Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C[C:19]([N:21]([CH3:23])[CH3:22])=O>CN(C=O)C>[N+:15]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1/[CH:1]=[CH:19]/[N:21]([CH3:23])[CH3:22])([O-:17])=[O:16]
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(C(F)(F)F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 8.0 mmol) and DMA (1.0 g, 8.2 mmol) in DMF (20 mL) was stirred at 100° C. for 30 min. The mixture was poured into ice-water and stirred for 1 h. The precipitate was filtered and washed with water to give (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-N,N-dimethylethenamine (2.1 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)nc1
Reaction time: 72 h
Yield: 42 %

Procedure:
2-Bromo-5-hydroxypyridine (1 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methoxy-ethane (1.1 eq.) is added and the reaction solution is stirred 3 days. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-(2-methoxyethoxy)-pyridine is obtained after column chromatography as colorless powder in a yield of 42%; HPLC (method C): 1.48 min; LC-MS (method A): 1.11 min, 231.95 (M+H+).
Reaction SMILES: Cl.[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)C[C@H]1C(OCC1C=CC=CC=1)=O.[CH3:21][OH:22]>[Pd]>[NH2:2][C@H:10]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:21][OH:22]
Reactant: CO
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Agent: [Pd]
Agent: Cl
Product: N[C@H]1CCCC[C@@H]1CO

Procedure:
In yet another embodiment, (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3), is produced using a starting material of crystalline ((1S,2S)-2-(S)-1-phenylethylamino)cyclohexyl)methanol (11). The first step of the process involves reaction with a catalyst including palladium on carbon in the presence of methanol to produce ((1S,2S)-2-aminocyclohexyl)methanol (17). Compound (17) is subjected to treatment with sodium cyanide in the presence of formaldehyde to produce compound (18). Subsequently, compound (18) is first reacted with trimethylsilyl chloride, and then the product of that reaction is treated with benzyl chloride to produce compound (19). Further, compound (19) is subjected to three sequential reactions to produce compound (20) as illustrated in FIG. 3. Specifically, compound (19) is first subjected to treatment with hydrochloric acid. Subsequently, methanesulfonyl chloride is added to the reaction mixture. Thereafter, potassium hydroxide is added to the reaction to produce compound (20). After compound (20) is produced, the compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound (5).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[C:3]([OH:11])=[C:4]([CH2:8][CH2:9][NH:10][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(F)c1O
Reactant: CC(=O)OC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NCCc1cccc(F)c1O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.54 g of (3-fluoro-2-hydroxyphenyl)acetonitrile, 1.87 ml of acetic anhydride and 2.41 g of nickel chloride hexahydrate in 75 ml of methanol is admixed at 0° C. with 2.72 g of sodium borohydride in portions and stirred at room temperature over 22 hours. The reaction mixture is concentrated by evaporation, and the residue is diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution and clarified by filtration. The aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (95:5 dichloromethane-methanol); Rt=2.60.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23].[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23]
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 26.2 %

Procedure:
6.24 g (18.2 mmol) of (S)-8-chloro-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were stirred with 3.43 g (20 mmol) of chloroacetic anhydride and 40 ml of N,N-dimethylformamide at room temperature for 60 hours and at 105° for 2.5 hours. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.88 g (26%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 214°-217°.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2](C)C.C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][CH3:30])=[C:26]=[O:27]>C(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:26]([NH:25][CH2:28][CH2:29][CH3:30])=[O:27])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC(C)CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)Nc1ccc(N2CCN(CC)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 20 mg (0.1 mmol) 6-(4-isobutyl-piperazin-1-yl)-pyridin-3-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml DCM was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 15.5 mg (53%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][Zn]C.C1(C)C=CC=CC=1>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:35])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (100 mg, 0.192 mmol) and dimethyl zinc in toluene (0.192 mL, 0.383 mmol), the title compound was obtained as a solid (50 mg, 49% yield). MS (ESI): 502 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: O=C1C(Cc2ccc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Yield: 48.9 %

