Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25]3)[C:8]2([NH:15][C@@H](C2C=CC=CC=2)CO)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[NH2:15][C:8]1([C:11]([O:13][CH3:14])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[CH2:28][CH2:29]2
Reactant: COC(=O)C1(N[C@H](CO)c2ccccc2)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 2 h
Yield: 123.1 %

Procedure:
To a solution of methyl 6′-bromo-1′-(((S)-2-hydroxy-1-phenylethyl)amino)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (0.0180 g, 0.03 mmol) in CH2Cl2 (3 mL) and MeOH (1.5 mL) was added Pb(OAc)4 (0.0500 g, 0.11 mmol) at 0° C. The mixture was stirred for 2 h. After the solvents were evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0136 g (94%) of methyl 1′-amino-6′-bromo-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate as a TFA salt. LC-MS tR=1.11 min in 3 min chromatography, m/z 368, 370 (MH), 351, 353, 319, 321; 1H NMR (400 MHz, CD3OD) δ 7.57-7.54 (m, 2H), 7.31 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.35 (s, 3H), 3.25-3.15 (m, 2H), 3.04 (d, J=16 Hz, 1H), 2.09-2.06 (m, 2H), 1.61-1.29 (m, 6H); 13C NMR (100 MHz, CD3OD) δ 170.36, 143.46, 140.64, 134.50, 128.89, 128.09, 121.70, 79.44, 75.22, 56.11, 54.06, 52.58, 39.97, 31.11, 29.52, 29.44, 28.88.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[CH2:6]([O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26]Br)=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]CC.[Na+]>C(O)C>[CH2:6]([O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:4]=[C:2]([CH3:3])[NH:5][CH:26]=2)=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=N)N
Reactant: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)c[nH]1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
Acetamidine hydrochloride (112 mg, 1.18 mmol), benzyl-[2-(4-bromoacetyl-phenoxy)-ethyl]-carbamate (160 mg, 0.39 mmol), and sodium ethoxide (80.3 mg, 1.18 mmol) were combined in a round-bottomed flask, dissolved in ethanol, and heated to about 80° C. for about two hours. The reaction mixture was then allowed to cool to room temperature, and the resulting heterogenous mixture was filtered. The filtrate was then concentrated in vacuo to an oil which was purified by column chromatography (silica gel; 5% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 92 mg (64% yield) of the desired product. LRMS ([M+H]+)=352.2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:16]4[CH2:21][CH2:20][N:19](CC5C=CC=CC=5)[CH2:18][CH2:17]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(CO)c(N3CCN(Cc4ccccc4)CC3)c(F)cc2c1=O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(CO)c(N3CCNCC3)c(F)cc2c1=O
Reaction time: 6.5 h
Yield: 32.4 %

Procedure:
To 1-cyclopropyl-7-(4-benzyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (132 mg) are added 10% Pd-C (68 mg) and ethanol (10 ml), and the mixture is subjected to catalytic reduction under hydrogen gas atmosphere at 60° C. for 6.5 hours. After filtering off the catalyst, the filtrate is concentrated. The resulting residue is recrystallized from ethanol-acetone-dichloromethane to give 1-cyclopropyl-7-(1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (34.2 mg), as white powder, m.p. 149°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1ccc(CO)nc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-n3cccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH3:27])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C/C=C/C1CCCCC1)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CCCC1CCCCC1)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 104.7 %

Procedure:
A solution of Example 36C (3.52 g, 9.71 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.352 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (2.79 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[S:13][C:14]=2[C:15]2[N:19]=[CH:18][N:17](COCC[Si](C)(C)C)[N:16]=2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[S:13][C:14]=2[C:15]2[N:19]=[CH:18][NH:17][N:16]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2C(O)c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OC(c1ccc(Cl)cc1)c1nc(-c2ccncc2)sc1-c1nc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
(4-Chlorophenyl)[2-pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol (266.0 mg, 0.530 mmol) was dissolved in methylene chloride (3.0 mL, 47 mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solution was stirred at rt overnight. After the reaction wars completed, saturated NaHCO3 was added and the reaction was stirred at it for 20 min, then EtOAc (5 mL) was added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 2-20% MeOH in DCM) to give the title compound as a white solid (200 mg). The racemic isomers were separated by chiral prep HPLC to yield 17 (34 mg, 12.7%) (peak 1, ret. time 13.04 min). LCMS: (FA) ES+, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.76 (s, 1H), 8.69-8.71 (dd, J=1.5 Hz, 2H), 7.86-7.88 (dd, J=1.5, 2H), 7.55-7.58 (d, J=8.5 Hz, 2H), 7.34-7.38 (d, J=8.5 Hz, 2H), 6.84-6.86 (s, br, 1H) and 70 (34.8 mg, 13.0%) (peak 2, ret. time 13.2 min). LCMS: (FA) ES+, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.68-8.72 (m, 3H), 7.86-7.88 (dd, J=1.69 Hz, J=1.5 Hz, 2H), 7.54-7.58 (d, J=8.47 Hz, 2H), 7.34-7.38 (d, J=8.47 Hz, 2H), 6.81-6.82 (s, br, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C#N)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (25 mL) was added dropwise 4-cyanobenzoyl chloride (92 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D −47° (c 1.0, CHCL3); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(N1CCN(C2N=CC(C3C=CC([C:71]([F:74])([F:73])[F:72])=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH3:30][CH:28]([CH3:29])[C@@H:24]([CH2:23][S:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:71]([F:74])([F:73])[F:72])=[CH:3][CH:4]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[C:25]([OH:27])=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)O
