Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:29]O>>[CH3:29][O:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(NC(=O)Nc2cc(Cl)ccc2OC)c1

Procedure:
N-(3-carboxyphenyl)-N'-(2-methoxy-5-chlorophenyl) urea (3.00 g, 9.4 mmol) was suspended in methanol (100 ml). Concentrated sulfuric acid (1.0 ml) was added and the reaction was heated at reflux for 6 hours. The reaction mixture was poured into cold (0° C.) water (600 ml). Filtration of the suspension afforded the crude product. The crude product was purified by column chromatography on silica using dichloromethane/ethyl acetate 19:1 as eluent. 2.35 g of the title compound was isolated.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].S(=O)(=O)(O)O.[I:22](O)(=O)(=O)=O.II>C(O)(=O)C.O>[I:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:3]2
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Yield: 483.7 %

Procedure:
Intermediate 1 (1.75 g, 7.32 mmol) was dissolved in glacial acetic acid (30 ml) and then treated with concentrated sulfuric acid (0.8 ml) followed by water (2.8 ml) with stirring. This mixture was then treated with periodic acid (0.23 eq., 0.38 g, 1.67 mmol) then iodine (0.43 eq., 800 mg, 3.15 mmol), and the whole mix was stirred at 60° C. for 3-4 h. The reaction mixture was allowed to cool and then partitioned between ethyl acetate and 10% aqueous sodium metabisulfite. The organic layer was separated and dried over sodium sulphate and evaporated in vacuo to give the title compound as a yellow oil (2.95 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][N:17]1[C:21]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[N:20][N:19]=[C:18]1[SH:34]>O=P(Cl)(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]3[S:34][C:18]4=[N:19][N:20]=[C:21]([C:22]5[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=5)[N:17]4[N:16]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2nnc(S)n2N)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc3sc(-c4ccc(N5CCOCC5)cc4)nn23)cc(OC)c1OC
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A mixture of 4-morpholinobenzoic acid (86 mg, 0.42 mmol) and 4-amino-3-mercapto-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (102 mg, 0.36 mmol) was refluxed in POCl3 (5 mL) for 2 h. The reaction mixture was cooled to room temperature and excess POCl3 was removed under vacuum. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography (80% ethyl acetate/hexane; 1 mL methanol/100 mL of solvent) to give the title compound as a yellow solid (40 mg, 0.088 mmol, 24%). 1H NMR (CDCl3): 7.78 (m, 2H), 7.73 (s, 2H), 6.98 (m, 2H), 4.00 (s, 6H), 3.94 (s, 3H), 3.89 (m, 4H), 3.41 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetate (i.e. the product of Example 10, Step D or D1) (218 mg, 0.85 mmol) in tetrahydrofuran (1 mL) was treated with a 50 wt. % aqueous solution of sodium hydroxide (0.2 mL) in water (0.6 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with concentrated aqueous hydrochloric acid to lower the pH to 1 and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 140 mg of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[F:24].O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][C:17]=1[F:24]
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H](C2COC(c3ccc(Br)c(F)c3)OC2)CC1

Procedure:
A solution of 4.0 g (0.02 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 5.1 g (0.025 mol) of 4-bromo-3-fluorobenzaldehyde, and 0.2 g of TsOH in 100 cm3 of dichloromethane was refluxed over a hot water bath fitted with a Dean-Stark trap for 3 hours and the water formed was continuously removed from the reaction system. The resulting solution was washed with water and dichloromethane was distilled off. The residue was recrystallized from acetone to yield 6.2 g (0.016 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. This compound contained about 10% of the cis isomer of the 1,3-dioxane ring.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=O.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21]1.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[N:14]([CH2:15][CH3:16])[C:24](=[O:25])[C:23]=2[CH2:22][CH2:21][C:20]([OH:26])=[O:27])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCC(=O)O1
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Br)c1
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Br)c2)c2ccc(C)nc21
Temperature: 150 °C
Yield: 64.1 %

