Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].N1C(C)=CC=CC=1C.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:57])([F:56])[CH:22]([C:49]1[CH:54]=[CH:53][N+:52]([O-])=[CH:51][CH:50]=1)[O:23][C:24]1[C:33]([N:34]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:1][N:2]([C:53]1[CH:54]=[C:49]([CH:22]([O:23][C:24]2[C:33]([N:34]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[N:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[C:21]([F:20])([F:57])[F:56])[CH:50]=[CH:51][N:52]=1)[C:3](=[O:5])[CH3:4]
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Reactant: CNC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccnc(N(C)C(C)=O)c1)C(F)(F)F
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
N-methylacetamide (0.097 mL, 1.30 mmol) was dissolved in dichloromethane (1.0 mL). To the solution were added at 0° C. 2,6-lutidine (0.30 mL, 2.5 mmol) and oxalyl dichloride (0.11 mL, 1.30 mmol). After stirring at the same temperature for 15 minutes, a solution of Compound B4 (145 mg, 0.253 mmol) obtained in Step 1 of Example 42 in dichloromethane (1.0 mL) was added and the mixture was further stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/10) to give Compound B7 (157 mg, 99% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])[C:10](=[O:12])[CH3:11])=[CH:6][C:5]([F:21])=[C:4]([Cl:22])[N:3]=1.CCN(CC)CC.O>CN(C=O)C.Cl[Pd]Cl>[C:10]([N:9]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH:20][C:2]2[N:3]=[C:4]([Cl:22])[C:5]([F:21])=[CH:6][C:7]=2[CH2:8]1)(=[O:12])[CH3:11]
Reactant: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Temperature: 120 °C
Yield: 21.4 %

Procedure:
To a stirred solution of 1C (0.63 g, 1.85 mmol) and Et3N (0.78 mL, 5.55 mmol) in DMF (15 mL) was added PdCl2 (49 mg, 0.28 mmol) and the reaction was heated to 120° C. When the reaction was complete by HPLC, the mixture was poured into H2O and extracted with Et2O. The Et2O layer was washed with H2O (2×20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, 100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give 1D (0.12 g, 21%). HPLC Rt=2.77 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA); LCMS Found: (M+H)+=303.
Reaction SMILES: [Br-].[C:2](/[CH:5]=[CH:6]/[C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)([OH:4])=[O:3].[C:33]([C:36]1[CH:41]=[CH:40][N:39]([C:42]2[CH:43]=[CH:44][C:45]([CH:48]=O)=[N:46][CH:47]=2)[CH2:38][CH:37]=1)(=[O:35])[CH3:34]>>[C:33]([C:36]1[CH:37]=[CH:38][N:39]([C:42]2[CH:43]=[CH:44][C:45]([CH:48]=[CH:11][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:2]([OH:4])=[O:3])=[CH:32][CH:31]=3)=[N:46][CH:47]=2)[CH2:40][CH:41]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)/C=C/c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)C1=CCN(c2ccc(C=O)nc2)C=C1
Agent: [Br-]
Product: CC(=O)C1=CCN(c2ccc(C=Cc3ccc(/C=C/C(=O)O)cc3)nc2)C=C1
Yield: 95.3 %

Procedure:
Production Example 108, step 4, {4-[(E)-2-carboxyvinyl]benzyl}(triphenyl)phosphonium bromide (503.9 mg, 1.001 mmol) and 5-(4-acetylpyridin-1-yl)pyridine-2-carbaldehyde (257.3 g, 1.103 mmol) were condensed to give (2E)-3-(4-{2-[5-(4-acetylpyridin-1-yl)pyridin-2-yl]vinyl}phenyl)prop-2-enoic acid (355.1 mg, yield 94.0%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:24])[CH:3]=1.C([O-])(=O)C.[NH4+].CN1CCCC1=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:7])[C:8]3[C:9]([C:18]([F:19])([F:20])[F:21])=[N:10][NH:11][C:12]=3[C:13](=[O:15])[NH:24][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(C(F)(F)F)n[nH]c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Alternatively, the title compound can be preferably prepared as follows: A mixture of ethyl 4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (1.0 g, 2.76 mmol), ammonium acetate (0.21 g, 2.76 mmol) and 1-methyl-2-pyrrolidinone (2.3 mL) was heated with stirring at 160° C. under N2 for one hour. After cooling to room temperature, water (25 mL) was added to the stirred reaction mixture. The resulting aqueous mixture was filtered after stirring for ten minutes. The filter cake was washed with water (2×25 mL) then dried under vacuum to give a tan solid. The solid was placed in methylene chloride (25 mL) and the mixture was stirred for fifteen minutes, then filtered. The filter cake was washed with methylene chloride (2×25 mL) and dried under vacuum to give the title compound as a tan solid (0.66 g, 76%, m.p. 334-336° C.).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([Br:20])[CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+].OP([O-])(O)=O.[K+]>O>[NH2:2][C@H:3]([C:10]1[CH:15]=[C:14]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH:13]=[C:12]([Br:20])[CH:11]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(N)c1cc(Br)cc(C(C)(C)C)c1
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1cc(Br)cc([C@@H](N)CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl 3-amino-3-(3-bromo-5-tert-butylphenyl)-propionate hydrochloride (125 g, 0.38 mol) in water (500 mL) was basified with 2.5 N NaOH (pH ˜12) by drop-wise addition to give a creamy oily residue. The pH of the aqueous layer was adjusted to pH=8.2 by the addition of 50 mM KH2PO4 solution. Amano lipase PS (75 g) was added to above reaction mixture and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the solid was washed with ethyl acetate to give a colorless solid of the resolved (S)-acid (37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([OH:36])=O)=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19].[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:24][N:23]2[C:31]([C:34]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]3)=[O:36])=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19]
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2)N1CCN(CCO)CC1

