Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[N:11]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:12]([CH3:14])=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3].[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[CH2:1]([O:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[N:11]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([CH3:14])=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)c1ccc2c(c1)nc(C)n2C1CCNCC1

Procedure:
A solution of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-2-methyl-1H-benzoimidazole-5-carboxylic acid allyl ester (1.60 g, 4.01 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 300.4 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH2:2][C:3]4[CH:16]=[N:15][C:6]5[C:7]6[N:8]([CH:12]=[CH:13][CH:14]=6)[C:9](=[O:11])[NH:10][C:5]=5[CH:4]=4)[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)[CH2:19][CH2:18]1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25 mg, 0.116 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (35.6 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-cyclopropyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0355 g, 0.080 mmol, 69.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.47-0.59 (m, 2 H) 0.59-0.70 (m, 2 H) 2.52-2.59 (m, 4 H) 2.79 (tq, J=7.36, 3.94 Hz, 1 H) 3.19-3.31 (m, 4 H) 3.62 (s, 2 H) 6.70-6.78 (m, 1 H) 6.93 (d, J=9.09 Hz, 2 H) 7.07 (dd, J=3.66, 1.64 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.66-7.68 (m, 1 H) 7.68-7.73 (m, 2 H) 8.14 (d, J=4.29 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.62 (br. s., 1 H). ESI-MS: m/z 443.4 (M+H)+. mp=269.9-271.7° C.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1O)[CH3:2].O.[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1(c2c[nH]cn2)Cc2ccccc2C1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1(c2c[nH]cn2)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(2-ethyl-2,3-dihydro-1-hydroxy-1H-inden-2-yl)-1H-imidazole (5 kg), water (40 kg), 30% HCl (34 kg), ethanol (22 kg) and 10% palladium on charcoal (0.5 kg) are charged. The mixture is stirred under 2.2 bar overpressure of hydrogen at 80±3° C. for 12 hours. The reaction mixture is filtered at 73±2° C., the filter cake is washed with water (7 kg) and the filtrates are combined. The reaction mixture is heated to boil and 50 l of the solvent is distilled off. The solution is cooled to 0±2° C. during 2 h. The solution is seeded during the cooling procedure with atipamezole HCl at 100±5° C., 90±5° C., 80±5° C. and at 70±5° C., until the crystallization starts. The mixture is agitated for two hours at 0±2° C. The crystalline compound is recovered by centrifugation and washed with HCl-water mixture (0.34 kg HCl and 10 kg of water) and then with 18 kg of acetone. The product is dried under reduced pressure raising the temperature gradually to 85±3° C. The yield is 4.8 kg (89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Product: COC(=O)c1cc(Cl)c(C)c(Cl)c1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 1), except that 3,5-dichloro-4-methylbenzoic acid (Japanese Unexamined Patent Publication (Kokai) No. 6-192196) was used and methanol was used as the solvent, and that the crude product was purified by silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([Cl:23])[CH:14]=1)=O>C(O)C>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: CCOC(=O)C(N)=S
Reactant: COc1cc(C(=O)CBr)cc(Cl)c1OC
Solvent: CCO
Product: CCOC(=O)c1nc(-c2cc(Cl)c(OC)c(OC)c2)cs1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of ethyl aminothioxoacetate (16.2 g) in ethanol (80 ml), stirred under nitrogen at reflux, was added dropwise over 10 min, a hot solution of 2-bromo-1-(3-chloro-4,5-dimethoxyphenyl)-ethanone (31.9 g) in ethanol (180 ml). The mixture was heated at reflux for 4 h, then cooled to room temperature. The precipitated solid was collected by filtration and dried under vacuum at 60° C. Recrystallisation from ethanol gave ethyl 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxylate as a white solid (21.9 g), m.p. 92°-94° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]([F:57])([F:56])[C:12]1[CH:13]=[C:14]([CH:53]=[CH:54][CH:55]=1)[CH2:15][NH:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=2)[CH2:43][S:44][CH2:45][CH2:46][C:47](O)=[O:48])=[O:39])[CH:20]=1)=[O:18].O1CCN(CCNC(=O)CCSCC2C=C(C=CC=2)C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C=CN=2)C(NCC2C=CC=C(C(F)(F)F)C=2)=O)=O)CC1>ClCCl.C(O)(C(F)(F)F)=O>[N:31]1([C:29]2[CH:28]=[CH:27][C:26]([NH:37][C:38]([C:40]3[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=3)[CH2:43][S:44][CH2:45][CH2:46][C:47]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:48])=[O:39])=[C:25]([C:21]3[CH:20]=[C:19]([C:17](=[O:18])[NH:16][CH2:15][C:14]4[CH:53]=[CH:54][CH:55]=[C:12]([C:11]([F:57])([F:10])[F:56])[CH:13]=4)[CH:24]=[CH:23][N:22]=3)[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h