Procedure:
Treat a solution of 3-(2-chloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (0.2 g, 0.58 mmol) and 2-Iodopropane (0.06 mL, 0.64 mmol) in DMF (4 mL) with potassium carbonate (0.1 g, 0.7 mmol) and stir reaction overnight at room temp. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography and remove the solvent to afford 0.11 g (48%) of product. MS (m/e): 388 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25](=[O:30])N(OC)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)c3ccc(F)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A solution of 200 mg (0.456 mmol) (2R,4R)-4-(4-Methoxy-benzylsulfanyl)-2-[2-(methoxy-methyl-carbamoyl)-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 3 ml THF was treated at 0° C. with 1.14 ml (1.14 mmol, 1M THF solution) of a 4-fluorophenyl-magnesium bromide solution and after 10 min warmed up to room temperature. The reaction was partitioned between aqueous aqueous 10% KHSO4/t-butyl methyl ether (3×). The organic phases were washed with aqueous 10% NaHCO3 and saturated NaCl solution, dried over MgSO4 and evaporated to give 144 mg (68%) of (2R,4R)-2-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 474 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:17][CH2:16][CH2:15][C:13]3=2)[CH:8]=[CH:7]1.[OH-].[Na+].O.CN(C)[C:23](=[O:25])[CH3:24]>>[C:23]([C:8]1[C:9]2[C:14](=[C:13]3[CH2:15][CH2:16][O:17][C:12]3=[CH:11][CH:10]=2)[NH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)N(C)C
Reactant: c1cc2ccc3c(c2[nH]1)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1c[nH]c2c3c(ccc12)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To stirred N,N-dimethylacetamide (2.1 mL) under Ar at 0° C. was added phosphorous oxychloride (1.0 mL, 10.7 mmol) dropwise over 10 min. The resultant pale yellow mixture was allowed to warm to ambient temperature, then a solution of 7,8-dihydrofuro[2,3-g]indole (800 mg, 5.0 mmol) in N,N-dimethylacetamide (1.5 mL) was added over 3 min and the mixture was stirred for 2 h. The resultant suspension was heated at 65° C. for 30 min, then cooled in an ice-water bath. Ice (10 g) was added portionwise to the stirred mixture followed by the cautious addition of 20% aqueous sodium hydroxide (10 mL), then water (15 mL). The resultant mixture was heated to reflux for 10 ml then cooled to room temperature and diluted with ice-water (50 mL). The suspension was filtered-off and dried to give the crude product (870 mg, 86%) as a beige solid. Recrystallisation from hot ether (10 mL) afforded the product (746 mg, 74%) as a cream-coloured solid: m.p. 233-234.5° C.; NMR (400 MHz, DMSO-d6) δH 2.41 (3H, s), 3.32 (1H, 2H, t, J 8.5 Hz), 4.58 (2H, t, J 8.5 Hz), 6.69 (1H, d, J 8.5 Hz), 7.91 (1H, d, J 8.5 Hz), 8.18 (1H, d, J 3.0 Hz) and 11.76 (1H, br s).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][S:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2sccc12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2sccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Into a 10-mL sealed tube was placed (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chlorothieno[2,3-d]pyrimidine (250 mg, 1.47 mmol, 1.16 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg) and BuOH (5 mL). The resulting solution was stirred for 1 overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0:100-80:20) to afford 260 mg (55%) of 143 as a light yellow solid. LC-MS (ES, m/z): 372 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.19 (s, 1H), 7.70 (d, 1H), 7.68-7.08 (m, 10H), 5.74-5.67 (m, 1H), 1.73 (d, 3H)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[Cl:16][CH2:17][CH:18](OS(C)(=O)=O)[CH3:19].O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH:18]([N:11]([C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:19]
Reactant: CC(CCl)OS(C)(=O)=O
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(C(C)CCl)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
5.2 g of a 80% mineral oil dispersion of sodium hydride are added in small portions, at room temperature, to a suspension of 31.5 g (0.158 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 400 ml of dry toluene. The resulting mixture is heated slowly, within about one hour, to 100° C., and then 27.3 g (0.158 moles) of 1-chloro-2-methanesulfonyloxy-propane are added dropwise to the mixture at the same temperature within 0.5 hours. The reaction mixture is stirred at 100°-110° C. for 12 hours, thereafter it is cooled, placed into an ice bath, and 100 ml of water are introduced dropwise. The aqueous phase is separated, the toluene phase is washed with 100 ml of water, twice with 100 ml of 1 n aqueous sodium hydroxide and finally with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The thick, yellow, oily residue, weighing 33.9 g, is distilled under reduced pressure. 26.15 g of 1-chloro-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained as a slightly opalescent oil; b.p.: 150°-154° C./26.6 Pa.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([C:18]3[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=3)=[O:17])[C@H:11]([O:26][CH3:27])[CH2:10]2)=[N:6][C:5]=1[C:28]([O:30]CC)=[O:29])(=[O:3])[CH3:2].[OH-].[Li+]>CO.C1COCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([C:18]3[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=3)=[O:17])[C@H:11]([O:26][CH3:27])[CH2:10]2)=[N:6][C:5]=1[C:28]([OH:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C(C)=O)s3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl cis(±)-5-acetyl-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-4-carboxylate obtained in Example (190b) (54 mg, 0.11 mmol) was dissolved in methanol (2 ml) and THF (2 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration and washed with distilled water, to obtain the title compound as a solid.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C1COCC1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15]>O>[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:2]=[O:4])[CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCC(C=O)CC1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To dried MTP 50.0 g (146 mmol), THF 500 ml was added, and potassium-t-butoxide 18.0 g (160 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (100 ml) of 4-oxocyclohexane carboxylic acid methylester 21.9 g (140 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 500 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). Such resulting purified material was stirred in mixed solvent of 2N-hydrochloric acid 500 ml and acetone 500 ml for 5 hours at room temperature, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-formylcyclohexane carboxylic acid methyl ester 18.8 g (111 mmol). The yield was 79.2% from 4-oxocyclohexane carboxylic acid methylester.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxo-ethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.73 g (75%) of (R)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used without further purification in the next reaction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([C:17]#[N:18])=[C:10]([N:12]=[CH:13][N:14](C)C)[CH:11]=1.N[C:22]1[NH:26][N:25]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=1.O>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]2[C:9]([C:17]([NH:18][C:22]3[NH:26][N:25]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=3)=[N:14][CH:13]=[N:12]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: Nc1cc(CC(=O)O)n[nH]1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2cc1OCCCCl
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Alternatively, N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (14.78 g, 50 mmol) in acetic acid (40 ml) was heated at reflux with (5-amino-1H-pyrazol-3-yl) acetic acid (8.1 g, 57.5 mmol) for 1.5 h. The reaction mixture was cooled to ambient temperature, water (250 ml) was added to the mixture and the solid was recovered by suction filtration. The solid was washed with 1) water, ii) ethyl acetate and iii) diethyl ether and dried in vacuo at 50° C. to yield (5-((7-(3-chloropropoxy)-6-methoxy-quinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetic acid as a yellow solid (13.6 g, 69% yield):
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC>[CH2:1]([O:8][C:9]1[C:15]([CH3:16])=[CH:14][C:12]([NH:13][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cc(C)c1OCc1ccccc1
Reactant: CCCCCCCCC(=O)O
Solvent: CCOCC
Product: CCCCCCCCC(=O)Nc1cc(C)c(OCc2ccccc2)c(C)c1