Yield: 24 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(3-methyl-2-(R)-{4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine -sulfonylmethyl}butyryl)oxazolidin-2-one(0.480 g), to give the title compound as a white solid (0.086 g, 24%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:18][NH:19][CH3:20]>O1CCCC1>[CH3:18][N:19]([CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:20]
Reactant: COC(=O)c1sc(-c2ccccn2)nc1CBr
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccn2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound prepared in Example 152 (500 mg) and dimethylamine (1.8 mL) in tetrahydrofuran (3 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1 then ethyl acetate=1) to obtain the title compound (191 mg) having the following physical data. 1H NMR (CDCl3): δ 8.63-8.59 (m, 1H), 8.34-8.25 (m, 1H), 7.84-7.76 (m, 1H), 7.40-7.33 (m, 1H), 4.01 (s, 2H), 3.91 (m, 3H), 2.41 (s, 6H);
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:30]=[CH:29][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([OH:17])=O)=[CH:9][CH:8]=2)=[N:4][N:3]=1.N#N.Cl.CN(C)CCCN=C=NCC.[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@H:22]4[CH2:26][CH2:25][N:24]([CH3:27])[C:23]4=[O:28])[CH:20]=3)[C:15]([NH:45][C:46]3[S:47][CH:48]=[CH:49][N:50]=3)=[O:17])=[CH:29][CH:30]=2)=[N:4][N:3]=1
Reactant: Nc1nccs1
Reactant: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(Oc3cc(O[C@H]4CCN(C)C4=O)cc(C(=O)Nc4nccs4)c3)cc2)o1
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a stirring solution of S-(+3-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]-5-[(1-methyl-2-oxo-pyrrolidin-3-yl)oxy]benzoic acid (3.5 g) (Intermediate 13) in dry DCM in single necked round bottomed flask fitted with stop cock with N2(g) balloon, 4-(dimethylamino)pyridine (2.24 g) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI. HCl) (3.3 g) were added at room temperature. After stirring at the same temperature for 15 min, 2-aminothiazole (0.94 g) was added and stirring was continued for 16 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with DCM (200 mL), washed with dil HCl (20 mL, 0.05 N), saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude brown solid (3.5 g). The crude brown solid was purified by solvent trituration.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:29])([F:30])[F:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: COCCN
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COCCNCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methoxy-ethylamine according to the procedure of Example 66. MS m/z 465.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)ccc1CNS(C)(=O)=O
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(C)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a stirred solution of phenyl 3-methyl-4-(methylsulfonamidomethyl)-phenylcarbamate (46 mg, 0.137 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (36 mg, 0.137 mmol) in acetonitrile were added 4-dimethylaminopyridine (17 mg, 0.137 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Methyl-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 81) (61 mg) was obtained as 88% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([F:19])[C@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([F:19])[C:10]1=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H](F)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2C(F)C1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of (±)-(1S,2S,3R)-3-tert-butoxycarbonylamino-1-fluoro-1,2,3,4-tetrahydro-2-naphthalenol (140mg) in anhydrous methylene chloride (5 ml) was added Dess-Martin periodinane (340 mg) and tert-butyl-alcohol (70 mg). Stirring was maintained at room temperature for 31/2 hours. The reaction was quenched with isopropanol and the reaction mixture was poured on a silica gel column (50 g, elution with cyclohexane: ethyl acetate, 9:1) to afford the title compound (105 mg) as an oil. Step G: 3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone. hydrochloride
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>O1CCOCC1>[CH:10]1([NH:16][C:2]2[N:4]=[C:5]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]=[C:8]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:1]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: C1CCC(Nc2nc(NC3CCCCC3)nc(NC3CCCCC3)n2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 400 mL of 1,4-dioxane. The mixture solution was warmed to 50° C. While stirring, the warmed solution was dropwise added with 60.2 g (0.6 mol.) of cyclohexylamine over two hours in such a manner that the reaction temperature did not raise over 50° C. While continuing further stirring, the temperature was raised to 85° C. and 60.2 g (0.61 mol.) of cyclohexylamine by keeping the temperature. Thereafter, the temperature was again raised and the reaction was carried out at the reaction temperature of 95° C. for six hours. 230 g of water were added to the reaction solution so that the temperature did not fall less than 90° C. and then, cooled. to the room temperature while stirring. Product was separated, from the reaction solution through filtration and washed with each 150 mL of water four times. The filtered product was dried at 70° C. for six hours under vacuum to obtain 34.2 g of 2,4,6-tris(cyclohexylamino)-1,3,5-triazine (yield: 225° C.)
