Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]([NH2:27])[NH2:26])=[CH:20][CH:19]=1.C(O)(O)=O>CN1C(=O)CCC1.O>[C:21]1([NH:24][C:25]2[N:27]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:26]=2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: NC(N)=Nc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (0.49 g, 2 mmol) and phenylguanidine carbonate salt (0.30 g, 2.2 mmol) in NMP (4 ml), is stirred at 120° C. for 2 days. It is then cooled to room temperature and diluted with water (40 ml). The resulting suspension is filtered, and the precipitate is washed with 50% ammonium chloride solution, water, and hexanes, and then dried in vacuo to give 0.56 g of an off-white solid; mp 162-163° C.; HRMS: calcd for C17H12F3N3, 315.0983; found (ESI_FTMS, [M+H]1+), 316.1048.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]1[CH2:9][CH:8]([C:10]#[N:11])[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]1[CH2:9][CH:8]([CH2:10][NH2:11])[CH2:7]1
Reactant: N#CC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile (0.083 g, 0.347 mmol) in dry THF (2 ml) cooled to 0° C. is treated with a 1.0 M solution of lithium aluminium hydride in THF (0.347 ml). The reaction mixture is allowed to warm to ambient temperature and stirred for a one hour. The reaction mixture is quenched with saturated sodium sulphate solution and filtered. The filtrate is evaporated to afford the title compound. [MH] 244.97.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1Cc2ccccc2CN1
Yield: 99.6 %

Procedure:
5.7 kg of benzyl 3(S)-(t-butylcarbamoyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were dissolved in 40 l of ethanol and hydrogenated in an autoclave in the presence of 1.1 kg of 10% palladium-charcoal at a pressure of 10 bar and an internal temperature of 20°-25°. After approximately 2 hours the hydrogen uptake ceased, whereupon the content of the autoclave was filtered, the autoclave and the filter residue were each rinsed twice with 20 l of ethanol each time and the combined filtrates were evaporated, whereby approximately 3.6 kg of crude N-t-butyl-1,2,3,4-tetrahydro-3(S)-isoquinoline-carboxamide were obtained as a beige solid.
Reaction SMILES: [CH2:1]1[C:14]2[CH:5]([NH:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH:4]([C:15]([NH2:17])=O)[CH2:3][CH2:2]1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[CH2:1]1[C:14]2[CH:5]([NH:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH:4]([C:15](=[S:20])[NH2:17])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCCC2=CC3=CC=CCC3NC21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Product: NC(=S)C1CCCC2=CC3=CC=CCC3NC21

Procedure:
A solution of sym. octahydroacridine-4-carboxamide (1.8 gm.) in pyridine (17 ml.) was treated with hydrogen sulphide for 5 mins. The reaction mixture was treated with phosphorus pentasulphide (1.4 g.) and heated at reflux for 45 mins maintaining a slow stream of hydrogen sulphide throughout. The cooled reaction mixture was evaporated and the residue treated with 10% sodium hydroxide until alkaline. The aqueous solution was extracted with chloroform (3× 50 ml.) and the combined extracts washed with brine, dried and evaporated and the residual solid recrystallised from di-isopropyl ether giving the title compound as a pale yellow powder (0.3 g. 16% ) m.p. 104°-6° (solidifies and remelts at 148°). (Found: C, 68.69; H, 7.54; N, 10.98%. C14H18N2S requires: C, 68.26; H, 7.36; N, 11.37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1>CC(O)=O.[Rh]>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9]
Reactant: COc1ccccc1N
Agent: [Rh]
Solvent: CC(=O)O
Product: COC1CCCCC1N
Yield: 22.7 %