Procedure:
The title compound was prepared from 10-{[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C and 1-(2-hydroxyethyl)-piperazine in the manner of Example 1, Step G.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].[C:38]([NH-:40])#[N:39].O>CN(C)C=O>[C:38]([NH:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23])#[N:39]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCI)cc1
Reactant: N#C[NH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCNC#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a solution of (3RS,4RS)-4-[9-iodononyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (381 mg, 0.69 mmol) in anhydrous dimethylformamide (2 ml) were added potassium carbonate (238 mg, 1.72 mmol) and cyanoamide (116 mg, 2.76 mmol), which was then stirred for 4 h at 50° C. Water was added thereto, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (238 mg, yield 74%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-4-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.011-8.983 (d, 2H), 8.919 (s, 1H), 7.813 (s, 1H), 7.792-7.763 (d, J=8.7 Hz, 2H), 7.624-7.595 (d, J=8.7 Hz, 2H), 7.518-7.488 (d, J=9 Hz, 2H), 7.357-7.327 (d, J=9 Hz, 2H), 4.327-4.276 (m, 1H), 3.680 (s, 3H), 2.285-2.216 (m, 1H), 0.979-0.957 (d, J=6.6 Hz, 6H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=O)=[O:7])[CH3:2].N12CCCN=C1CCCCC2>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[N:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CC(=O)N1CCCN1C(=O)c1ccnc(SC)n1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccnc(SC)n2)n2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-1-yl]-3-oxo-propionic acid ethyl ester, 12, (9.6 g, 28.4 mmol) in DMF (280 mL) was added 1.8-diazabicyclo[5.4.0]-undec-7-ene (12.7 mL, 85.2 mmol). The reaction solution is stirred for 2 hours at room temperature then diluted with H2O. The aqueous phase is extracted three times with CHCl3. The combined organic phases are washed with aqueous saturated NH4Cl (×3), dried (MgSO4), filtered and concentrated in vacuo. The residue is purified over silica (5% MeOH/CHCl3) to afford 3.1 g of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=5.1 Hz, 1H), 7.61 (d, J=5.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 4.31 (t, J=7.2 Hz, 2H), 4.09 (t, J=7.2 Hz, 2H), 2.74 (dddd, 7.2, 7.2, 7.2, 7.2 Hz, 2H), 2.61 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 321.1 (100, M++H).
Reaction SMILES: B#B.[F:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1>O1CCCC1>[F:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc(F)cc1)C(=O)O
Agent: B#B
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
To 95 ml of 1 Molar diborane in tetrahydrofuran is added 10.2 g of 2-(p-fluorophenoxy)propionic acid in 100 ml of tetrahydrofuran. The mixture is stirred at room temperature for 20 hrs. and poured onto 600 g of ice. The mixture is extracted with chloroform and the chloroform extracts dried (MgSO4). The solvent is removed under vacuum and the residual liquid distilled to give 8.7 g of colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[C@H:13]([N:14]=[N+]=[N-])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N=[N+]=[N-]
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N
Reaction time: 8 h

Procedure:
trans-(4-Azido-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate F) (3.3 g, 14 mmol) was dissolved in 27 mL methanol. Platinum (IV) oxide (307 mg, 1.4 mmol) was added was the reaction mixture was hydrogenated with a H2-balloon at room temperature overnight. The catalyst was filtered off and the solvent was evaporated off. The crude material, off-white solid (2.74 g, 93%), MS: m/e=161 [(M-buten)+] was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[N:9]=2)[CH:7]=1.[BH4-].[Li+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1noc(-c2cc(C)ccc2[N+](=O)[O-])n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(-c2nc(CO)no2)c1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Ethyl 5-(5-methyl-2-nitro-phenyl)-1,2,4-oxadiazole-3-carboxylate (60 mg, 0.22 mmol) was dissolved in ethanol (3 mL) and treated with lithium borohydride (9 mg, 0.43 mmol) at room temperature. The mixture was stirred for 1 h, then quenched with saturated NH4Cl and extracted into dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide (5-(5-methyl-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)methanol (35 mg, 69% yield). LC/MS m/z 236.0 [M+H]+.
Reaction SMILES: C(OC([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[CH2:25][CH2:26][C@@H:22]([NH:8][C:9]3[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=3)[CH2:23]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(c3ccc([N+](=O)[O-])cc3)C2)nc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(c3ccc(N)cc3)C2)nc1
Yield: 85.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-nitrophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (297 mg) in ethanol (3 mL) was added tin(II) chloride (583 mg), and the mixture was heated at reflux for 6 hours. After cooling, the reaction mixture was basified with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-1-(4-aminophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (186 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>O1CCCC1>[CH:2]12[S:1][CH:5]([CH:4]=[CH:3]1)[CH:7]1[C:6]([O:11][C:9](=[O:10])[CH:8]21)=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: c1ccsc1
Solvent: C1CCOC1
Product: O=C1OC(=O)C2C3C=CC(S3)C12
Temperature: 700 °C
Reaction time: 24 h