Procedure:
A mixture of 1.2 g of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine and 2.1 g of glutaric anhydride was stirred under heating at 150° C. for 15 hours. After cooling to room temperature, 10 ml of 1M hydrochloric acid was added thereto and the whole was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. To the residue was added 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid, followed by heating under reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (chloroform). Thereafter, similar operations to those in Example 2 were carried out to obtain 1.00 g of 3-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as pale yellow crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2cccnc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of quinolin-8-ol (3 g, 0.0207 mol) in MeCN (10 mL) was added ethyl bromoacetate (4.12 g, 0.025 mol) and K2CO3 (5.75 g, 0.0414 mol). The mixture was stirred at 80° C. for 12 h, filtered and concentrated. The residue was purified by column chromatography. (3.9 g, yield 81%) MS (ESI+) e/z: 232.1 [M+1]+.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19](I)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>>[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([C:38]4[O:39][C:35]([CH:31]5[O:32][CH2:33][CH2:34][O:30]5)=[CH:36][CH:37]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(I)cc12
Agent: Cl
Product: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(-c3ccc(C4OCCO4)o3)cc12

Procedure:
Prepared according to Procedure B from (4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ1H NMR (400 MHz, DMSO-d6) 10.49(s, 1H), 8.88(d, 1H), 8.63(s,1H), 8.1 (d, 2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m,1H), 6.75(d, 1H), 6.01 (s,1H), 4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[C:19]#N.C(O)=[O:22]>[Ni]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[CH:19]=[O:22]
Reactant: N#Cc1cnn(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Reactant: O=CO
Agent: [Ni]
Product: Nc1c(C=O)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Yield: 62 %

Procedure:
12 g (0.042 mol) of 5-amino-4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-pyrazole are boiled under reflux with 5 g of Raney nickel in 50 ml of 75% strength aqueous formic acid for 1 hour; the still warm solution is filtered under suction, the residue is rinsed with water, the filtrate is extracted several times with ether, and the combined ether phases are washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated down in vacuo. 8.0 g (62% of theory) of 5-amino-1-(2-chloro-4-trifluoromethoxy-phenyl)-4-formyl-pyrazole are obtained in the form of an oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25]>CC(N(C)C)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:25][C:24]([NH2:26])=[N:23]3)=[CH:17][CH:16]=1
Reactant: Cc1ccc(COc2cccc(F)c2C#N)cc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(COc2cccc3nc(N)nc(N)c23)cc1
Yield: 37.8 %

Procedure:
2-Fluoro-6-(4-methylbenzyloxy)benzonitrile (241.3 mg; 1 mmol) and guanidine carbonate (180.2 mg; 1 mmol) were heated at 145° C. in dimethyl acetamide for 7 hours. The solvent was removed. Purification by recrystallization in hot ethanol/water yielded 106 milligrams of 5-(4-methylbenzyloxy)quinazoline-2,4-diamine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11]Br)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[SH:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:13][C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: BrCc1nccc2c(Br)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 158 mg (0.515 mmol) of 3-bromo-7-bromomethylthieno[2, 3-c]pyridine (i-1), 85 mg (1.1 equivalents) of 2-mercaptobenzimidazole, 284 mg (4 equivalents) of anhydrous K2CO3 and 4 ml of anhydrous DMF was stirred for 1 hr. at room temperature. Water was added to the mixture, and crystals separated out. The crystals collected by filtration were dried, whereby 183 mg (94.5%) of 2-[(3-bromothieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-6) was obtained as an objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>[OH-].[NH4+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Brc1cccc2cnccc12
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reaction time: 1 h

Procedure:
The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (˜300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1>[Ni]>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Ni]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Yield: 90.8 %

