Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:19])[C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11][CH:10]1[CH2:17][CH3:18])=[O:8])(=O)C.Cl>O.N>[CH2:17]([CH:10]1[N:9]([C:7](=[O:8])[CH:6]([CH3:19])[CH2:5][SH:4])[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11]1)[CH3:18]
Reactant: CCC1SCC(C(=O)O)N1C(=O)C(C)CSC(C)=O
Agent: Cl
Agent: N
Solvent: O
Product: CCC1SCC(C(=O)O)N1C(=O)C(C)CS
Temperature: 25 °C

Procedure:
3-(3-Acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid (1 g.) is dissolved in a mixture of water (3 ml.) and concentrated ammonia (3 ml.) under a blanket of argon. The mixture is stirred at room temperature for thirty minutes and acidified with concentrated hydrochloric acid. The organic layer is dried and concentrated to dryness in vacuo to yield 2-ethyl-3-(3-mercapto-2-methylpropanoyl)-4-thiazolidinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[C:29]([NH2:30])=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][N:26]=1)=O)C.C([O-])([O-])=O.[K+].[K+]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:23](=[O:22])[C:25]3=[N:26][O:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[C:29]3[N:30]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1N
Reactant: CC(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)onc3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 180 °C

Procedure:
A suspension of N-(4-chloro-phenyl)-4-isopropyl-benzamide (20.0 mg, 0.073 mmol) in thionyl chloride (0.5 mL) is heated at 80° C. for 1.5 h before thionyl chloride is removed in vacuo. The reaction residue is then taken in anhydrous acetonitrile (1.5 mL), followed by the addition of 4-amino-5-phenyl-isoxazole-3-carboxylic acid ethyl ester from step B (18.7 mg, 0.081 mmol) and anhydrous K2CO3 (25.2 mg, 0.182 mmol). The reaction mixture is heated under nitrogen atmosphere at 180° C. in a microwave for 2 h, then cooled down to room temperature. K2CO3 is removed by filtration. The filtrate is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.37 (dd, 2H), 7.53 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H), 7.11 (m, 4H), 2.87 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated for C26H20ClN3O2 (M+H+) 442.1. Found: 442.2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH:14]=[CH2:15])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24]=[C:25]1CC[CH2:26]1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCCl.CCOC(C)=O>[Si:1]([O:8][C@@H:9]([C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH:14]=[C:15]1[CH2:26][CH2:25][CH2:24]1)[CH2:10][OH:11])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C1CCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC=C1CCC1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A solution of tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-1-hydroxyhex-5-en-3-ylcarbamate (1.0 g, 2.9 mmol) and Grubbs Catalyst 2nd generation (0.12 g, 0.14 mmol) in DCE (6 mL) was treated with methylenecyclobutane (0.79 g, 12 mmol) and heated to 80° C. in a sealed vial overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, and brine. The organics were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography gave tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-5-cyclobutylidene-1-hydroxypentan-3-ylcarbamate (0.900 g, 81% yield) as a 2:1 mixture with starting alkene.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH:10]=3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH:10]=3
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=C(F)F
Yield: 80.7 %

Procedure:
A suspension of 950 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),7-tetraene in 20 ml of methanol and 2.0 ml of water is refluxed with 950 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra-1,3,5(10),7-tetraen-3-ol is obtained as colorless crystals with a melting point of 126-129° C., [α]D22 =+163.7° (c=0.505% in pyridine)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+:24]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([O-:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Na+:24]
Reactant: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)c2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cc1cc(C(=O)c2ccc(Cl)cc2)c2occc2c1

Procedure:
To a solution of 250 mg of (7-(4-chlorobenzoyl)benzofuran-5-ylacetic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide in the form of 0.1N solution. The solvent is evaporated to dryness and the residue taken up in 2 ml of methanol, followed by precipitation with ether, to yield sodium 7-(4-chlorobenzoyl)benzofuran-5-ylacetate.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2)cc1

