Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([O:34]C)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1.C1COCC1.Cl>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cc(F)cc(F)c2)c2oc(N3CCOC[C@@H]3C)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
2N NaOH (0.206 mL, 0.41 mmol) was added to a stirred suspension of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (90 mg, 0.20 mmol) in MeOH (1 mL)/THF (1 mL) and cooled with an ice-water bath. The resulting suspension was stirred at RT for 2 hours. The reaction was incomplete thus the temperature was increased to 35° C. and stirred for an additional hour. The reaction mixture was cooled with an ice bath, the pH was adjusted to 2-3 with hydrochloric acid 1M and the volatils were evaporated. The resulting precipitate was collected by filtration, dried, triturated with diethyl ether, collected by filtration and dried again under vacuum to give 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (75 mg, 86%). Mass Spectrum: M+H+ 445.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:30])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)O)c(F)c1
Yield: 113 %

Procedure:
To a solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.5 g, 1.215 mmol) in MeOH (10 mL) stirred under nitrogen at 20° C. was added Pd/C (0.013 g, 0.122 mmol) in one charge. The reaction mixture was reacted with a H2 balloon at 20° C. for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (0.4 g, 1.373 mmol). TLC (DCM/MeOH=10:1, Rf=0.2): 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.15 (m, 4H), 5.78 (s, 1H), 4.01-4.00 (m, 2H), 3.59 (s, 2H), 1.26-1.23 (m, 3H); ES-LCMS m/z 292 (M+H).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:12])C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:12]
Reactant: Cn1nccc1-c1cccc(NC(=O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cccc(NC(=O)C(CN)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 52 %

Procedure:
1,1-dimethylethyl[3-{[3-(1-methyl-1H-pyrazol-5-yl)phenyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate (170 mg, 0.39 mmol) was dissolved in DCM (10 mL) and treated with TFA (1 mL). After 1 h, the solution was concentrated and purified using reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) affording the bis-TFA salt of the title compound (115 mg, 52%) as a white solid. LC-MS (ES) m/z=335 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ 7.76 (br s, 1H), 7.43 (br s, 1 h), 7.35-7.23 (m, 9H), 4.55 (m, 1H), 3.72 (s, 3H), 3.23 (dd, J=3.5, 13.1 Hz, 1H), 3.13 (dd, J=10.4, 13.1 Hz, 1H), and 3.03-2.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[H-].[Na+].ClC[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.[I-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:33][CH2:32][CH2:31][O:30][CH:29]1[CH2:34][CH2:26][CH2:27][O:28]1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: ClCCCOC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCOC1CCCO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of compound 11a (950 mg, 3.20 mmol) in anhydrous DMF (10 mL) under argon at room temperature was carefully added sodium hydride (60% suspension in oil) (140 mg, 3.50 mmol). The solution was stirred for 30 min and 2-(3-chloropropoxy)-tetrahydro-2H-pyran (656 mg, 3.66 mmol) was dropwise added. Finally, sodium iodide (480 mg, 3.20 mmol) was added and the solution was heated at 50° C. for 36 hrs. The resulting solution was diluted with diethyl ether (75 mL), washed successively with a 10% potassium phosphate and brine solution, and finally dried with magnesium sulphate. The crude compound was purified by flash chromatography using EtOAc/Hexane (3:7) as an eluant to give pure compound 12a (1.03 g, 73%). 1H NMR (300 MHz, Acetone-d6) δ: 1.51 (m, 4H), 1.57 (s, 6H), 1.6-1.9 (m, 2H), 2.04 (m, 2H), 3.50 (m, 4H), 3.80 (m, 2H), 4.59 (t, 1H, J=3.42 Hz), 8.18 (m, 2H), 8.27 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][OH:7])[CH2:4][CH3:5].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].O>CN(C)C=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:7][N:6]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])([O-:19])=[O:18]
Reactant: CCC(CC)=NO
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)=NOc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
To a solution of pentan-3-one oxime (6.00 g) in dimethylformamide (30 ml) was added sodium hydride (60% oil suspension, 2.37 g) under ice cooling. After 15 minutes, to the above mixture was added dropwise 1-fluoro-2-nitrobenzene (5.98 g) in dimethylformamide (30 ml). The mixture was stirred for 3 hours at ambient temperature and poured into a mixture of ice and water. The separated oil was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo to give pentan-3-one O-(2-nitrophenyl)oxime (10.51 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:15]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[CH:9]=1
Reactant: COc1c(C=O)cc(Br)cc1C(C)C
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C(C)C)c1OC