Procedure:
Shake a mixture of o-anisidine (5.0 g, 41 mmol) and rhodium on carbon (5% Rh; 5.0 g) in AcOH (65 mL) under H2 (60 psig) at 60° C. for 6 h. Filter the reaction mixture and rotary, evaporate the filtrate (75° C.). Dissolve this material in CHCl3 (100 mL) and basifiy with satd aq NaHCO3 (50 mL). Dry the organic layer (Na2SO4) and rotary evaporate (40° C.) to yield 1.20 g of 2-methoxy-cyclohexylamine as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])C3SC=CN=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29].C(#N)C.NC1C(F)=C(F)C(F)=[C:44]2[C:39]=1[C:40](=O)[C:41](C(O)=O)=[CH:42][N:43]2[C@@H]1C[C@@H]1F>C(N(CC)CC)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:41]3[CH:42]=[N:43][CH:44]=[CH:39][CH:40]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29]
Reactant: Nc1c(F)c(N2CC[C@@H](C(N)c3nccs3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 54.6 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]pyrrolidine [F1] (70 mg, 0.252 mmol) was added to an acetonitrile suspension (3 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (87.0 mg, 0.275 mmol), and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.3 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (50 ml), this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (2 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (2 ml) at room temperature and then washed with chloroform (30 ml×4),and the insoluble matter was removed by filtration. This hydrochloric acid solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol-aqueous ammonia to obtain 65.1 mg (54%) of the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CCCCCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:30])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1>O1CCCC1.C(O)(=O)C>[C:1]([CH2:2][C:23]([C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[Cl:15])([OH:30])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1)#[N:3]
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 44.5 %

Procedure:
Acetonitrile (2.25 g, 0.055 mole) was dissolved in dry tetrahydrofuran (100 ml) and the resulting solution was cooled to -70° C. under nitrogen in a acetone/dry ice bath. A solution of n-butyllithium in hexane (39 ml, 1.55 molar, 0.060 mole) was added dropwise over five minutes. After stirring for about 45 minutes at -70° C., 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (12.8 g) in dry tetrahydrofuran (100 ml) was added dropwise over a 15 minute period. Stirring was continued at -70° C. for about one hour and then glacial acetic acid (20 ml) in tetrahydrofuran (20 ml) was added dropwise. The cooling bath was then removed. The reaction mixture was allowed to warm to 0° C., quenched in water (400 ml), and solid sodium carbonate was added to raise the pH to 8.0. After extraction with ethyl acetate (3×75 ml), the combined organic extracts were washed with saturated brine (3×50 ml), dried (Na2SO4) and evaporated to a pale yellow solid. This solid was washed well with ethyl ether to give the title compound (6.61 g, 44.5%), identical to the product of Example 1 as confirmed by n.m.r. and i.r. spectroscopy.
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[C:9]([CH3:31])([CH3:30])[CH2:10][O:11][C:12]=1[C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:18][C:16]=2[CH:17]=1)([CH3:7])([CH3:6])[CH3:5].[Na].[O:33]=[O:34]>>[C:4]([C:8]12[O:34][O:33][C:12]1([C:13]1[O:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])=[CH:18][C:16]=3[CH:17]=1)[O:11][CH2:10][C:9]2([CH3:31])[CH3:30])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)C1=C(c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3o2)OCC1(C)C
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc3cc(O[Si](C)(C)C(C)(C)C)ccc3o1)OCC2(C)C
Yield: 85 %

Procedure:
Adding 1 mg of TPP to 4 ml of methylene chloride dissolving 132 mg (0.286 mmol) of 4-t-butyl-5-(5-(t-butyldimethylsiloxy)benzofuran-2-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [18]), the mixture was stirred in oxygen atmosphere, at the temperature of −78° C. This solution was externally irritated with a 940 W sodium lamp for 4 hours. The reaction mixture was concentrated and fractionated with aliquot thin layer chromatography using the mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:1) to obtain 114 mg of 5-t-butyl-1-(5-(t-butyldimethylsiloxy)benzofuran-2-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [19]) as a white solid. Yield 85.0%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4](Cl)[N:3]=1.Cl.[N:23]1([C:29]([N:31]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:30])[CH2:32][CH2:33]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2c(OC2CCC2)c1OC
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(OC2CCC2)c1OC
Yield: 386.7 %

