Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>C(#N)C>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 5 °C
Yield: 82.6 %

Procedure:
To a 50 liter glass reactor containing ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (2.000 kg, 1.000 equiv.) was added cesium carbonate (3.266 kg, 1.300 equiv.) and acetonitrile (15.720 kg) under nitrogen. To the resulting mixture was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (2.228 kg, 1.100 equiv.) over approximately one hour while maintaining the stirred reactor contents at 40° C.±5° C. After the addition of 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene the reactor contents were heated to 65° C.±5° C. with stirring until the concentration of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate in the reaction mixture was less than 2.0% area by HPLC. The reaction mixture was cooled to 50° C.±5° C. and filtered under nitrogen through a fine filter cloth with suction to remove cesium salts (Note: ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate may precipitate below 30° C.). The filter cake was washed with fresh hot (50° C.±5° C.) acetonitrile (5.658 kg divided in approximately three equal portions). The filtrates were returned to the reactor. The combined filtrates were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C. To the reactor was added ethyl alcohol (3.156 kg) and once again concentrated with stirring by vacuum distillation with a jacket temperature of 60° C.±10° C. Once again, ethyl alcohol (3.156 kg) was added to the reactor and the contents were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C. to a reactor volume of approximately 14 L. The stirred reactor contents were cooled to 0° C. f 5° C. and the temperature maintained for 4 hours to facilitate the crystallization of the product. The resulting slurry was filtered. The filter cake was washed with cold 0° C.±5° C. ethyl alcohol (2×3.156 kg). The filter cake was dried under vacuum at 35° C.±5° C. until the weight loss over hour was to provide 3.0943 kg (81.0% yield) of the title compound as a solid.
Reaction SMILES: [Na].[CH3:2][N:3]1[CH:7](P(OCC)(=O)OCC)[C:6](=[O:16])[NH:5][C:4]1=[O:17].[CH:18]1([N:24]([CH3:42])[C:25](=[O:41])[CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([CH:39]=O)[CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:18]1([N:24]([CH3:42])[C:25](=[O:41])[CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([CH:39]=[C:7]3[N:3]([CH3:2])[C:4](=[O:17])[NH:5][C:6]3=[O:16])[CH:31]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Agent: [Na]
Solvent: CCO
Product: CN1C(=O)NC(=O)C1=Cc1cc(OCCCC(=O)N(C)C2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
Sodium (0.079 g, 0.003 g atom) was dissolved in ethanol (20 mL) and diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate (0.86 g, 3.4 mmol) added. After 5 minutes, N-cyclohexyl-4-(3-formyl-4-nitrophenoxy)-N-methylbutanamide (1 g, 2.9 mmol) was added and the mixture stirred at room temperature for 90 minutes. The solvent was evaporated and the residue diluted with water and extracted with dichloromethane to give a foam. Crystallization from hexane/dichloromethane afforded N-cyclohexyl-N-methyl-4-[3-[(1-methyl-2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]butanamide (0.96 g, 75%) as a 3:1 mixture of geometrical isomers, m.p. 149°-154° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:3]([N:9]=[C:10]=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1ncc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To 3,5-dichloropyridin-2-amine (0.36 g, 2.209 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.523 g, 2.253 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature and the crude was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield to yield 3,5-dichloro-2-isothiocyanatopyridine (0.4 g, 1.951 mmol, 88% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.50 (t, J=2.59 Hz, 1H), 8.45 (t, J=2.59 Hz, 1H). MS (LC/MS) R.T.=2.07; [M+H]+=204.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.BrC[CH:24]1[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH:24]2[CH2:26][CH2:25]2)[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: BrCC1CC1
Product: NC(=O)c1ccc(OCC2CC2)c(C(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and (bromomethyl)cyclopropane by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][N:30]([CH3:38])[CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2CNCCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nnc(OCC2CN(C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
A suspension of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-piperidin-3-ylmethoxy)-pyridazine dichloride (0.17 mmol, 90 mg), 37% paraformaldehyde (0.4 mmol, 32 mg), and 1 drop of acetic acid in 5 mL of DCM was stirred for 5 min then added sodium triacetoxyborohydride (0.4 mmol, 85 mg) and continued stirring for 0.5 h at room temperature. Quenched with water, solvent was evaporated; the residue was diluted with ethyl acetate, and then washed with saturated NaHCO3 solution, brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-1-methyl-piperidin-3-ylmethoxy)-pyridazine (52 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:31]=[C:30]([O:32]C)[C:29]2[C:24](=[CH:25][C:26]([O:36][CH3:37])=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1>C(O)CCCC>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:22]3[NH:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][C:26]([O:36][CH3:37])=[C:27]([O:34][CH3:35])[CH:28]=4)[N:23]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1cc2nc(Cl)nc(OC)c2cc1OC
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
4-(Piperidin-4-ylamino)benzoic Acid tert-Butyl Ester (49) (0.47 mmol) was added to a solution of 2-chloro-4,6,7-trimethoxy-quinazoline (0.1 g, 0.39 mmol) in n-pentanol (5 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.06 g (32%) of (15): TLC (Rf =0.30; 5% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 11.24 (s, 1H), 7.61 (d, 2H, J=8.4), 7.26 (s, 1H), 6.76 (s, 1H), 6.60 (d, 2H, J=8.7), 6.36 (d, 1H, J=7.8), 4.24 (d, 2H, J=13.6), 3.83 (s, 3H), 3.78 (s, 3H), 3.60 (m, 1H), 3.09 (m, 2H), 1.94 (d, 2H, J=10.4), 1.48 (s, 9H), 1.40 (m, 2H) 13C NMR (DMSO) δ 165.2, 162.4, 154.9, 151.4, 150.1, 146.7, 145.6, 130.9, 117.6, 111.2, 109.2, 106.0, 105.3, 78.9, 55.7, 55.5, 48.4, 43.9, 30.9, 28.0; HRMS (FAB) m/z 481.2444 (M+H)+ (C26H32N4O5 requires 481.2443); Anal. (C26H32N4O5 ·1/2HCl) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24]C)=[O:23])=[N:20][CH:21]=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[N:20][CH:21]=1)[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: COC(=O)c1cnc(Cl)cn1
Product: O=C(O)c1cnc(-c2ccc3cc(O)ccc3c2)cn1