Procedure:
5-bromo-3-isopropyl-2-methoxybenzaldehyde (26.76 g) was dissolved in n-hexane (50 mL) and triethyl orthoformate (22 mL), and Amberlyst-15 (2.68 g) was added to the solution, and then the mixture was refluxed for 4 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (31.55 g) as a brown oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:15])[C:11]([CH2:13][O:14][C:17]3[CH:49]=[CH:48][C:20]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]4=[O:47])=[CH:19][CH:18]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 88.9 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.00 g of 5-ethoxy-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 98), 2.25 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.2 ml of tributylphosphine, 1.22 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.81 g of the title compound, melting at 88-100° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:10]
Reactant: OCc1c(Cl)cncc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
(3,5-dichloro-pyridin-4-yl)-methanol (918 mg, 5.15 mmol) was dissolved in dry DCM (25 mL). Triphenylphosphine (2.70 g, 10.3 mmoles) was added, and the mixture was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C., and CBr4 (5.12 g, 15.4 mmoles) was added. The mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated, and the crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt 95/5) to yield 850 mg of the title compound.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH3:21]
Reactant: CCCCCCCCCCCCCC=O
Reactant: CCOC(C)=O
Product: CCCCCCCCCCCCC/C=C/C(=O)OCC

Procedure:
IR (thin film) 2920, 2850, 1725, 1465, 1265, 1175, 1045 cm-1 ;1H NMR (CDCl3, 300 MHz) δ 7.00 (dt, 1, J=15.5, 6.8 Hz, CH2CH=), 5.84 (dt, 1 J=15.5, 1.2 Hz, COCH=), 4.21 (dd, 2, J=14.2, 7.2 Hz, CH2O), 2.23 (qd, 2, J=6.9, 1.2 Hz, CH2CH=), 1.49 (t, 2, J=7 Hz, CH2CH2CH3), 1.3 (m, 20, CH2CH2CH2), 0.92 (t, 3, J=7 Hz, CH2CH2CH3). Rf (5% ethyl acetate:hexanes): tetradecanal, 0.29; ester product, 0 31. MS (FD): m/e 282 (M+).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:8]([Br:17])=[CH:7]C=1)(=O)C.BrC1C(C(O)=O)=N[C:22]([S:25]C)=NC=1>>[Br:17][C:8]1[C:9]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:10][C:5]([S:25][CH3:22])=[N:4][CH:7]=1
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Reactant: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Product: CON(C)C(=O)c1nc(SC)ncc1Br

Procedure:
The title compound (11A) was prepared according to the method presented for the synthesis of compound 1B of Example 1 utilizing 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid. MS (m/z) 292.16 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27](=O)[CH2:28][C:29](=[O:31])[CH3:30]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[S:16][C:15]3[N:17]=[C:27]([CH3:26])[C:28]([C:29](=[O:31])[CH3:30])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[C:11]=2[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCN(C(=O)OC(C)(C)C)C3
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 11.9 %

Procedure:
To a stirred solution of 0.50 g (1.39 mmol) 2-amino-3-benzoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester in 6 ml acetic acid was added 0.19 ml (1.89 mmol) of pentane-2,4-dione and two drops of sulfuric acid. The mixture was then stirred at 100° C. for 25 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 4:1) afforded 70 mg (12%) 3-acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid tert-butyl ester as a yellow oil. ES-MS m/e (%): 423 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[N:15]1([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)N1CCc2ccccc21)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCc3ccccc32)c2ccccc2)c1
Yield: 27.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.8 g of 2-amino-N-[2-(1-indolinyl)-2-oxoethyl]-N-phenylacetamide and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from a mixture of ethyl acetate and dimethylformamide (80-20 by volume), 0.7 g of N-[2-(1-indolinyl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 190° C. is obtained.
Reaction SMILES: [C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[NH:7][C@@H:6]([CH3:26])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[N:7]([C:34](=[O:36])[CH3:35])[C@@H:6]([CH3:26])[CH2:5]1)[NH2:2]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](OC(N)=O)c2c(ccc3oc(=O)cc(Cc4ccccc4)c23)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](OC(N)=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Step 3] 226 mg of the cis-benzyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate and 0.15 mL of pyridine were dissolved in 10 of dichloromethane followed by adding 66 μL of acetyl chloride while cooling with ice and stirring for 1 hour at room temperature. Following completion of the reaction, the solution was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was added to the resulting residue followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 250 mg of cis-benzyl-7-acetyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate in the form of a yellow solid (99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 44 h
Yield: 0.1 %