Procedure:
4-Methylaminophenol sulfate and equivalent 4-acetamidobenzenesulfonyl chloride and double equivalent triethylamine were reacted in ethanol at room temperature for 4 hours. After the solvent was removed in vacuo, the residue was extracted with diethyl ether. The ether layer was washed successively with 2 N hydrochloric acid, saturated aqueous NaHCO3 solution and water, then dried over anhydrous Na2SO4 The solvent was removed and the residue was recrystallized from ethanol to give N-(4-hydroxyphenyl)-N-methyl-4-acetamidobenzenesulfonamide, mp 202-203° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[C:14]([OH:20])[C:13]=2[NH2:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].Br[CH:23]([CH3:29])[C:24](OCC)=[O:25].C(=O)([O-])[O-].O>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]2[C:13]3[NH:21][C:24](=[O:25])[CH:23]([CH3:29])[O:20][C:14]=3[C:15]([Cl:19])=[CH:16][C:17]=2[F:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-c2c(F)cc(Cl)c(O)c2N)c(Cl)c1OC(F)F
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC1Oc2c(Cl)cc(F)c(-c3nn(C)c(OC(F)F)c3Cl)c2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
Step 3 A mixture of 4-chloro-3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.88 g), ethyl 2-bromopropionate (0.70 g) and potassiun carbonate (0.711 g) in acetonitrile (30 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine (×3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the oily product was subjected to silica gel chromatography eluted with ethyl acetate and hexane (1:4) to afford 4-chloro-3-(8-chloro-6-fluoro-2-methyl-2H-1,4-benzoxazine-3-one-5-yl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.054 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:20]O)[CH2:18][OH:19])=[CH:11][CH:10]=1.Cl.C(N(S(F)(F)[F:30])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:22][C:17]([CH2:20][F:30])([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][CH:11]=1)[CH2:18][OH:19]
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(N)(CO)CF)cc1
Temperature: -78 °C

Procedure:
FTY 720 (310 mg, 1.00 mmol) was suspended in dry dichloromethane (10 mL) and cooled down to −78° C. Diethylaminosulfur trifluoride (DAST, 0.13 mL, 1.00 mmol, 1.0 eq.) was slowly added to this suspension and the mixture was allowed to warm up to r.t. overnight. The reaction was neutralized with saturated sodium bicarbonate solution (30 mL) at −10° C. The phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 20×3 cm, dichloromethane/methanol, 4:1) and subsequently by gradient HPLC (RP-HPLC Nucleodur 100-10 C18ec column (250×16 mm), acetonitrile/water (0.1% TFA)) with a Knauer HPLC system. The obtained TFA salt was dissolved in methanol (1 mL) and 1 M sodium hydroxide solution (3 mL) and the mixture was extracted with dichloromethane (5×5 mL). The organic phases were dried over Na2SO4 and concentrated. The product was dried in high vacuum and obtained as highly viscous oil. Yield: 5 mg (2%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:33])([CH3:32])[C:28]([O:30]C)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].[CH3:37]O>O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:37])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of methyl 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate and corresponding acid (100 mg, 0.22 mmol) was treated with 1 M of lithium hydroxide in water (2 mL) and methanol (0.37 mL). The reaction was stirred at room temp for 12 h. Acidified by 10% aqueous citric acid to pH=5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated to give 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 216. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.39 (s, OH), 8.37 (s, 1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.72 (d, J=42.8, 6H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[C:29](=O)[C:28]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:27]=4[O:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH2:25][O:26][C:27]4[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=4[CH:29]=3)(=[O:22])=[O:23])[CH2:17][C:16]2=[O:36])([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)c3coc4cc(Cl)ccc4c3=O)CC2=O)CCN(C(C)=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of the obtained 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-(7-chloro-4-oxo-4H-benzopyran-3-sulfonyl)-2-piperazinone (1.10 g) in methanol (20 ml) was added sodium borohydride (116 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and to the residue was added citric acid solution. The mixture was extracted with ethyl acetate, washed with brine, dried and concentrated, and the residue was dissolved in dichloromethane (20 ml). To the solution were added triethylamine (1.23 g) and methanesulfonyl chloride (420 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed with citric acid solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol=20:1) to give colorless solid of the title compound (790 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 4.26 g of 3,4-dichlorobenzaldehyde and 3.0 g of 2,4-pentanedione. Yield 1.3 g, mp 73° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: Cc1noc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-benzo[d]isoxazole-5-carbaldehyde (intermediate 6) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]([C:29]2[S:30][C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]([CH3:34])[N:33]=2)[C:25](=[O:40])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][N:26]([C:29]4[S:30][C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]([CH3:34])[N:33]=4)[C:25](=[O:40])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1sc(-n2ccc(Cl)cc2=O)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-n2ccc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OCC)C3)cc2=O)nc1C
Yield: 6.5 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), ethyl 2-(4-chloro-2-oxopyridin-1(2H)-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (140a) (106 mg, 0.355 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMSO (1 mL). The suspension was subjected to same operation as in Example (131b) to obtain 10.8 mg of the title compound as a pale yellow solid (6%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([S:8][C:9](=N)N)=[N:6][N:5]=[N:4]1.[OH-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH2:22][CH2:23]CCl)=[O:21]>C(O)C>[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH2:23][CH2:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[O:21])=[N:6][N:5]=[N:4]1
Reactant: O=C(CCCCl)c1ccccn1
Reactant: Cn1nnnc1SC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 19.5 %

