Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24](=[N:37][C:38]1[CH:45]=[C:44]([CH2:46]Br)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:46][C:44]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([N:37]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:45]=2)[C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC[C@H]1C(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a solution of 4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (1.15 g, 3.74 mmol) in 10 ml of DMF is added at 0° C. sodium hydride (164 mg at 60% in oil, 4.12 mmol). The solution is stirred 10 minutes then 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (2.6 g at 52%, 3.74 mmol) in 25 ml of DMF is added dropwise. The resulting mixture is stirred for 20 hours at room temperature, diluted with ethyle acetate, washed with water, with a saturated aqueous NaHCO3 solution, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography on silica gel eluting with 2% MeOH:CH2Cl2. The title compound (1.8 g, 80% yield) is obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13]>O.Cl.C(O)C.[Rh]>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: Cc1cnc2c(S(=O)(=O)O)cccc2c1
Agent: [Rh]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CNc2c(cccc2S(=O)(=O)O)C1
Temperature: 70 °C
Yield: 68.4 %

Procedure:
20 g (90 mmoles) of 3-methylquinoline-8-sulphonic acid is placed in a mixture of 200 ml of water and 25 ml of 12N hydrochloric acid. 6 g of 5% rhodium on charcoal catalyst is added and the reaction mixture is heated at 70° C. for 16 hours. The catalyst is filtered and washed with hot water and the filtrate is evaporated to provide a residue which is dissolved in 50 ml of ethanol. After evaporation of ethanol the residue is dried over phosphorus pentoxide at 50° C. 14 g of product is obtained.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([F:26])[CH:25]=1)[NH2:22].CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:7](=[O:8])[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[N:13][C:5]=2[O:4][CH2:3][CH:2]([F:17])[F:1])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(Cl)c1)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
Prepared analogously to example 6c with 2-(2,2-difluoro-ethoxy)-5-nitro-nicotinic acid chloride (prepared analogously to 6b) (179 mg; 0.67 mmol); 3-chloro-5-fluoroaniline (98 mg; 0.67 mmol) and TEA (112 μL; 0.81 mmol) in 5 mL DCM. Yield: 230 mg (91%); MS: [m+H]+=376 (Cl isotope pattern); HPLC: Rt=2.35 min (Method MC-6)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[C:10]1([CH2:16][C@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]2[O:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=3[N:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C([Li])CCC.CCCCCC>[O:24]=[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:20]=1[NH:19][C:18]([C@@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:23])[CH2:2][C:1](=[O:3])[NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 103 %

Procedure:
Using the procedure of Step B of Example 7, a solution of 9.09 g of 2-acetylaminothiazole in 280 ml of tetrahydrofuran, 91 ml of n-butyllithium in solution in hexane and 13.9 g of product of Step A in 100 ml of tetrahydrofuran were reacted to obtain 19 g of 1,1-dimethylethyl N-[(S) 1-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino-carbonyl]-2-(phenyl)-ethyl]-carbamate.
Reaction SMILES: ClCCl.[F:4][C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][C:6]=1[OH:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CS(O[CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]=[CH2:44])[CH2:39][CH2:38]1)(=O)=O>C1(C)C=CC=CC=1.O>[F:4][C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH2:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][C:6]=1[O:22][CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH2:43][CH3:44])[CH2:39][CH2:38]1
Reactant: C=C[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: CC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: C=C[C@H]1CC[C@H](COc2ccc(OC[C@H]3CC[C@H](CC)CC3)c(F)c2F)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In the dichloromethane (50 mL) solution containing 10 g of 2,3-difluoro-4-(trans-4-ethylcyclohexyl)methoxyphenol, 12 g of tripotassium phosphate and 8.1 g of (trans-4-vinylcyclohexyl)methyl methanesulfonate were dissolved, and the solution was stirred at 80 to 100° C. for 2 hours. Water and toluene were added to the solution, and the organic layer was fractioned, washed with water and saturated saline, and then dried over silicagel. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization and column chromatography, to thereby obtain 7.9 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxy-4-(trans-4-vinylcyclohexyl)methoxybenzene (1b) in the form of colorless crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:19].[Br:22][C:23]([Br:27])=[CH:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4]=1[O:19][CH2:25][CH:24]=[C:23]([Br:27])[Br:22]
Reactant: OCC=C(Br)Br
Reactant: CCOc1ccc(Oc2ccc(O)c(C(F)(F)F)c2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Oc2ccc(OCC=C(Br)Br)c(C(F)(F)F)c2)cc1
Yield: 32.8 %