Procedure:
To an ice-cooled mixture of methyl 2-(4-fluoro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (3.39 g, 9.06 mmol) and triethylsilane (3.06 g, 26.3 mmol) in dichloromethane (180 mL) was added a solution of trifluoroacetic acid (4.24 g, 37.1 mmol) in dichloromethane (90 mL) dropwise during 3 hours. After addition, ice-bath was removed and the reaction mixture was stirred at room temperature for 44 hours. Solid sodium carbonate was added and stirred for 15 minutes, filtered, and concentrated. The oil residue was purified by column (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1 due to bad solubility) to afford methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 2.44 mg (75%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][NH:9][C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][CH:11]=1>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:8][N:9]([C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][CH:11]=1)[C:5](=[O:6])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: CNc1cnc(-c2cccnc2)s1
Reactant: CSCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CSCCC(=O)N(C)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
A solution of 3-methylsulfanyl-propionyl chloride (120 mg, 0.9 mmol) in DCE (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-(2-pyridin-3-yl-thiazol-5-yl)-amine (114 mg, 0.6 mmol) in DCE (5 mL), and the mixture was stirred for 5 min before adding a solution of DMAP (80 mg, 0.6 mmol) in DCE (1 mL). The ice bath was removed after 30 min, and the mixture was stirred at reflux under nitrogen for 15 min. The reaction mixture was cooled, diluted with DCE (70 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over MgSO4 and purified by silica gel chromatography (3:1 ethyl acetate/hexanes) to afford a fine yellow powder (131 mg, 75%): mp 116-118° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.0 Hz, 1H), 8.61 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (dt, J=9.8, 1.8 Hz, 1H), 7.81 (s, 1H), 7.51 (dd, J=7.7, 4.7 Hz, 1H), 3.56 (s, 3H), 3.02 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.12 (s, 3H); ESIMS m/z 294 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([F:11])[C:3]=1[F:12].NC1C(F)=CC([OH:21])=CC=1F>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:21])=[C:3]([F:12])[C:4]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Nc1c(F)cc(O)cc1F
Product: Nc1ccc(O)c(F)c1F
Yield: 84 %

Procedure:
This compound was prepared from 1,2,3-trifluoro-4-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, affording 0.60 g (84%) of 4-amino-2,3-difluorophenol. 1H-NMR (DMSO-d6) δ 9.19 (s, 1H), 6.59 to 6.53 (m, 1H), 6.48 to 6.41 (m, 1H), 4.85 (s, 2H); TLC (12% DCM/Hex), Rf=0.08.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:35])[CH2:4][O:3]1
Reactant: CC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(c2ccsc2)OCC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
Prepared from 5-[5-methyl-2-oxo-5-(3-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile and Lawesson's reagent generally according to example 10. 1H NMR (DMSO-d6): δ 12.67 (s, 1H), 12.01 (s, 1H), 7.71-7.74 (m, 2H), 7.54 (dd, J=5.08, 2.99 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.2 (dd, J=2.87, 1.3 Hz, 1H), 7.05 (dd, J=5.04, 1.31 Hz, 1H), 7.00 (dd, J=3.84, 2.1 Hz, 1H), 6.76 (dd, J=3.79, 2.51 Hz, 1H), 4.4 (d, J=15.34 Hz, 1H), 4.27 (d, J=15.33 Hz, 1H), 1.98 (s, 3H); MS (ESI) m/z 366 ([M+H]+); MS (ESI) m/z 364 ([M−H]−). Anal. calcd for C19H15N3OS2: C, 62.44; H, 4.14; N, 11.5. Found: C, 61.9; H, 4.14; N, 11.27.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(I)cc4)cc3c2C1
Yield: 45.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 20.3 mg (0.067 mMol) 4-iodobenzenesulfonyl chloride, 10.3 mg (47%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (800 mg), 5% palladium-carbon (400 mg), ethanol (30 ml), and tetrahydrofuran (10 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (770 mg, yield: 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).