=[C:3]([CH:2]=[CH:9][N:10]3[CH2:23]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C1Cc2cccc3ccn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl) -1 H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino) malonate. The bulk of the product was converted to the maleate salt, mp 114°-115° C. from THF/ether.
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:28].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:28])[CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)[CH3:3]
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: O=C=O
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CC(C)Br
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCCn1nc(N)c2c(O)cccc21
Reaction time: 12 h
Yield: 40 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 2.81 g of 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole obtained by the same method as described in Example 1, 2.06 g of iso-propyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.01 g of 1-(3-diethylaminopropyl)-3-amino-4-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]O)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:39])(=O)=O.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][Cl:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a slurry of 3.3 g (9.2 mmol) N-(4-fluorobenzyl)-2-(hydroxymethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 200 mL anhydrous DMF at 0° C., was added 3.0 mL (22.7 mmol) 2,4,6-collidine and 0.75 g (6.14 mmol) 4-(dimethylamino) pyridine. To this mixture, 1.8 mL (23.3 mmol) of methanesulfonyl chloride was added in two portions of 0.9 mL. The mixture was allowed to slowly warm to room temperature with stirring over night. After 19 hours, the homogeneous dark brown mixture was poured into 1.0 L of water. The resulting slurry was stirred for 2 hours at room temperature. The solids were then collected by vacuum filtration, washed with additional water, and dried in a vacuum oven at 60° C. over a weekend. This provided 2.91 g of the title compound as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.C(N(CC)CC)C.CS(C)=O>O>[CH:8]1[C:9]2[C:4](=[C:3]([CH:2]=[O:1])[C:16]3[C:11]([C:10]=2[CH:17]=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c2ccccc2c(CO)c2ccccc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 0.83 h

Procedure:
To a solution of 1.20 g. of 10-hydroxymethyl-9-anthracenecarboxaldehyde in a mixture of 14 ml. of triethylamine and 20 ml. of dry dimethylsulfoxide is added a solution of 4.80 g. of sulfur trioxide pyridine complex in 25 ml. of dry dimethylsulfoxide. The mixture is stirred for 50 minutes and then poured into 200 ml. of water. The crystals are collected and washed with water, giving 1.18 g. of the desired product as orange crystals, mp. 224°-245° C.