Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([C:11]3([CH2:14][OH:15])[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.CO[CH2:20][CH2:21]OC>C([O-])([O-])=O.[K+].[K+].[Cl-].[Na+].O.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>[OH:15][CH2:14][C:11]1([C:9]2[N:10]=[C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([C:13]4[CH:12]=[C:11]([CH:14]=[CH:20][CH:21]=4)[C:9]#[N:8])[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: COc1ccc(I)n2nc(C3(CO)CC3)nc12
Reactant: COCCOC
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: [Cl-]
Solvent: O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
[1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methanol (compound 308)(0.24 g, 0.07 mmol) was dissolved in DME (4.5 mL) and 1 M K2CO3 (1.4 mL). 5-CN-3-pyridinyl boronic acid (0.21 g, 1.4 mmol) was added followed by Pd(PPh3)4 (0.04 g, 0.035 mmol). The mixture was shaken at 80° C. for 18 h. Brine was added and aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent. The impure product was suspended in 2-propanol and filtered to provide the title compound as a solid.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[C:22]([F:21])([F:31])[F:32])[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[2-(trifluoromethyl)phenyl]methyl]-1,4-diazepan-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.CO.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=1>O>[NH:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[S:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: Sc1nc2ncccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCSc2nc3ncccc3[nH]2)cc1
Yield: 32.4 %

Procedure:
To a mixture of 570 mg 2-mercapto-1H-imidazo[4,5-b]pyridine and 18 ml methanol, was added a mixture of 166 mg sodium hydroxide, 6 ml water and 1.8 g ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate. The resulting mixture was heated under reflux for 12 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, affording 610 mg ethyl 6-[p-[5-(1H-imidazo[4,5-b]pyridin-2-ylthio)pentyloxy]phenoxy]-2,2-dimethylhexanoate as waxy solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[C:21]([CH3:37])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=1)=[O:8].[Li+].[OH-].Cl>O1CCCC1>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][CH:14]([C:11]2[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:8])=[CH:13][CH:12]=2)[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([CH3:37])[C:22]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(OC(F)(F)F)cc3)c(C)c2)C(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)s2)C(C)C)cc(C)c1-c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-({5-[1-(2,6-Dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (Isomer 2) in tetrahydrofuran (2.0 mL) is added 1 N LiOH (2.0 mL) and stirred overnight. The reaction mixture is acidified with 1 N HCl (2.2 mL) and extracted with EtOAc (3×10 mL). Combined extracts are dried over MgSO4, filtered, and concentrated to provide 3-({5-[1-(2,6-dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid (Isomer 2) (0.101 g, 89%) as a white foam. MS (ES): 536.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].[OH-:22].[NH4+].Cl>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:5]([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:22]
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Yield: 56.3 %

Procedure:
To a 250 mL flask was charged 38.16 g (0.119 mole) of alpha-n-butyl-alpha(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 100 mL (0.63 moles) of 48% hydrobromic add. The mixture was stirred at reflux for 48 hours after which GLC indicated disappearance of the starting material. The reaction was cooled to room temperature and neutralized with concentrated ammonium hydroxide (100 mL) to pH 8 and then to neutral pH with concentrated hydrochloric acid. A gummy oil formed which was diluted with 200 mL of ethyl acetate. The organic phase (3×200 mL ethyl acetate) was washed with 100 mL of water (3×). The organic phase was dried and concentrated to give a tan solid which was recrystallized from ethyl ether. The product was filtered and gave 22.78 g (56.3% yield) of a solid, melting point 170°-172° C.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[S:20][CH:21]=[C:22]([Br:28])[C:23]=3[C:24]([O:26][CH3:27])=[O:25])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl.N1CCOCC1>[NH2:18][C:19]1[S:20][CH:21]=[C:22]([Br:28])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(Br)csc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCN1
Solvent: ClCCl
Product: COC(=O)c1c(Br)csc1N