Procedure:
4-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazoline (184 mg, 0.00059 mol) was added to a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (163 mg, 0.00065 mol) and triethylamine (184 μl, 0.0013 mol) in n-butanol (6 ml) and the reaction stirred at reflux for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 7:93 v/v) to give the title compound as a white foam (1110 mg, 38%). MS m/z=487 (MH)+. 1H-NMR (CDCl3): δ=1.53 (1H, m), 1.76 (1H, m), 2.04 (2H, m), 2.25 (2H, m), 2.38 (2H, m), 3.20 (4H, t), 3,36 (2H, t), 3.55 (2H, t), 3.66 (4H, t), 3.80 (3H, s), 3.85 (3H, m), 3.94 (6H, m), 4.86 (1H, m), 6.62 (1H, s). Found: C, 58.09; H, 6.96; N, 16.69; C24H34N6O5 0.15CH2Cl2, requires C, 58.09; H, 6.92; N, 16.83%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (64) (40 mg, 0.2 mmol) using Method D. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10](N(OC)C)=[O:11])=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=2[CH:20]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=2[CH:20]=1
Reactant: CNC(=O)c1c(C(=O)N(C)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(C=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: -15 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a mixture of 5-bromo-N2-methoxy-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (1 g, 2.3 mmol) in THF (10 mL) was added DIBAL-H (11.5 mL, 11.5 mmol) at −78° C. dropwise. The mixture was stirred at −15° C. for 2 h. Then it was quenched with HCl (a.q.), extracted with CH2Cl2, dried over Na2SO4, concentrated. The residue was crude product of 5-bromo-2-formyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (700 mg, yield: 74%). 1H-NMR (CDCl3, 400 MHz) δ 10.07 (s, 1H), 9.14 (br s, 1H), 9.00 (s, 1H), 7.80 (s, 1H), 3.35 (s, 3H), 3.10 (s, 3H), 3.05 (d, J=4.4 Hz, 3H). MS (M+H)+: 389/391.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>O1CCCC1.C(OCC)C.[Zn]>[F:16][C:10]([F:17])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1

Procedure:
To a solution of benzaldehyde (3.0 g, 28 mmol) in anhydrous tetrahydrofuran (80 mL) was added zinc (2.4 g, 36 mmol). The mixture was heated at 75° C. under inert atmosphere and ethyl 2-bromo-2,2-difluoroacetate (4.4 mL, 34 mmol) was slowly added. The mixture was heated under the same conditions for 2 hours. After cooling, 2N hydrochloric acid (25 mL) was added until the complete consumption of unreacted zinc. The solvent was removed under reduced pressure. The crude reaction was dissolved in ethyl ether (150 mL) and washed with brine (2×100 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.4 g, 99%) as yellow oil and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[O:16]=[C:17]1[CH2:21][CH2:20][S:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[C:18]1[C:17](=[O:16])[CH2:21][CH2:20][S:19]1
Reactant: O=C1CCSC1
Reactant: COC(=O)C(C)c1ccc(C=O)c(F)c1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c(F)c1
Yield: 52.4 %

Procedure:
By using methyl 2-(3-fluoro-4-formylphenyl)propionate (1.05 g) obtained in Example 58 and 3-oxothiolane (1.02 g), the title compound (770 mg, 52%) was obtained in the same manner as that of Example 1.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1.[CH3:14]N(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C

Procedure:
Iodomethane (11.2 mL) was added to a mixture of compound 6b (32.6 g), DMF (100 mL), and potassium carbonate (62.5 g) at 0° C. The mixture was stirred and allowed to warm to RT over 2 hr. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford 1-(4-bromo-2-methoxyphenyl)-1-ethanone (compound 6c, 33.1 g) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:28]2[CH2:27][CH2:26][N:25]([CH:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH2:30][CH2:29]2)=[O:17])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CN1CCC(N2CCNCC2)CC1
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)OC(C)(C)C)n3)CC2)CC1

Procedure:
47.1 Using general method C, (2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid (example 37.2) was coupled with 1-(N-methylpiperidin-4-yl)piperazine to give (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester. Off-white powder. MS 424.0 ([M+H]+)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=3[Cl:25])[CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl>CO>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:19]([F:20])[C:14]=1[O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Agent: Cl
Solvent: CO
Product: Fc1cc(C(F)(F)F)cc(Cl)c1Oc1ccc2cn[nH]c2c1
Reaction time: 48 h
Yield: 72.6 %