Procedure:
To a solution prepared by dissolving 0.55 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)phenol, 0.40 g of 3,3-dibromoallyl alcohol and 0.49 g of triphenylphosphine in 10 ml of tetrahydrofuran, a solution prepared by dissolving 0.38 g of diisopropylazodicarboxylate in 5 ml of tetrahydrofuran was added dropwise at room temperature with stirring. After stirring at room temperature for 12 hours, the reaction solution was concentrated. Then, 20 ml of diethyl ether was added thereto, and the precipitate was filtered off. The resulting filtrate was concentrated, and subjected to silica gel column chromatography to give 0.30 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)-1-(3,3-dibromo-2-propenyloxy)benzene, yield 32%; nD24.0 1.5480.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH:12]=O)[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[C:8]([CH2:10][CH2:11][CH:12]=[CH:20][CH2:21][CH3:22])[CH:9]=1
Reactant: COC(=O)c1cc(CCC=O)c(OC)c(OC)c1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC=CCCc1cc(C(=O)OC)cc(OC)c1OC

Procedure:
3-Hex-3-enyl-4,5-dimethoxybenzoic acid methyl ester was prepared from 3,4-dimethoxy-5-(3-oxopropyl)benzoic acid methyl ester and propyltriphenylphosphonium bromide by following Method J. The crude product was purified by flash column chromatography on silica gel using 20% EtOAc in hexanes as an eluent to furnish 3-hex-3-enyl-4,5-dimethoxybenzoic acid methyl ester in 63% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:49][N:50]([CH3:54])[C:51](Cl)=[O:52]>CN(C=O)C>[CH3:49][N:50]([CH3:54])[C:51]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:52]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)N(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL) is added dimethylcarbamyl chloride (11 mg, 0.1 mmol). The mixture is stirred at room temperature for 1 hour. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid dimethylamide (155) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.29 (s, 1H), 8.26 (br, 1H), 7.96 (dd, 1H), 7.93 (s, 1H), 7.72 (dd, 1H), 7.48 (dd, 1H), 7.35 (s, 1H), 4.50 (s, 2H), 4.35-4.29 (m, 1H), 3.83 (d, 2H), 3.38-3.30 (m, 2H), 3.02-2.95 (m, 3H), 2.88 (s, 6H), 1.88-1.84 (m, 3H), 1.36 (d, 6H), 1.25 (d, 6H); ESMS m/z 670.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])[C:9](=[O:17])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:5]2=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.O1CCCC1.C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[CH:31]=4)[C:11]3=[O:16])[C:9](=[O:17])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:5]2=[CH:6][CH:7]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)CN1C(=O)C2(CC(=O)NC2=O)c2cc(Cl)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21
Yield: 52 %

Procedure:
Following the general procedure (Route A) as outlined above for the synthesis of intermediate 16, methyl (5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 47, (2.94 g, 9.11 mmol) was reacted with potassium tert-butoxide (1.07 g, 9.57 mmol) and 3-chlorobenzyl bromide (1.25 ml, 9.57 mmol) in anhydrous N,N-dimethylformamide (90 ml) at ambient temperature for two hours to give the title compound (2.10 g, 52%) as slightly pink powder after trituration from tetrahydrofuran/diethyl ether. The compound was isolated in several fractions (HPLC purity: 96-99%). MS (ESI+): 447.3; MS (ESI−): 445.3
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[N:5]3[N:20]=[CH:21][N:22]=[C:4]3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3ncnn23)nc1
Temperature: 150 °C

Procedure:
50 mg (0.16 mmol) of 6-({2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}amino)-nicotinonitrile (Example 54A), 29.5 mg (0.16 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and 18 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 3.3 ml of dioxane and 1.1 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 6.5 mg (10% of theory) of the product as a solid.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1N[C:18]([C:21]2[CH:26]=CC(C#C)=[CH:23][CH:22]=2)=[CH:19]N=1)=O)C(C)C.[CH3:30][O:31][C:32](=[O:57])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=2)=[CH:48][N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36]>>[CH3:30][O:31][C:32](=[O:57])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53]3[C:52](=[CH:19][CH:18]=[C:21]([C:22]#[CH:23])[CH:26]=3)[CH:51]=2)=[CH:48][N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Product: C#Cc1ccc2cc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)ccc2c1