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-bromothiophene-3-carboxylate (1 g) was stirred in DCM/morpholine (12 mL, 1:1) at rt until all the ester was consumed. The crude mixture was concentrated under reduced pressure. The residue was dissolved in ethyl ether. The white solid was removed. The mother liquid was concentrated under reduced pressure and a 1:1 mixture of ethyl ether/pentane (20 mL) was added. An additional white solid was removed. The organic layer was concentrated under reduced pressure and the crude mixture was placed under high vacumn to remove the excess of morpholine. The crude amine was taken directly to the next reaction step without further purification. Method[1], MS (ESI) 235.9 [M+H], Retention time=1.919 min.
Reaction SMILES: C([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1.C1COCC1.CO.O.[OH-].[Li+]>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:12]2[C:13]([CH3:16])=[N:14][O:15][C:11]=2[CH2:10][OH:9])=[O:31])=[CH:25][CH:26]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate from Example 12 (0.780 g, 1.806 mmol), THF (4 mL), MeOH (4 mL), and water (2 mL). The solution was cooled to 0° C. before addition of lithium hydroxide monohydrate (0.227 g, 5.42 mmol). The reaction was stirred at 0° C. for 45 min before diluting with water and extracting with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone (0.451 g, 1.376 mmol). LC/MS m/z 328 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:21]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:21]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cncc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.5 g, 6.5 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.1 g, 90%) as a white solid: LC/MS m/e calcd for C21H25N3O3 (M+H)+: 368.45, observed: 368.1.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[CH3:32].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][CH2:40][C:41]1[N:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[S:44][C:45]=1[CH:46]=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9](/[CH:10]=[CH:46]/[C:45]2[S:44][C:43]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:57])[F:55])=[CH:50][CH:49]=3)=[N:42][C:41]=2[CH2:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:8][C:7]=1[CH3:32]
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 242mg, 6.32mmoles, 1.4eq) in dry CH2Cl2(15ml) was added (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62g, 6.32mmoles, 1.4eq). This was allowed to stir at room temperature for 1.5hours followed by the dropwise addition of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (1.68g, 4.51mmoles, 1eq) in anhydrous carbon tetrachloride (25ml). The resulting reaction mixture was refluxed overnight at which point (after cooling to room temperature) the reaction washed with 1N NaOH, H2O, brine, dried over Na2SO4and concentrated in vacuo to yield a >100% yield of a light green oil. The crude material was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[C:18]2[CH:24]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(ccc2c1)-c1ccccc1C3c1ccc(OCCN2CCCCC2)cc1

Procedure:
Eight g of the compound of Example 2 was combined with 16.3 g of potassium carbonate and 4.6 g of 1-(2-chloroethyl)piperidine hydrochloride in 75 ml of dimethylformamide under anhydrous conditions, and the process was carried out and the product isolated as described in Example 6 above. The 9.5 g of product from the chromatography was recrystallized from isopropanol to obtain 8.74 g of the desired product, m.p. 130°-133° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=3[N:24]=2)=[CH:17][CH:16]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:34])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc2[nH]c(SCc3ccc(C(=O)Nc4ccccc4O[Si](C)(C)C(C)(C)C)cc3)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(SCc3ccc(C(=O)Nc4ccccc4O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a stirred solution of compound 198 (313 mg, 0.600 mmol) in THF (15 ml) was added TBAF 1M in THF (1.20 ml, 1.20 mmol). The reaction mixture was stirred 16 h at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc, washed with sat. NH4Cl and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound 199 (150 mg, 61% yield) as a white powder. 1H NMR (DMSO-d6) δ (ppm): 9.72 (bs, 1H), 9.49 (bs, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=9.5 Hz, 1H), 7.08-6.89 (m, 4H), 6.81 (dd, J=7.0, 7.0 Hz, 1H), 4.76 (s, 2H), 3.81 (s, 3H). m/z: 406.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]([C:10]1[S:11][C:12]([S:38][CH3:39])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:32]([NH:34][CH2:35][CH2:36][NH2:37])=[O:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[N:41]([CH2:44][C:45]([O:47][CH2:48]C)=[O:46])=[C:42]=[O:43]>C(Cl)Cl>[CH3:48][O:47][C:45](=[O:46])[CH2:44][NH:41][C:42]([NH:37][CH2:36][CH2:35][NH:34][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:40])=[NH:9])[S:11][C:12]=2[S:38][CH3:39])(=[O:16])=[O:17])[CH:19]=1)=[O:33])=[O:43]
Reactant: CCOC(=O)CN=C=O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCN)c1
Solvent: ClCCl
Product: COC(=O)CNC(=O)NCCNC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 86 %