Procedure:
Followed the two step procedure described for Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and methyl 5-chloropyrazine-2-carboxylate. 1H-NMR (MeOD-d4 500 MHz): 9.31 (s, 2H), 8.64 (s, 1H), 8.19-8.21 (d, J=9.0 Hz, 1H), 7.90-7.91 (d, J=8.5 Hz, 1H), 7.80-7.82 (d, J=8.5 Hz, 1H), 7.15-7.18 (t, J=2.0, 10.0 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.
Reaction SMILES: [N:1]1([C:12]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[CH2:17][N:18](C)[C:19](=O)OC(C)(C)C)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[CH2:2]1>Cl.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:19][NH:18][CH2:17][C:16]1[CH:15]=[C:14]([CH:29]=[CH:28][CH:27]=1)[C:12]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[CH2:2]1)=[O:13]
Reactant: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CNCc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1
Yield: 46.7 %

Procedure:
A solution of tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-on-1-carbonyl)benzyl)-N-methylcarbamate (280 mg, 0.71 mmol) in 4N hydrogen chloride/dioxan (30 ml) was stirred at room temperature for 1 h. The mixture was reduced in vacuo, taken up in chloroform, washed with saturated sodium hydrogen carbonate solution and brine, dried and reduced. Chromatography (10% methanol/90% chloroform) afforded 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (98 mg, 49%) as an orange solid.
Reaction SMILES: C[N:2]([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])[CH3:3].[CH3:14][C:15]1[CH:21]=[CH:20]C(N)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:21]=[CH:20][C:3]([NH:2][CH2:4][CH:5]2[CH2:12][N:11]3[C:7](=[CH:8][CH:9]=[CH:10]3)[C:6]2=[O:13])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)cc1
Reactant: CN(C)CC1Cn2cccc2C1=O
Product: Cc1ccc(NCC2Cn3cccc3C2=O)cc1
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 17.5 g, compound (2) and 10 g 4-methylaniline was allowed to stand at room temperature for 12 hours. 22 g yellow solid was obtained after filtering. Recrystallized from ethanol, 19 g (5) was obtained as a white crystal, mp 112°-114° C., yield 83%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-nitro-3-(trifluoromethyl)phenyl]-1-ethanone (1.41 g, 6.05 mmol), Fe powder (1.69 g, 30.2 mmol), and NH4Cl (324 mg, 6.05 mmol) in EtOH (24 ml) and water (9 ml) was heated to reflux for 2.5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated. And the residue was dissolved with ethyl acetate (100 ml), washed with water (100 ml), dried-over MgSO4, and concentrated in vacuo to give 1.22 g (quant.) of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([C:17](O)=[O:18])=[CH:3][CH:2]=1>O1CCCC1>[CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4]([CH2:17][OH:18])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1CCCCc1ccccc1-2
Solvent: C1CCOC1
Product: OCc1cccc2c1CCCCc1ccccc1-2
Yield: 86.4 %