Procedure:
Tert-butyl glycinate was coupled to 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoic acid 1.1 using the procedure described for the synthesis of 2-(2-(3-(((3-((2-morpholinoethyl)amino)-3-oxopropyl)thio)methyl)benzamido)-5-(piperidin-1-yl)-phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 4.16. This material was dissolved in 2 mL of 1:1 dichloromethane/TFA and stirred for 1 h. The solvent was evaporated to give 4.6 mg of product. MS (ES, m/z): 734 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C:16]1([CH3:29])[CH3:28])=O)(C)(C)C>C(Cl)Cl>[CH3:28][C:16]1([CH3:29])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2ccccc2)C(=O)CN1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
1.0 ml of trifluoroacetic acid (13 mmol) was added to a solution of 0.40 g of 2,2-dimethyl-5-oxo-4-phenylpiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.31 mmol) in methylene chloride (2 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 0.23 g of the title compound (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=O.S(O)(O)(=O)=O.[NH2:17][OH:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: NO
Reactant: Cc1c(Cl)ccc(Cl)c1C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1c(Cl)ccc(Cl)c1C=NO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
198 g (0.975 mol) of 93% pure 3,6-dichloro-2-methylbenzaldehyde and 416.2 g (0.634 mol) of a 25% strength aqueous solution of hydroxylamine sulfate are mixed in 1.5 l of toluene and heated at 80° C. Over a period of 2 h, 109.2 g (1.36 mol) of 50% strength NaOH are then added dropwise such that the pH is between 3 and 5. Stirring at 80° C. is continued for 1 h, and the phases are then separated at 80° C. The organic phase is washed once with 250 ml of water. The organic phase is concentrated and the residue is recrystallized from cyclohexane. This gives 165.4 g of the aldoxime (83.3% of theory). 1H-NMR: (DMSO-D6): 2.4 ppm (s, 3H, Me), 7.4 ppm (d, 1H, arom-H), 7.5 ppm (d, 1H, arom-H), 8.3 ppm (s, 1H, NH), 11.7 ppm (s, 1H, OH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CC1CC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)C1CC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-(3-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)cyclobutyl)acetate from step 2 in a mixture of MeOH and H2O was added 1N NaOH (8 mL). The resultant reaction mixture was stirred at RT overnight. Half of the solvents were removed under reduced pressure and 1N HCl was added to adjust pH of the solution to 4. The aqueous phase was extracted with EtOAc for three times. The combined organic phase was then dried and concentrated in vacuo to afford the acid (0.9 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20]O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Br)([Br:39])=O>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][Br:39])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Reactant: O=S(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12

Procedure:
0.6 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are taken up in 7 ml of dichloromethane and 0.25 ml of triethylamine are added at ambient temperature with stirring. Then 0.15 ml of thionyl bromide are added. After 2 hours' stirring at constant temperature the reaction is complete. For working up, the mixture is diluted with 20 ml of dichloromethane and washed successively with 15 ml of water and 15 ml of aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off in vacuo. The residue remaining is recrystallised from diethyl ether. 0.45 g of the title compound remain, pure enough to be used in the subsequent reactions.
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][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.[N:21]1[N:22]=[C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[NH:24][CH:25]=1.N1C=CC(N)=CC=1.Cl.CN(C)CCCN=C=NCC>O.C(OCC)(=O)C.ClCCl.CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:23]3[NH:24][CH:25]=[N:21][N:22]=3)[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(O)CCCCc1nnc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCc1nnc[nH]1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Yield: 27 %

Procedure:
Add N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.189 g; 1.0 equiv; 0.71 mmoles) to a solution containing 5-(4H-1,2,4-triazol-3-yl)pentanoic acid (0.40 g 1.0 equiv; 0.71 mmoles), followed by dimethylformamide (2 mL). Stir the resulting solution at room temperature until homogeneous. Add 4-pyridinamine, N,N-dimethyl-(0.017 g; 0.2 equiv; 0.141 mmoles), and cool the solution to 0° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.204 g; 1.5 equiv; 1.06 mmoles) in one portion. Allow the mixture to warm to room temperature and stir for 30 minutes. Add dichloromethane (2 mL), heat to 40° C., and stir for 24 hours. Dilute with 250 mL water and then 50 mL ethyl acetate. Extract the mixture with ethyl acetate (5×25 mL). Wash the combined organic extracts with brine (10 mL). Dry the organics over magnesium sulfate, filter, concentrate, and purify via column chromatography (hexanes to 12% methanol in ethyl acetate) to give 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(4H-1,2,4-triazol-3-yl)pentan-1-one (0.08 g; 27% yield) as a white foam: MS (m/z): 418 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:20])[N:3]=1.[NH4+].[Cl-]>CO.O1CCOCC1.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH:5]=[C:4]([Br:20])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Yield: 81.4 %

