Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=1)[CH3:20].ClCCl>C(#N)C.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: C#Cc1ccc(OCC)cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1ccc(C#Cc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To 5.00 g (13.8 mmol) [2-(4-iodo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (I52.5) and 2.02 g (13.8 mmol) 4-ethoxyphenylacetylene in 80 mL ACN are added 4.46 mL (32.2 mmol) TEA, 135.6 mg (0.17 mmol) [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 32.3 mg (0.17 mmol) CuI, and the reaction mixture is stirred at r.t. over night. The precipitate is filtered and washed with ACN. The resulting crude product is purified by column chromatography (CyH/EtOAc 100/0→90/10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=S)[NH:8][C:7]=2[CH:18]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)NC(=S)c1ccccc1N2
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: COc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 24.7 %

Procedure:
A solution of 0.25 g (0.98 mmol) of 8-methoxy-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of 2-ethoxyethanol was treated with 0.22 mL (2.1 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 /hexane (80/20) to CH2Cl2 /MeOH (94/6) gave 80 mg (25% yield) of the product as a yellow solid, mp 160-161° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =331.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.P(=O)(O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Agent: O=P(O)(O)O
Solvent: O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The batch was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5% brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)[N:6]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].O>C(Cl)(Cl)Cl>[CH2:29]([S:31]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)[N:6]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: COC(=O)Cc1ccc(CCc2csc(N)n2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)OC)cc2)cs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl {4-[2-(2-amino-1,3-thiazol-4-yl)ethyl]phenyl}acetate (2.00 g, 7.24 mmol) in chloroform (20 ml) was added N,N-diisopropylethylamine (6.3 ml, 36.2 mmol), and the mixture was cooled to 0° C. Ethanesulfonyl chloride (0.82 ml, 8.7 mmol) was added dropwise, and the mixture was stirred at 0° C. overnight. Iced water (40 ml) was added to the reaction mixture, and the mixture was stirred for 10 mins. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→1:0) to give methyl [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetate (1.76 g, yield 66%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[NH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 45.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylpropanamide (0.60 g, 1.82 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (502 mg, 3.63 mmol) and 3-aminophenol (278 mg, 2.54 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.26 g, 47%) was obtained as a dark brown powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.[ClH:24].C(O)C>C(O)C>[ClH:24].[N:1]1([C:17]2[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[S:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Piperazine (53.6 g) was added to the resulting toluene solution, reflux was conducted for 1 hour, and the resulting solution was cooled to room temperature. Washing was carried out with water (125 ml×3) to remove remaining piperazine, and an organic layer was vacuum distilled to produce oil. The oil was dissolved in ethanol, and a hydrochloric acid-ethanol solution was added thereto, to produce 11-piperazinyl-dibenzo[b,f][1,4]thiazepine hydrochloride (46.4 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:8][CH2:9][OH:10].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC1C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][CH:7]1[C:6]2[S:5][CH:4]=[N:3][C:2]=2[O:10][CH2:9][CH2:8]1
Reactant: OCCC(OC1CCCCO1)c1scnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1nc2c(s1)C(OC1CCCCO1)CCO2

Procedure:
A soln. of 3-(4-chlorothiazol-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (520 mg, 1.87 mmol) in MePh (10 mL) was added to a Ar-filled vial charged with Pd(OAc)2 (63 mg, 0.28 mmol), 2-(di-tert-butylphosphino)-1,1′-binaphthyl (140 mg, 0.35 mmol) and Cs2CO3 (915 mg, 2.81 mmol). The vial was sealed and placed in a preheated oilbath (100° C.) overnight. Subsequently, the mixture was diluted with DCM, filtrated over Celite, and conc. in vacuo. Purification by means of CC (20-80% EtOAc/Hept) provided the product as a yellow oil as an isomeric mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.[NH2:15][OH:16]>CO.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[N:15][OH:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(=O)c2ccccc2O1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2ccccc2O1
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
A reaction mixture prepared from 10 mmol of 2,2-dimethyl-4-chromanone, 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated with stirring over the course of 2 hours to 80-85° C., the solvent is distilled off on a rotary evaporator and the oily residue is crystallized under water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:24]([CH:25]=[O:26])=CC=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:24]/[CH:25]=[O:26])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Product: O=C/C=C/c1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 210 (M+H)+.
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2>Cl>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(Cl)C1
Agent: Cl
Product: CN1CCC2(Cl)CNCC12

