Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.C(N(CC)CC)C.C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([N:41]=[N+:42]=[N-:43])=[O:19])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)cc1/C=C/C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(Br)cc1/C=C/C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of (2E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylic acid (4.5 g) in DMF (40 mL) was added a solution of triethylamine (2.0 mL) and diphenylphosphoryl azide (3.75 g) in DMF (5 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.56 g).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: CCOC(=O)Cc1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(-c2cn3cccnc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A mixture of 6 g of ethyl 4-(imidazo[1,2-a]pyrimidin-2-yl)phenyl-acetate, 30 ml of ethanol, 1.1 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The crystalline precipitate is filtered off, washed with ethanol, and then dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 3.2 g of 4-(imidazo-[1,2-a]pyrimidin-2-yl)phenylacetic acid as colorless crystals melting at 264°-265°C with decomposition.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]3[CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21]3)[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: c1ccc2c(c1)CNC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1Cc2ccccc2C1)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and isoindoline. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and isoindoline (0.025 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (35 mg). 1H-NMR (300 MHz, DMSO-d6), 11.67 (br s, 1H), 9.97 (br s, 1H), 8.69 (s, 1H), 8.31 (d, J=9.0 Hz, 2H), 7.84 (m, 2H), 7.65 (t, J=9.0 Hz, 1H), 7.27 (m, 5H), 4.11 (s, 4H), 3.60 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][Br:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)c(OC)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of methyl 3-methoxy-4-methylbenzoate (10 grams) and 2,2-azobis(2-methyl-propionitrile) (25 milligrams) in carbon tetrachloride (200 mL) was heated to gentle reflux. Bromine (9 grams) was added in portions and resulting solution was heated at reflux for 1 hour then stirred at room temperature overnight. The carbon tetrachloride was evaporated and the residue dissolved in ether. The ether solution was washed with water. The ether layer was dried over sodium sulfate then evaporated to give 13.9 grams of crude product. NMR (CDCl3) δ:3.92 (s, 3H), 4.45 (s, 2H), 7.65-7.00 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][C:10](=[O:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1COCC1>[F:18][C:19]([F:29])([F:30])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH2:6][CH2:5][C:4]3([CH2:12][CH2:11][C:10](=[O:13])[C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[NH:7]3)[CH2:3][CH2:2]2)=[CH:23][CH:22]=1
Reactant: O=C1CCC2(CCNCC2)Nc2ccccc21
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: O=C1CCC2(CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)Nc2ccccc21
Reaction time: 12 h
Yield: 68.2 %

Procedure:
A solution of diamine 11 (5 mg, 0.022 mmol) in anhydrous THF (0.2 mL), KF-Celite (12.6 mg, 0.109 mmol), and 4-trifluoromethoxybenzyl bromide (5.22 μL, 0.033 mmol) was agitated at RT for 16 h. The reaction was filtered and piperidinomethyl polystyrene N-2-(mercaptoethyl) aminoethyl polystyrene (26 mg, 0.033 mmol) was added to the filtrate. The reaction was agitated for another 12 h and then filtered. The filtrate was concentrated to yield 18 (6 mg, 0.015 mmol, 68%) as an oil. LRMS: M+=403.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].[CH3:10][O:11][N:12]=[C:13]([C:29](=O)[CH:30](Br)Br)[C:14]([NH:16][CH:17]1[C:27](=[O:28])[N:19]2[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]12)=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:30]=[C:29]([C:13](=[N:12][O:11][CH3:10])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:4]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C(=O)C(Br)Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Thiourea (235 mg) and sodium acetate (253 mg) were added to a solution of 7-(2-methoxyimino-3-oxo-4,4-dibromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 500 mg) in tetrahydrofuran (10 ml) and water (100 ml), and the mixture was stirred at 30° C. for 4 hours. The resultant solution was adjusted to pH 3.5 with 6 N hydrochloric acid, and concentrated under reduced pressure. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 163 mg).
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15](N2N=CC=N2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.[F:50][C:51]([F:63])([F:62])[O:52]C1C(C(O)=O)=NC=CC=1.C(N(CC)CC)C>>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([O:52][C:51]([F:63])([F:62])[F:50])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: O=C(O)c1ncccc1OC(F)(F)F
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1OC(F)(F)F