Procedure:
In a 500-mL autoclave were added 100.0 g (0.65 mol) of the 1-isopulegol obtained in Example 42 and 0.4 g of Raney nickel in a nitrogen atmosphere. Hydrogenation was conducted under a hydrogen pressure of 2.5 MPa at 70° C. for 10 hours. The reaction mixture was filtered and the residue was distilled to obtain 92.3 g (0.59 mol, 90% e.e.) of 1-menthol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:23]([O:25]CC)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[C:5]3[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
The title compound was prepared from ethyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 1 Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H, 2.85 (dd, J=13.9, 10.9 Hz, 1H, 3.16 (dd, J=13.9, 4.2 Hz, 1H, 3.48 (s, 3H, 4.66 (ddd, J=13.9, 10.9, 4.2 Hz, 1H, 7.05 (dd, J=8.9, 2.0 Hz, 1H, 7.12-7.32 (m, 11H, 7.40 (d, J=8.8 Hz, 1H, 7.53 (d, J=8.9 Hz, 2H, 7.58 (d, J=8.7 Hz, 2H, 8.98 (d, J=8.2 Hz, 1H, 9.83 (s, 1H, 12.89 (br s, 1H; MS (ESI) m/z 610 (MH+); MS (ESI) m/z 608 [M-H]−; HRMS calcd for C35H36N3O5S: 610.2373; found (ESI+): 610.2362; Anal. calcd for C35H35N3O5S.0.7H2O: C, 67.55; H, 5.90; N, 6.75. Found: C, 67.30; H, 5.93; N, 6.80.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 67.1 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and ethanol (170.1 g) were mixed, and the resultant mixture was heated to 30° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (10 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.8 g of p-cyanobenzamide (yield 67%).
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]2)[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 2.5 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (70 mg, 0.24 mmol) and 2-aminothiazole (26.3 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.63 mL, 0.43 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (2.3 mg, 2.7%) as a light yellow oil: EI-HRMS m/e calcd for C17H17Cl2N2OS (M+H)+ 387.0496. found 387.0499.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:27])[C:25]=1F)[C:21]#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:25]1[C:18]([F:17])=[CH:19][C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:27]
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1Nc1c(F)cc(C#N)cc1F
Temperature: 210 °C

Procedure:
A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amin (i.e. the product of Step B) (0.25 g, 1.0 mmol), 3,4,5-trifluorobenzonitrile (0.188 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol) in acetonitrile (3 mL) was heated at 210° C. in a Biotage Initiator™ microwave apparatus for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a pad of silica gel on a sintered glass frit funnel. The filtrate was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.065 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (110 mg, 0.34 mmol) and ammonium acetate (270 mg, 3.4 mmol) in methanol (1.9 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled and sodium cyanoborohydride (43 mg, 0.69 mmol) was added. The reaction was heated at 65° C. for another 4 hours. The mixture was cooled, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (98 mg, 93%). LCMS calculated for C16H17ClFN2O (M+H)+: m/z=307.1. found: 306.9.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].[C:24]1([CH3:55])[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[CH:39]=3)[CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:14]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:23])=[C:2]([C:37]4[CH:36]=[C:35]5[C:40](=[CH:39][CH:38]=4)[CH2:41][N:33]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:55])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[CH2:34]5)[C:11]=3[O:12][CH3:13])[C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(Br)c(F)cc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O

Procedure:
In 5 ml of toluene was suspended 0.25 g of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, and to this suspension were added 0.55 g of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline and 0.09 g of bis(triphenylphosphine)palladium (II) chloride, after which the resulting mixture was heated under reflux for eight hours under an argon stream. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: chloroform), after which diethyl ether was added thereto. The crystals formed were collected by filtration to obtain 0.19 g of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:40](/[S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41]\[CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([NH:48][S:45](/[CH:40]=[CH:41]/[CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])=[O:11]
Reactant: CCC/C=C/S(N)(=O)=O
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2/C=C/C(=O)O)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC/C=C/S(=O)(=O)NC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(OCCCCC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
(E)-3-(4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-2-propenic acid (150 mg) was dissolved in N,N-dimethylformamide (1.5 ml) and carbonyldiimidazole was added. The mixture was stirred at room temperature for 3 hr. To the reaction mixture was added (E)-1-penten-1-ylsulfonamide sodium salt (97 mg), and the mixture was stirred at room temperature for 3 hr and left standing for one day. The reaction mixture was diluted with water (1.5 ml) and adjusted to pH 4 with 1N hydrochloric acid under ice-cooling. The precipitated powder was collected by filtration and washed with water. The resulting white powder was suspended in ethanol (0.75 ml) and heated. The mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol and dissolved in N,N-dimethylformamide (0.75 ml) at 80° C. Water (0.25 ml) was added at the same temperature and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed with N,N-dimethylformamide—water (1:1) and then with water to give (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-N-((E)-1-penten-1-ylsulfonyl)-2-propenamide (160 mg) as colorless crystals.