Procedure:
9.3 g (40 mmol) of ethyl 5-chloro-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 30 ml of water, and the mixture is rendered alkaline with potassium carbonate and extracted five times with 50 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].Cl>CCOCC.O1CCCC1.CCCCCC>[CH3:10][C:6]1([CH3:11])[C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[S:9][CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: CC1(C)CCSc2cc(Br)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCSc2cc(C(=O)O)ccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
11 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran were dissolved in a mixture of 100 ml of ether and 10 ml of tetrahydrofuran and treated at -78° C. with 33 ml of a 1.6 molar solution of n-butyllithium in hexane. The reaction solution was held at -50° C. for 15 minutes, again cooled to -78° C. and gassed with carbon dioxide for 2 hours. Thereafter, the mixture was poured on to ice, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic phases were washed with water, dried and evaporated. After recrystallization of the crude product from ethyl acetate/hexane, there were obtained 4.6 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxylic acid, melting point 202°-204° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:6]([O:8]C(C)(C)C)=[O:7])#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)C>[C:1]([CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:22])[F:21])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)C(CCC#N)c1ccccc1C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCC(C(=O)O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
tert-Butyl 4-cyano-2-(2-trifluoromethylphenyl)butanoate (7.2 g) was dissolved in methylene chloride (40 mL). Trifluoroacetic acid (50 mL) was added at 0° C. and the reaction was initiated. After stirring at room temperature for one hour, concentration under reduced pressure gave an oil. The resulting oil was dissolved in diethyl ether, washed with water (three times) and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a yellow oil. The oil was dissolved again in diethyl ether and partitioned between diethyl ether and 5 N sodium hydroxide (15 mL). The resulting aqueous layer was made acidic with 5 N hydrochloric acid (16 mL) and extracted with methylene chloride twice to obtain the title compound (6.76 g) as a colorless transparent oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Mg]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
4-Bromobenzotrifluoride (6.05 mL, 43.21 mmol) dissolved in ether (5 mL) was added dropwise over 10 minutes to magnesium turnings (1.25 g, 51.42 mmol). The mixture became mildly exothermic and turned red-brown while the Grignard reagent formed during 1.5 hours of stirring. The mixture was chilled with ice and 1-benzyloxycarbonyl-4-piperidone (10.0 g, 42.87 mmol dissolved in 50 mL of ether) was added dropwise over 10 minutes to the reaction. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated ammonium chloride and the phases were separated. The aqueous layer was further extracted with ether. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (3×6 inches, 30% ethyl acetate/hexane) to give 1-benzyloxycarbonyl4-hydroxy-4-(4-trifluoromethylphenyl)piperidine as an orange oily product which solidified on standing (12.48 g, 77%). The material was suitable for use in the next step. A sample recrystallized from ether/hexane had mp 102°-102.5° C. Analysis calculated for C20H20F3NO3 : C, 63.32; H, 5.31; N, 3.69. Found: C, 63.25; H, 5.27; N, 3.71.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>ClCCl.C1(C)C=CC=CC=1>[F:12][C:9]([F:11])([CH3:10])[CH2:8][C@H:3]([N:2]=[C:19]=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(C)(F)F)N=C=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Under argon, 2.0 g of methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride (9.8 mmol) were dissolved in 80 ml of dichloromethane, admixed with 3.2 ml of pyridine (4 eq.) and cooled to approx. 5° C. (ice bath). After 10 min, 6.7 ml (1.3 eq.) of a 20% phosgene solution in toluene were slowly added dropwise. The resulting suspension was stirred with ice bath cooling for 3 h and then concentrated under reduced pressure. The residue thus obtained was taken up in toluene and filtered. After the solvent had been removed under reduced pressure, methyl (S)-4,4-difluoro-2-isocyanatopentanoate was obtained as a brown oil which was used in the subsequent reaction without further purification. Yield: 1.1 g (58% of theory).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[B:20](OC)([O:23]C)[O:21]C>CCCCC>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([B:20]([OH:23])[OH:21])[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COB(OC)OC
Reactant: COCOc1ccc(C(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: COCOc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 110.1 %