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 48 mg, 0.15 mmol), 3-(trifluoromethoxy)pyridine-2-carboxylic acid (CAS number 1221171-81-8; 42 mg, 0.20 mmol) and triethylamine (0.077 ml, 0.55 mmol) except this was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C@@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C@@H:5]([CH2:6][CH:7]=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9]2)[CH2:4]1)[CH3:2].[Na+].[I-].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([N:3]1[CH2:12][CH2:11][C@@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@@H:5]([CH2:6][CH:7]=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(c3ccccc3)=CC[C@H]2C1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CC[C@]2(c3cccc(O)c3)CC(c3ccccc3)=CC[C@H]2C1
Yield: 15.7 %

Procedure:
The reaction was conducted as described in Example 10, using 0.77 g (2.2 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-phenyl-1 ,2,3,4,4a,5,8,8a-octahydroisoquinoline, 1.32 g (8.8 mmol) of NaI, 1.1 ml (8.8 mmol) of chlorotrimethylsilane and 20 ml of acetonitrile. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2 /MeOH/conc. NH4OH 90:7:0.7 respectively. The resulting solid was triturated in acetone, yielding 0.115 g of the title compound. M.p.=215-218° C. C23H27NO
Reaction SMILES: Cl.I[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.CC(C)([O-])C.[K+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][SH:40])=[CH:35][CH:34]=1.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([NH:16][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([S:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:13]([NH2:15])=[O:14])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Reactant: COc1ccc(CS)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc3ncc(C(N)=O)c(Nc4cccc(OC)c4)c3c2)cc1
Temperature: 60 °C

Procedure:
Intermediate 14 (0.020 g), potassium tert-butoxide (0.0061 g) and [4-(methyloxy) phenyl]methanethiol (available from Aldrich) (0.007 ml) were added to a stirred solution of tris(dibenzylidineacetone)dipalladium(0) (0.002 g) and (oxydi-2,1-phenylene)bis (diphenylphosphine) (0.002 g) in N,N-dimethylformamide (1.5 ml), and the mixture was heated under microwave irradiation at 60° C. for 8 min. The solvent was evaporated in vacuo, and the residue purified by Mass Directed Preparative HPLC (Method A) to give the title compound (0.0048 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH:29]1([CH2:32][N:23]2[C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=4)=[CH:28][C:18]=3[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
In 1,2-dichloroethane (5 ml) were dissolved methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) and cyclopropanecarboaldehyde (0.22 g). To the solution was added sodium triacetoxyborohydride (0.33 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g) as yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[I:23])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1nccc(I)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Yield: 93.7 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (90 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 h. Concentrate the solution in vacuo to afford crude 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (65 mg, 92%) as light yellow oil. The crude product was used directly for next step. MH+ 365.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:9][CH:8]=2)[N:6]=1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([NH:25][CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:15])=[CH:16][CH:17]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(OCC(=O)O)cc2)cs1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(OCC(=O)NCC3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of the product of example 3 (358 mg, 1.0 mmol) in DMF (10 mL) were added successively cyclohexanemethylamine (130 μL, 1.0 mmol), DIPEA (700 μL, 4.0 mmol) and TBTU (321 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The mixture was washed with a saturated aqueous solution of NaHCO3 and then brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 4:1, EtOAc:hexane) to afford the title compound (300 mg, 87% yield) as a white solid: M.p. 145-147°; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (broad t, J=6.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 6.98 (s, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.84 (s, 1H), 4.48 (s, 2H), 2.97 (t, J=6.4 Hz, 2H), 0.82-1.66 (m, 11H); MS (FAB) m/z 346 (MH)+. Anal. Calcd for C18H23N3O2S: C, 62.58; H, 6.71; N, 12.16. Found: C, 62.48; H, 6.74; N, 12.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:16](O)[CH:17]([OH:19])[CH3:18].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][C:10]3[S:14][CH:13]=[N:12][CH:11]=3)[O:19][CH:17]([CH3:18])[CH2:16][O:15]2)=[CH:4][CH:3]=1
Reactant: CC(O)CO
Reactant: O=C(Cc1cncs1)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1COC(Cc2cncs2)(c2ccc(F)cc2)O1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(5-thiazolyl)ethanone (0.75 g, 3.3 mmol) obtained by a process analogous to that described in Example 1, propane-1,2-diol (2 ml) and methanesulphonic acid (0.5 ml) in xylene (30 ml) was stirred at reflux under an atmosphere of nitrogen for 2 hours using a Dean and Stark apparatus and then cooled to room temperature. The reaction mixture was then poured into water, extracted with ethyl acetate and dried over magnesium sulphate. Evaporation of the solvent under reduced pressure afforded a dark brown oil and flash chromatography of this oil on a silica gel column using 2:8 (v/v) ethyl acetate: petroleum 60-80 yielded two enantiomeric pairs of 2-(4-fluorophenyl)-2-(thiazol-5-ylmethyl)-4-methyl-1,3-dioxolane as Sample A (2R,4R)(2S,4S) 0.17 g and Sample B (2R,4S)(2S,4R), 0.11 g, as oils.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:17]=O.C(O)CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]3[N:10]([C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[CH:17][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)cn1
Solvent: CCCCCO
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)cn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5-(4-fluorophenyl)pyrimidin-2-amine (50 mg, 0.3 mmol), 2-chloro-3-(4-methoxyphenyl)propanal (52 mg, 0.26 mmol) in tent-amyl alcohol (1.0 mL) in a sealed reaction vial was heated at 130° C. for 3 hours. After cooling, the mixture was purified by preparative HPLC to afford the desired product. LCMS: (M+H)=334.0.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C@@H:3]([CH3:19])[CH2:4][C@H:5]([NH:8]C(=O)OCC1C=CC=CC=1)[CH2:6][OH:7]>CCO.[Pd]>[NH2:8][C@@H:5]([CH2:4][C@H:3]([CH3:19])[C:2]([F:1])([F:20])[F:21])[CH2:6][OH:7]
Reactant: C[C@@H](C[C@@H](CO)NC(=O)OCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C[C@H](N)CO)C(F)(F)F
Reaction time: 8 h