Procedure:
22.30 g (0.052 mol) of 2,6-dibromo-4-(4-nitrobenzenesulphonyl)-pyridine were suspended in a mixture of 275 ml of methanol and 275 ml of dioxane, treated with 22.30 g of powdered iron and a solution of 22.30 g of NH4Cl in 550 ml of water and heated at reflux for 1.5 hrs. Then, the organic solvents were distilled off on a rotary evaporator and the residue was diluted with 1.0 l of dichloromethane and suction filtered. The filter material was suspended in a mixture of 250 ml of methanol and 250 ml of dichloromethane in an ultrasound bath, again suction filtered and the filtrate was retained. The first filtrate was separated in a separating funnel and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated together with the second filtrate. The residue was chromatographed on silica gel with dichloromethane. There were obtained 16.6 g (80%) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine as yellowish crystals; m.p.: 196-198° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
(3RS,4RS)-3-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) was dissolved in CH2Cl2 (2 ml) and treated successively with 4 Å molecular sieves (56 mg, powder) and pyridinium dichromate (56.4 mg, 0.15 mmol). After 3 hours stirring at room temperature, the reaction mixture was directly chromatographed over silica gel (hexane-ethyl acetate 4:1 then 1:1) to provide (RS)-3-(4-benzyloxy-benzenesulfonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (27 mg, 48%) as an oil, MS: m/e=374.2 (M-tbutyl).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:4]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32].CCN(C(C)C)C(C)C>CN(C=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][N:5]1[C:6]2=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[C:3]([CH2:2][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:4]1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Solvent: CN(C)C=O
Solvent: COCCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OC)cc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (4 mL, 0.197M in CH2Cl2, 0.788 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (10 mL) was added 2-(methoxyethoxy)-ethanol (0.47 g, 3.94 mmol, 0.43 mL, 5 eq.) followed by i-Pr2NEt (0.407 g, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed and eluted with CH2Cl2-EtOAc 70:30 v/v, 0.4 L, CH2Cl2-EtOAc-MeOH 80:18:2 1.0 L, and CH2Cl2-EtOAc-MeOH 80:17.5:2.5 1.0 L, 25 mL fractions) using the flash technique. Fractions 42-80 were combined to afford 0.339 g (78%) of methyl 1-(2,4-difluorobenzyl)-3-{[2-(2-methoxyethoxy)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate: 2-(methoxyethoxy)-ethanol (1:1) as a clear, colorless, viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): δ=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH2:29][CH:28]([O:31]C)[CH2:27]5)=[O:25])[S:23][C:16]=34)=[CH:13][C:8]=2[O:7][C:6]=1[CH2:33][CH3:34])=[O:4].B(Br)(Br)Br.CNC(C1C2C=CC(O)=CC=2SC=1C)=O>>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]5)=[O:25])[S:23][C:16]=34)=[CH:13][C:8]=2[O:7][C:6]=1[CH2:33][CH3:34])=[O:4]
Reactant: CCc1oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc2c1C(=O)NC
Agent: BrB(Br)Br
Agent: CNC(=O)c1c(C)sc2cc(O)ccc12
Product: CCc1oc2cc(Oc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)ccc2c1C(=O)NC

Procedure:
This material was prepared from 2-ethyl-6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid methylamide 14 by treatment with BBr3 in a manner as previously described for 1d. 1H NMR (DMSO-d6) δ 8.56 (1H, d, J=5.3 Hz), 8.07(1H, s), 8.00 (1H, d, J=4.1 Hz), 7.82 (1H, d, J=8.6 Hz), 7.68 (1H, d, J=2.0 Hz), 7.25 (1H, dd, J=8.6, 2.0 Hz), 6.73 (1H, d, J=5.3 Hz), 5.07 (1H, t, J=3.5 Hz), 4.35 (1H, m), 3.97 (1H, m), 3.86–3.46 (3H, m), 3.03 (2H, q, J=7.6 Hz), 2.80 (3H, d, J=4.5 Hz), 2.10–1.80 (2H, m), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH2:17].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH2:1]([O:3][C:4]([NH:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2ccccc2c1
Yield: 84 %

Procedure:
A mixture of 16.7 g of ethoxycarbonyl chloride and 20 ml of methylene chloride is added dropwise to a mixture of 20.0 g of 2-naphthylamine, 17.6 g of sodium bicarbonate, 100 ml of water and 200 ml of methylene chloride under ice-cooling and stirring. The mixture is stirred overnight at room temperature. Chloroform is added to the mixture and the organic layer is separated, dried and treated with charcol. The residue is recrystallized from ethyl acetate-hexane to give 25.26 g of N-ethoxycarbonyl-2-naphthylamine.