Procedure:
In tetrahydrofuran solvent (500 g), thiophene (1 mole) and maleic anhydride (1 mole) are dissolved, and the solution is introduced into a 2-liter flask. After stirring at 700° C. for 24 hours, the solvent is removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 7-thiabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride of the following Chemical Formula 201 (yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=2[F:24])=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1cccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1F
Yield: 33.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-fluoro-3-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 2-fluoro-3-methoxyphenylboronic acid (0.041 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.034 g (34%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.CCO.Cl.C([O-])(O)=O.[Na+]>[Fe]>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=23)=[CH:16][CH:17]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)c12
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccc(Oc2ccc(-c3nc(C4CCC4)n4ccnc(N)c34)cc2)c1

Procedure:
A mixture of 3-cyclobutyl-1-[4-(3-nitrophenoxy)-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine (10 mg, 0.02 mmol), iron (10 mg, 0.2 mmol), EtOH (10 mL, 0.2 mol) and conc. HCl (100 uL, 0.003 mol) was refluxed for 1 h. Sat. NaHCO3 was added to quench, and the EtOH was removed in vacuo. The mixture was transferred to a separatory funnel, and DCM was used to extract the product. The organic layer was concentrated in vacuo, redissolved in minimal MeOH/DCM, and loaded onto a prep TLC plate. After eluting with 10% (7N NH3 in MeOH)/DCM, the band containing the pure product was collected, and the material filtered off using 1:1 MeOH/DCM. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.00-2.08 (m, 1H) 2.13-2.24 (m, 1H) 2.44-2.55 (m, J=8.91, 8.75, 8.75, 2.91, 2.78 Hz, 2H) 2.64 (quin, J=9.28 Hz, 2H) 3.71 (br. s., 2H) 3.82 (dq, J=8.84, 8.59 Hz, 1H) 5.05 (br. s., 2H) 6.38 (t, J=2.15 Hz, 1H) 6.46 (dd, J=8.08, 1.26 Hz, 2H) 7.05-7.16 (m, 5H) 7.63 (d, J=8.59 Hz, 2H). MS (ES+): m/z 372.10 (20) [MH+]. HPLC: tR=2.22 min (Open Lynx, polar—5 min).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a mixture prepared by adding to 3-thiophenemethanol (1.27 g, 0.0093×1.2 mol) successively tetrahydrofuran and sodium hydride (0.39 g, (ca.60% in mineral oil), 0.0093×1.05 mol), 2,6-dichloro-4-trifluoromethylpyridine (2.0 g, 0.0093 mol) was added, and the resultant solution was refluxed for about 1 hour.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([C:9](=[CH:19][O:20][CH2:21][CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(Cl)c(F)c(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(Cl)c(F)c(F)c1F
Yield: 92.3 %

Procedure:
103 g (0.37 mole) of the ester obtained and 83 g (0.56 mole) of triethyl orthoformate are heated with 95 g of acetic anhydride at 150°-160° for 2 hours and then concentrated at 120°-130° under atmospheric pressure and thereafter under high vacuum. 115 g (92% of theory) of ethyl 2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyacrylate are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1
Reactant: COC(OC)c1cccc(N)c1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: COC(OC)c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
334 mg of 3-aminobenzaldehyde dimethyl acetal was dissolved in 10 ml of anhydrous benzene, and 212 mg of benzaldehyde and 2 g of molecular sieve 4A (a product of Nippon Chromato Kogyo Co., Ltd.) were added. The mixture was stirred at room temperature for 4 hours. The molecular sieve was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 20 ml of methanol, and 100 mg of sodium borohydride was added. The mixture was stirred for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from hexane to give 451 mg (yield 87.7%) of 3-benzylaminobenzaldehyde dimethyl acetal having a melting point of 55° to 56° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CO.O>[CH2:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNCC(=O)O
Yield: 41.6 %

Procedure:
A! A 32% solution of sodium hydroxide (123 ml) was added to a mixture of glycin (50 g, 0.66 mole) and butyl bromide (75 ml, 0.66 mole) in methanol (600 ml) and water (600 ml), the reaction mixture was refluxed for 24 hours, then the solvend was evaporated under vacuum. The crude was dissolved in ethanol, the salts were filtered off 3 times, and the solvent was evaporated under vacuum. The resulting crude was purified by flash chromatography (eluent: chloroform/methanol/concentrated ammonia 6:4:0.5) yielding 36 g of N-butyl-glycine.