Procedure:
The above alcohol was dissolved in EtOH (150 mL) and 10% Pd/C (−500 mg) was added. The mixture was stirred under a H2 atmosphere (ballon) overnight. The catalyst was filtered off through celite and the filtrate was concentrated to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCNCCCC
Product: CCCCCCC/C=C/C(=O)N(CCCC)CCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and dibutylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([OH:27])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:5]=2[CH:4]=1)[CH3:2].[C:28](OCC)(=O)[CH2:29]S.C(N(CC)CC)C>>[CH2:28]([O:27][C:19]1[C:6]2[C:7](=[O:18])[N:8]([CH2:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[S:21][C:20]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:29]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c2c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c2c1OCC

Procedure:
In the same manner as in Reference Example 5, ethyl 6-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate was obtained from the compound of Reference Example 39 (3.6 g, 10.3 mmol), ethyl thioglycolate (14.4 mL, 103 mmol) and triethylamine (2.3 mL, 20.6 mmol). The title compound (900 mg, 47%) was obtained as a white solid from the thus-obtained ethyl 6-ethyl-3-hydroxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (1.8 g, 4.7 mmol) by a method similar to that in Reference Example 43.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:9]1[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:2]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNc1ccccc1
Reactant: Cc1ccccc1-n1ccc(=O)c(C(=O)C=CN(C)C)n1
Solvent: CO
Product: Cc1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Yield: 11.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-methylphenyl)pyridazin-4(1H)-one (crude, 1298 mg, 4.59 mmol) in 20 mL of methanol was added phenylhydrazine (744 mg, 6.89 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-methylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (180 mg, 12% for two steps) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:18]#[N:19])[C:10]([CH3:17])=[C:11]([C:14]([CH3:16])=[CH2:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CSC>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:18]#[N:19])[C:10]([CH3:17])=[C:11]([C:14]([CH3:16])=[CH2:15])[C:12]=3[N:31]3[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CSC
Product: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
2-Cyclopropyl-7-fluoro-6-isopropenyl-5-methyl-1,3-benzoxazole-4-carbonitrile (I-315) (34 mg, 0.13 mmol) was dissolved in dimethyl sulfide (2 ml), then triethylamine (38 μl, 0.27 mmol) and (3S)-3-(dimethylamino)pyrrolidine (36 μl, 0.28 mmol) were added, followed by stirring under nitrogen atmosphere at 90° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (21 mg, 25%) as a brown crystal.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([NH:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:22]=3)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(NCc5ccccc5)c4c3)cn2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(CNn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)cc1
Yield: 50.7 %

Procedure:
A solution of tert-butyl 4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (25 mg, 0.053 mmol) in MeOH (0.3 mL) was treated with HCl (4.0M solution in dioxane, 1.5 mL) at room temperature for 30 min. Solvents were evaporated and the residue was diluted with aq. NaHCO3, extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to give a white solid (10 mg, yield 51%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[OH:27])[CH:22]=[O:23].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[O:27][CH:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:31]=1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Yield: 64.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (2.62 mmol) of 3-chloro-4-hydroxy-5-methoxybenzaldehyde was alkylated with 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate to afford 0.570 g (64%) of the title compound.