Procedure:
1.0 g of 4-benzyloxy-3,5-dimethylaniline and 30 ml of nonanoic acid are stirred at 150° C. for 3 hours. To the reaction mixture is added 100 ml of ether, and the mixture is washed with an aqueous 10 % sodium hydroxide and water, and dried followed by evaporation of the solvent. The residue is purified by silica gel column chromatography [Solvent:chloroform-ethanol (10:1)], and from the eluate is obtained 260 mg of N-(4-benzyloxy-3,5-dimethylphenyl)nonaneamide as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)c(F)cc1Cl
Product: CC(=O)Nc1cc(F)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To acetic anhydride (20 mL) was added 2-chloro-4,5-difluoroaniline (4.7 g, 29 mmol), and the resulting solution was stirred at 100° C. for 1 h. After cooling to rt, the mixture was stored in a freezer overnight. A white crystalline precipitate formed, and it was collected by filtration. Residual acetic anhydride was removed in vacuo. The desired N-(2-chloro-4,5-difluorophenyl)acetamide (4.69 g, 22.8 mmol, 79% yield) was isolated as a white crystalline solid. 1H NMR (400 MHz, CDCl3): 8.38 (dd, 1H), 7.53 (br s, 1H), 7.23 (dd, 1H), 2.25 (s, 3H); MS (EI) for C8H6ClF2NO: 206 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH:2]([CH3:3])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccccc1
Reactant: C=CC
Product: CC(C)c1ccccc1

Procedure:
When benzene is alkylated with propylene to produce cumene, the reaction may also take place under liquid phase conditions including a temperature of up to about 250° C., e.g., up to about 150° C., e.g., from about 10° C. to about 125° C.; a pressure of about 250 atmospheres or less, e.g., from about 1 to about 30 atmospheres; and an aromatic hydrocarbon weight hourly space velocity (WHSV) of from about 5 hr−1 to about 250 hr−1, preferably from 5 hr−1 to 50 hr−1.