Procedure:
A solution of [(4-{2′-[3-(2-amino-ethyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester ((Example 194: step a) 0.030 g, 0.050 mmol) in CH2Cl2 (10 mL) was treated with ethyl isocyanatoacetate (6.70 μL, 0.060 mmol) and stirred at room temperature 35 min. The reaction was diluted with CH2Cl2 and washed with water (1×15 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid methyl ester (0.031 g, 86%) as an off-white solid. C32H40N6O8S3: 733.21 (M+1) found 732.90.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]([CH2:32][CH2:33][NH2:34])[CH3:31]>N1C=CC=CC=1>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][NH:34][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(Br)c1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 200 °C

Procedure:
90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is dissolved in 3 ml of pyridine and mixed with 1 ml of N,N-dimethyl-aminoethylamine and heated in a pressure vessel for 5 hours to a bath temperature of 200° C. After cooling, it is concentrated by evaporation, and 90 mg of 2-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained. Melting point: 100° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:5]1[N:4]([CH:12]([CH3:13])[CH3:14])[N:3]=[C:2]([OH:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(C(C)C)nc1O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)nn(C(C)C)c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.2 %

Procedure:
Ethyl 3-hydroxy-1-isopropylpyrazole-4-carboxylate (10.5 g) was dissolved in dichloromethane (100 mL) and to the stirred solution was added N-bromosuccinimide (14.1 g) under ice cooling. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 5.9 g of the title compound.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[O:11][N:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH:18]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:13]=[C:12]([CH2:14][C:15]([OH:18])=[O:16])[O:11][N:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C(=O)c2cc(CCO)on2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cc(CC(=O)O)on2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 10.7 g of 2-[3-(4-toluoyl)isoxazol-5-yl]ethanol, 1000 ml of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 150 ml of 9M H2SO4 was added 13.6 g of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 1.5 hour. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was extracted with CH2Cl2, and the organics were washed with water and brine, and dried over MgSO4. Concentration gave 11.0 g of an oil which solidified on standing. Recrystallization from toluene gave 4.8 g (43%) of a solid, m.p. 105°-107°.
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][O:26][CH3:27])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1>[Pd].C1COCC1>[CH3:27][O:26][CH2:25][C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1
Reactant: COCc1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (199 mg; manufactured by N.E. Chemcat Corp.) and 6-(benzyloxy)-3-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)indazole (450 mg) that can be produced by the method described in Reference Example 54 or the like, were dissolved in THF (12.7 mL; manufactured by Kanto Chemical Co., Inc.). The reaction system was purged with hydrogen, and under a hydrogen atmosphere, the reaction solution was stirred overnight at room temperature. The reaction solution was purged with nitrogen, and then was filtered. The filtrate was concentrated under reduced pressure, and thus the title compound (337.4 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH:19]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:18][CH2:17]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[O:34])C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH:19]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:18][CH2:17]4)[C:10]2=[O:34])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(=O)NC1CCc2cc(N3CCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(=O)NC1CCc2cc(N3CCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3=O)ccc21
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a solution of 235.7 mg N-{5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2,3-dihydro-1H-inden-1-yl}propanamide (0.5 mmol) in 20 ml toluene was added 1304 mg manganese(IV)dioxide (15.0 mmol) and stirred at 20° C. for 12 h. After standing for about 2 d at room temperature 100 μl acetic acid were added and the mixture stirred for 15.5 h. The reaction mixture was filtered through celite-silica gel. The crude product (198 mg) was subjected to silica gel column chromatography yielding 20 mg of compound (I-A-2) and 67 mg pure N-{5-[3-(3,5-dichlorophenyl)-2-oxo-3-(trifluoromethyl)pyrrolidin-1-yl]-2,3-dihydro-1H-inden-1-yl}propanamide (I-B-2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.3 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.