Procedure:
1-Acetyl-6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy) indazole (2.05 g) was stirred and heated under reflux with methanol (10 cm3) and concentrated hydrochloric acid (6 cm3) for 2 hours and then left to stand at room temperature for 48 hours. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with water, dried (MgSO4), filtered and the solvent removed from the filtrate under vacuum. The residue, a brown oil, was purified by flash chromatography (CHCl3 :ethyl acetate-85:15) to yield 6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazole (1.32 g) as a straw colored oil which solidified on standing. m.p.=133.9°-143.1° C. M+ =330.
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1)[CH2:2][CH3:3]>C(O)C.[Pd]>[CH2:11]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1)[CH2:12][CH3:13]
Reactant: CCCC1(CCC)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCC1(CCC)CCC(=O)CC1

Procedure:
4,4-Dipropyl-2-cyclohexenone (2.0 g) was dissolved in ethanol (20 ml), 10% palladium/carbon (200 mg) was added to the solution, and the mixture was hydrogenated at 25° C. The catalyst was removed by filtration from the reaction mixture, and the solvent was removed in vacuo to give 4,4-dipropylcyclohexanone. The product was dissolved in methanol/water=1/1 (20 ml). Hydroxylamine hydrochloride (1.55 g) and sodium acetate (1.83 g) were added to the solution, and the mixture was stirred with heating at 50° C. for 12 hours. After removing the methanol in vacuo, the residue was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.4 g of 4,4-dipropylcyclohexanone oxime. A solution of the product in tetrahydrofuran (10 ml) was added dropwise to a solution of lithium aluminium hydride (420 mg) in tetrahydrofuran (10 ml) under ice-cooling, and the mixture was stirred. After 3 hours, the reaction was quenched by adding water (0.42 ml), 15% aqueous sodium hydroxide (0.42 ml), and then water (1.26 ml) dropwise to the reaction mixture. The precipitate was filtered off and then the solvent was removed in vacuo. The residue was dissolved in 2 mol/l aqueous hydrochloric acid, washed with diethyl ether, basified with 2 mol/l aqueous sodium hydroxide, and then extracted with chloroform. The organic layer was concentrated under reduced pressure to give 165 mg of 4,4-dipropylcyclohexylamine. The product (100 mg) was dissolved in ethyl acetate (5 ml), and 4-hydroxy-3-methoxyphenyacetic acid (100 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg) were added to the solution, and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was washed with water and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 120 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cccc1C(=O)O
Product: COc1c(Cl)cccc1C(=O)Cl

Procedure:
A solution of 0.5 g (0.0027 mole) of 3-chloro-2-methoxybenzoic acid in 10 mL of thionyl chloride was heated under reflux for 2 hours and then evaporated to yield 3-chloro-2-methoxybenzoic acid chloride. The residual oil was dissolved in 20 mL of methlene chloride containing 0.4 g (0.003 mole) of 2-aminomethyl-1-ethyl-pyrrolidine and 1 mL of triethylamine. After 1 hour at room temperature, the solution was evaporated and treated with water. The oil which precipitated was taken up in methylene chloride, dried and evaporated. The residue was crystallized from ether-pentane to obtain 0.55 g (69%) of the invention compound, m.p. 55°-58°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>>[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)N1CCC(O)CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)N1CCC(Oc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 40 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2), 55 mg of 1-tert-butylpiperidin-4-ol, and 8 mg of NaH by a procedure analogous to that described in COMPOUND HHH6. Mass spectrum (ESI) 556 (M+1). 1H NMR (500 MHz, CDCl3; doubling of peaks due to restricted rotation) δ 1.44 and 1.42 (2 s, 9H); 2.20-2.53 (m, 4H); 2.77 (m, 0.6H); 3.05 (br s, 1.6H); 3.50 (m, 1.5H); 3.70 (m, 0.8H); 4.60-5.40 (m, 2.9H); 5.39 (br s, 0.8H); 5.75 and 5.80 (2 s, 1H); 6.54 and 6.56 (2 d, J=8.5 Hz and J=10 Hz, 1H); 7.36-7.66 (m, 8H).