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example AY), substituting (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(C(=O)N3CCC(=NCc4ccccc4)CC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(=O)N3CCC(NCc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thus obtained 6-(4-benzylimino-1-piperidyl)carbonyl-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol, then 1 g of sodium borohydride was added thereto gradually, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-diluted hydrochloric acid mixture, then the whole mixture was made alkaline by adding sodium carbonate, then extracted with chloroform, the extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a thin-layer chromatography (developing agent: chloroform:methanol=10:1) to yield 0.2 g of 6-(4-benzylamino-1-piperidyl)carbonyl-3,4-dihydrocarbostyril.1/2-hydrate.
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][C:9]2[S:13][C:12]3=[CH:14][N:15]=[CH:16][N:11]3[C:10]=2[CH3:17])C(=O)C2=CC=CC=C12>CO>[NH2:7][CH2:8][C:9]1[S:13][C:12]2=[CH:14][N:15]=[CH:16][N:11]2[C:10]=1[CH3:17]
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)sc2cncn12
Agent: NN
Solvent: CO
Product: Cc1c(CN)sc2cncn12
Yield: 86.6 %

Procedure:
A 0.052 ml portion of anhydrous hydrazine was added to 15 ml of a dry methanol solution containing 380 mg of 2-phthalimidomethyl-3-methylimidazo[5,1-b]thiazole, followed by heating under reflux for 6 hours. The reaction solution was cooled on ice, and the resulting crystal was filtered and then washed with a small amount of cold methanol. The filtrate was concentrated under reduced pressure, and to the resulting residue, 15 ml of dichloromethane was added. Afterward, the solution was extracted with 15 ml of 2N hydrochloric acid, and the hydrochloric acid extract was alkalified with potassium hydroxide. The organic layer extracted from the aqueous layer with dichloromethane (40 ml×3) was dried over anhydrous potassium carbonate, followed by filtration. The solvent was then evaporated under reduced pressure to obtain 185 mg of 2-aminomethyl-3-methylimidazo[5,1-b]thiazole as a milky white powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[O:12]1[CH:14]([CH2:15][CH3:16])[CH2:13]1.[OH-].[K+]>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH:14]([OH:12])[CH2:15][CH3:16]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
A mixture of 3-trifluoromethylphenol (75 ml, 0.617 moles), 1,2-epoxybutane (58 ml, 0.617 moles), potassium hydroxide pellets (86%, 0.062 moles), and water (100 ml) were heated with stirring at 65° C. for four hours. At this point more 1,2-epoxybutane (58 ml, 0.617 moles) was added and stirring at 65° C. continued overnight. The reaction was allowed to cool to room temperature and the lower phase taken off and the upper phase extracted with methylene chloride (2×100 ml). The organic phases were combined and washed with 5% sodium hydroxide solution (150 ml) and water (3×150 ml). This reaction solution was dried over anhydrous magnesium sulfate and stripped under vacuo to yield 138 g of the desired alcohol, as determined by infra-red spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy.
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([NH:36][C:37]([NH:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: CC[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride mono-ethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 1.37 mL (12.6 mMol) phenyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.40 gm (70%) N-phenyl-N'-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)urea. This material was dissolved in methanol and to it was added an equivalent of methanolic hydrogen chloride. The solution was then concentrated under reduced pressure and the residual oil crystallized from ethanol to give the title compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[OH:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(OCC)C>ClCCl>[O:17]=[CH:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of pyridinium chlorochromate (125.0 g) and sodium acetate (48.0 g) in dichloromethane (300 mL) was added a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (89.0 g) in dichloromethane (150 mL) at 0° C. The reaction system was stirred at 25° C. for 3 hr, diethyl ether (300 mL) was added, and insoluble material was collected by filtration by silica gel column chromatography, and washed with diethyl ether (1000 mL) and dichloromethane/diethyl ether (1000 mL). The filtrate was concentrated to give the title compound (60.0 g).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10]([OH:12])=O)=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.[C:35]1([C:41]2[N:42]=[C:43]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][NH:47]3)[NH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)CCCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH2:8][CH:9]([C:10](=[O:12])[N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[C:43]1[NH:44][CH:45]=[C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:42]=1)[CH2:13][C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:21]([NH2:22])=[O:23])=[CH:18][C:19]=1[CH3:20]
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 107.7 %

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by 1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solution was cooled to 0° C. To this reaction mixture was added 2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by (4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). The reaction was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then combined with 2N citric acid and washed multiple times with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 600 mg of desired product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester as a glass which was used as is without further purification. (TLC: 5:1 CHCl3:MeOH Rf=0.6)