Procedure:
The reaction between 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-carboxylic acid (1.7 g, 0.0067 mole) and borane-tetrahydrofuran complex (1.16 g of a 1.05M solution in tetrahydrofuran) in tetrahydrofuran (50 ml) produced 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-methanol as an oil (1.38 g). The IR and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A83) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][C:6]([OH:8])=O)[CH3:3].[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6](=[O:8])[CH2:5][O:4][CH2:2][CH3:3])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 32.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-ethoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 121, (2S,4R)-4-benzyl-1-(2-ethoxyacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.4 mg, 32.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.47 (m, 1H), 4.06 (d, 2H), 3.60-3.64 (m, 1H), 3.47-3.53 (m, 2H), 3.18-3.22 (m, 1H), 2.50-2.89 (m, 3H), 1.90 (m, 2H), 1.08 (m, 3H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10]([C:8]1[S:7][C:6]2[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:9]=1)=[O:12])[CH3:18]
Reactant: CCO
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Product: CCOC(=O)c1cc2cc(OC)c(OC)cc2s1

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid (10 g) was suspended in ethanol (80 ml) and the mixture was stirred and heated at reflux for 5 hours. The resultant solution was evaporated to dryness and then crystallised from dichlolormethane:methanol to give 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester as a white solid (9.5 g), m.p. 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Reaction time: 2 h
Yield: 110 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3-fluorobenzoyl chloride (0.019 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (45.3 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Yield: 100.8 %

Procedure:
A solution of 3-bromophenol (400 g, 2.31 mol), tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole (346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred overnight at room temperature. The reaction solution was poured into 2000 mL of water and the layers were separated. The organic layer was washed with 1N aqueous sodium hydroxide solution (3×1500 mL) and water (2×1500 mL) before passing through a pad of silica gel (400 g, silica 60, 230-400 mesh). The silica gel was washed with dichloromethane (2×500 mL), the filtrates were combined and the solvent removed under reduced pressure to give 669 g (98.4%) of 3-bromophenoxy-tert-butyldimethylsilane as a clear pale yellow liquid. 1H NMR (CDCl3, 300 MHz): δ7.1 (m, 2H); 7.0 (br s, 1H); 6.75 (m,1H); 1.0 (s, 9H); 0.2 (s, 6H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:16])[C:12]([CH3:15])([OH:14])[CH3:13])=[CH:9][N:10]=1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:16][CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[C:12]([OH:14])([CH3:15])[CH3:13]
Reactant: CC(C)(O)C(O)c1cnc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C(O)c1cnc(C=O)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2-methylpropane-1,2-diol (0.33 g), 1M hydrochloric acid (1 mL), water (2 mL) and tetrahydrofuran (6 mL) was stirred at 60° C. for 6 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.21 g, yield 77%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. MS: 202 (MH+).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:33]([NH:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH3:37])=[O:34])[NH:17][C:18](=[O:32])[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>O>[NH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:33]([NH:35][C@@H:36]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[CH3:37])=[O:34])[NH:17][C:18](=[O:32])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[S:11]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=S)NC(=O)c2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(N)=S)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
(R)-N5 -(Benzoylaminothiocarbonyl)-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide (2.25 g; 3.6 mmol; from step (a) above), methanol (250 mL), water (250 mL) and K2CO3 (1.49 g; 10.8 mmol) were combined and stirred for 24 h at room temperature. The reaction mixture was then partitioned between EtOAc (250 mL) and brine (250 mL). The EtOAc layer was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 1.86 g (99%) of the sub-title compound as a white foam.
Reaction SMILES: C(O)(=[O:3])C.FC(F)(F)C(O)=O.[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16].OO>O>[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])(=[O:3])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16]
Reactant: CC(=O)O
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F
Temperature: 90 °C

Procedure:
In a mixed solution consisting of 5 ml of acetic acid and 10 ml of trifluoroacetic acid was dissolved under heating 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea, and 1.5 ml of 30% hydrogen peroxide aqueous solution was added to the solution, followed by heating at 90° C. for 2 hours. The reaction mixture was diluted with water, and the crystals which separated out were recovered by filtration, and washed with water and ethanol successively to give 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl]urea (Compound No. 6), m.p. of 176°-177° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.O>CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCn2ccnc2)cc1
Temperature: 100 °C

Procedure:
Sodium hydride (0.6 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (0.79 g) in dry N,N-dimethylformamide (50 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. Ethyl 4-(3-chloropropoxy)benzoate (2.8 g) was added over 2 minutes and the resulting mixture was heated on a steam bath for 6 hours and then cooled. Water (1 ml) was added to decompose any unreacted sodium hydride and the solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave mineral oil and small amounts of impurity. Elution with chloroform/methanol (20:1) gave the pure 1-[3-(4-ethoxycarbonylphenoxy)propyl]imidazole as an oil on evaporation of the solvent.