Procedure:
S-(1-Methyl-1,2,3,4-tetrazole-5-yl)isothiourea hydrochloride (1.9 g) is dissolved in ethanol (50 ml). To the solution are added 10% aqueous sodium hydroxide (5 ml) and 3-chloropropyl 2-pyridyl ketone (1.8 g) and the mixture is refluxed for 2 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (0.5 g) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][CH2:55][CH2:56][OH:57]>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:13])[N:48]([CH2:49][CH2:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][CH2:55][CH2:56][OH:57])[CH3:47])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CNCCc1ccccc1OCCCO
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (357 mg, 1.08 mmol) and 1-hydroxy-7-azabenzotriazole (148 mg, 1.08 mmol) were dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (208 mg, 1.08 mmol) was added. The reaction mixture was stirred for 20 min at 0° C. A solution of 3-[2-(2-methylaminoethyl)phenoxy]propan-1-ol (227 mg, 1.08 mmol) in dichloromethane (2 ml) and ethyldiisopropyoamine (0.2 ml, 1.08 mmol) were added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layeres were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using ethyl acetate/heptane (2:1) as eluent, to give 383 mg of N-[(1R)-1-(N-{2-[2-(3-hydroxypropoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5]2.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][C:6]1([CH3:14])[C:7](=[O:12])[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][C:4]=2[CH2:5]1
Reactant: CC1(C)Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Temperature: 125 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 6-bromo-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Intermediate-7) (1.3 g, 5.10 mmol), tert-butyl acrylate (3.26 g, 25.50 mmol) in DMF/propionitrile (5 mL/20 mL) was added DIPEA (2.7 mL, 15.30 mmol) at 20-35° C. and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (114 mg, 0.51 mmol), P(o-tolyl)3 (310 mg, 1.02 mmol) were added, again degassed with N2 for another 10 minutes and heated at 125° C. for 16 h. The reaction mixture was cooled to 20-35° C. and filtered through Celite®. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 80% ethyl acetate/hexane as an eluent to get the desired compound as a pale yellow solid (1.2 g, 78%); 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.02 (d, J=1.0 Hz, 1H), 7.50 (d, J=15.6 Hz, 1H), 6.51 (d, J=16.1 Hz, 1H), 2.78 (s, 2H), 1.48 (s, 9H), 1.07 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([CH:6]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:7]23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc3c2N(CC1)C1CCCCCC31
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of 6-chloro-3-methyl-2,3,4,5,10,11,12,13-octahydro-1H,9H-cyclohepta[b][1,4]diazocino[7,8,1-hi]indole (0.20 g, 0.66 mmole) in acetic acid (50 mL) was added excess sodium cyanoborohydride (0.21 g, 3.3 mmole) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 3:2) provided 0.17 g of the title compound. This was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 190-193° C. MS (ESI) m/z 305 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH2:16]([NH2:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:16]([NH:23][C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Reactant: CCCCCCCN
Solvent: CCO
Product: CCCCCCCNC(=S)C1(c2ccccn2)CCCS1
Yield: 102.7 %

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (6.4 g) and n-heptylamine (2.9 g) in ethanol (75 cc) is heated under reflux for 2 hours 30 minutes. The reaction mixture is concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C. 6.8 g of a product prepared under the same conditions are added to the resulting residue (8.2 g) and the whole is chromatographed on neutral silica gel (150 g) contained in a column of diameter 3.5 cm. Elution is carried out with a cyclohexane-ethyl acetate mixture (98:2 by volume; 7300 cc), the following fractions of eluate being collected: fraction 1: 600 cc, fractions 2 to 8: 250 cc each and fractions 9 to 47: 100 cc each. Fractions 14 to 40 are combined and concentrated to dryness under reduced pressure (2 mm Hg; 0.27 kPa) at a temperature of 40° C. N-n-Heptyl-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (8.3 g) is thus obtained in the form of a clear yellow liquid [Rf=0.40; chromatography on a thin layer of silica gel; solvent: cyclohexane-ethyl acetate (80:20 by volume)].