Procedure:
Following a procedure by Ronald, R. C. et al (J. Org. Chem., 1980, 40, 2224-2229) a 1.7 molar solution of tert-butyl lithium in pentane (6.70 mL, 11.3 mmol) was added to a solution of 1-(tert-butyl)-4-(methoxymethoxy)benzene (2.00 g, 10.3 mmol, Kovacs, M. S. et al J. Chem. Soc. Dalton, 2001, 3015-3024) in pentane (40 mL) under a nitrogen atmosphere at 0° C. A solid precipitated and the pentane was evaporated under a steady stream of nitrogen gas. To this remaining solid was added tetrahydrofuran (50 mL) and the solution was cooled to −78° C. Trimethyl borate (1.70 mL, 15.5 mmol) was added slowly and the solution was stirred at −78° C. under nitrogen gas for 30 minutes. Thin layer chromatography showed consumption of the starting material and water (10 mL) was added and the solution was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide solution. The organic phase was separated and dried with sodium sulfate, filtered and concentrated under reduced pressure to give 2.70 g of crude (5-(tert-butyl)-2-(methoxymethoxy)phenyl)boronic acid which was used without further purification.
Reaction SMILES: C1O[C:4]2([CH2:8][CH2:7][CH2:6][CH:5]2[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[O:3]C1.Cl.[OH-].[K+]>>[N:10]1([CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][C:4]2=[O:3])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1cn(CC2CCCC23OCCO3)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C1CCCC1Cn1ccnc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In an oil bath, 3.5603 g of 2-(1H-imidazol-1-ylmethyl)cyclopentanone ethyleneketal (IV) and 17.8 ml of 2N hydrochloric acid added thereto were stirred at 60° C. for 5 hours. The resultant reaction solution was left cooling. Then, it was neutralized with an aqueous 1N potassium hydroxide solution and extracted with methylene chloride, to obtain an organic layer. This organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under a reduced pressure.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]([OH:21])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=1)[CH:2]=[CH2:3]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=1)=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCc1c(Br)cncc1C(O)c1ccc(C#N)c(F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C=CCc1c(Br)cncc1C(=O)c1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-[(4-allyl-5-bromo-pyridine-3-yl)-hydroxy-methyl]-2-fluoro-benzonitrile (as described above in Step B) (0.42 g, 1.21 mmol) in CH2Cl2 (50 mL) was added MnO2 (1.58 g, 18.1 mmol). After 6 hr the reaction was filtered and the CH2Cl2 was removed in vacuo to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([O:27]CC)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-].Cl>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([OH:27])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in H2O (5 mL) and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100° C. for 24 hours before it was cooled to room temperature. The mixture was acidified with 1N HCl and it was extracted with three 20 mL portions of dichloromethane. The organic extracts were dried over Na2SO4 and evaporated to yield 5-(1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 364.1. found 365.1 (M+1)+; retention time 2.70 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:23])[CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].C([O-])(O)=O.[Na+].[ClH:38]>C(O)C.CN(C)C=O.C(N(CC)CC)C>[ClH:38].[ClH:38].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:23])[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:21][CH2:22]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: COc1ccccc1Br
Reactant: O=C1CCc2c(OCC(O)CN3CCNCC3)ccc(Br)c2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC(O)COc2ccc(Br)c3c2CCC(=O)N3)CC1

Procedure:
2.5 Grams of 8-bromo-5-(2-hydroxy-3-piperazinylpropoxy)-3,4-dihydrocarbostyril, 2.0 g of o-bromoanisole and 2.0 g of triethylamine are mixed with 30 ml of dimethylformamide. The reaction mixture thus obtained is heated under a stream of argon gas at 120° to 130° C. for 5 hours. The reaction mixture is concentrated under a reduced pressure and to the residue thus obtained is added 30 ml of 5% NaHCO3 aqueous solution, and the organic layer is extracted with chloroform. Chloroform is removed by distillation and to the residue thus obtained are added 3 ml of concentrated hydrochloric acid, then 20 ml of ethanol are added and stirred. The crystals thus precipitated are collected by filtration to obtain 2.1 g of 8-bromo-5-{2-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.dihydrochloride in the form of colorless crystals with a melting point of 226°-228° C.