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](Cl)=[N:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.O>[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](=[O:1])[NH:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: Fc1ccccc1-c1nnc2cc(C3CC(OCc4ccccc4)C3)c(Cl)nn12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1

Procedure:
4N Sodium hydroxide (3 ml, 12 mmol) was added to a solution of 7-(3-benzyloxycyclobutyl)-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.98 g, 2.4 mmol) in 1,4-dioxane (30 ml) and water (8 ml), heated to reflux for 18 hours. The solvent was evaporated and the residue dissolved in diethyl ether (50 ml) and water (50 ml) and separated. The aqueous layer was acidified to pH 2 with 2N hydrochloric acid and the resultant solid collected by filtration, washed with water (50 ml), followed by diethyl ether (50 ml) and dried under vacuum at 100° C. for 18 hours. Data for the title compound: 1H NMR (400 MHz, CDCl3), cis and trans isomers present in 4:1 ratio, δ 1.95-2.03 (1.6H, m), 2.31-2.38 (0.4H, m), 2.50-2.56 (0.4H, m), 2.68-2.76 (1.6, m), 3.05-3.13 (1H, m), 3.65-3.73 (0.2H, m), 4.06-4.15 (0.8H, m), 4.46 (2H, s), 6.80-6.87 (2H, m), 7.22-7.37 (6H, m), 7.55-7.61 (1H, m), 7.63 (0.8H, m), 7.68 (0.2H, s); MS (ES+) m/e 391 [MH]+.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:82])([CH2:59][NH:60][C:61]([C:63]1[NH:64][C:65]2[C:70]([CH:71]=1)=[CH:69][CH:68]=[CH:67][C:66]=2[N:72]([CH3:81])[S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74])=O)[CH2:45][N:46]1[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]1)C1C=CC=CC=1.CSC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:81][N:72]([C:66]1[CH:67]=[CH:68][CH:69]=[C:70]2[C:65]=1[NH:64][C:63]([C:61]1[S:43][C:44]([CH3:82])([CH2:45][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[CH2:59][N:60]=1)=[CH:71]2)[S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74]
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCN(C(=O)OC(C)(C)C)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSC
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
To a mixture of triphenylphosphine oxide (3.09 g) and acetonitrile (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.93 mL) at 0° C., and the mixture was stirred for 10 min. tert-Butyl 4-{2-(benzylthio)-2-methyl-3-[({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate (1.55 g) and dimethylsulfide (0.24 mL) were added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was added to 4N hydrogen chloride-ethyl acetate solution, and the resulting crystals were collected by filtration, and washed with ethyl acetate. The obtained crystals were added to saturated aqueous sodium hydrogencarbonate, and the mixture was stirred for 30 min. The crystals were collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (0.49 g, yield 45%) as colorless crystals. melting point 178-180° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[NH2:31][OH:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[OH:32][NH:31][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)NO)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in step (a) of the Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was removed in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and then treated with hydroxylamine hydrochloride (140 mg, 2.0 mmol) and Na2CO3 (106 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 days. Methylene chloride (150 mL) was added to the mixture, washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) added and the solvent removed in vacuo. The residue was purified by flash chromatography (1:1 ethyl acetate/methylene chloride) to give the title compound as a white foam (95 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 2.25 (s, 3 H), 4.89 (br s, 1 H), 4.98 (d, 2 H, J=10.7 Hz), 5.58 (br s, 1 H), 6.15 (br s , 1 H), 7.33-7.64 (m, 6 H), 7.76-7.83 (m, 1 H), and 7.92 (d, 1 H, J=4.0 Hz). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O5SCl: 447.1 (M+H), 469.1 (M+Na). Found: 447.1, 469.2.