Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]Cl)[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1>CN(C)C=O>[OH2:7].[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: Oc1cccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCl)C[C@H]1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCOc2cccnc2)C[C@H]1OC
Product: O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
To a stirred solution of 1.43 parts of 3-pyridinol in 135 parts of N,N-dimethylformamide were added 0.77 parts of a sodium hydride solution 50% at a temperature below 30° C. The whole was stirred first for 1.5 hours at room temperature and then for 10 minutes at 60° C. After cooling with ice water, a solution of 5.64 parts of cis-4-amino-5-chloro-N-[1-(2-chloro-ethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide in 135 parts of N,N-dimethylformamide was added dropwise at a temperature between 17°-20° C. Upon completion, stirring was continued first overnight at room temperature and then for 3 hours at 50° C. Another portion of 5.64 parts of cis-4-amino-5-chloro-N-[1-(2-chloroethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide was added and the mixture was stirred for 1 hour at 50° C. After the addition of crushed ice, the reaction mixture was concentrated. The aqueous phase was extracted with trichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was solidified on scratching in 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.38 parts (20%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(3-pyridinyloxy)ethyl]-4-piperidinyl]benzamide monohydrate; mp. 90.2° C. (compound 47).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:28]3[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
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: CN(C)C=O
Solvent: O
Product: N#CCc1cc(-c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)cs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetonitrile (220 mg), tetrakis(triphenylphosphine)palladium(0) (68.1 mg), aqueous sodium carbonate solution (2 M, 0.589 mL) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 120° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (83.6 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][SH:16].O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][S:16][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1)[CH3:20]
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cnc(N)s1
Temperature: 0 °C
Yield: 50 %

Procedure:
5-Bromo-2-aminothiazole (25 g, 96 mmol) and K2CO3 (26.5 g, 192 mmol) was suspended in DMF (50 mL) and stirred at 0° C. Ethyl thioglycolate (11.6 mL, 96 mmol) was added over 10 min. The reaction mixture was allowed to reach room temperature and stirred for a further 13 h. The mixture was divided between H2O (100 mL) and EtOAc (150 mL). Separation of the organic phase followed by extraction of the aqueous phase with EtOAc (2×100 mL).The combined organic phases were washed with aqueous NaHCO3 (2000 mL), brine (2×200 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromathography (SiO2, 2% TEA in EtOAc-heptane, from 30%→100%) to give 50-65% pure (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester as a dark red-brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:27]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 mL, 1.800 mmol) were dissolved at 0° C. in dichloromethane (DCM) (15 mL). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo) dissolved in DCM (5 mL) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([Cl:34])=[O:33]>C1COCC1>[ClH:34].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][N:14]([CH3:15])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH2:10][CH2:11]1
Reactant: CNCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N(C)CCN2CCC(Oc3ccc(F)c(F)c3)CC2)c1
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of the product of Step c (0.145 g) and triethylamine (0.224 ml) in THF (3 ml) at 0° C. was added a solution 3-methoxybenzoyl chloride (0.083 ml) in THF (2 ml). The mixture was stirred for 1 hour then partitioned between ethyl acetate and water. The organic layer was separated and dried with MgSO4 and the solvent removed by evaporation. Purification by reverse phase HPLC (with a gradient eluent system 25% MeCN/NH4OAc(aq) (0.1%) to 95% MeCN//NH4OAc(aq) (0.1%)) evaporation of solvent and the residue was dissolved in diethyl ether and HCl (1 ml 1M solution in diethyl ether) added. Filtration gave the title compound (0.137 g).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CN(C)C=O>[C:26]([S:28][CH:19]1[CH2:18][N:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:11][NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[N:13]=2)[CH2:20]1)(=[O:29])[CH3:27]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (1.16 g, 2.98 mmol) (obtained as described in Reference Example 65(3)) in dimethylformamide (35 ml) was added potassium thioacetate (2.04 g, 17.9 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (5:1) as the eluant to afford 3-acetylthio-1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.00 g, yield 91%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].O1CCOCC1.Br.Br[CH2:23][C:24]([C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=O>O>[F:35][C:32]([F:33])([F:34])[C:31]1[C:26]([C:24]2[N:1]=[C:2]3[N:3]=[CH:4][CH:5]=[C:6]([NH2:9])[C:7]3=[N:8][CH:23]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccnc(N)c1N
Reactant: O=C(CBr)c1ncccc1C(F)(F)F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccnc2nc(-c3ncccc3C(F)(F)F)cnc12

Procedure:
Dissolve 2,3,4-triaminopyridine (2.5 mmol) in water (20 mL). Add NaHCO3 (0.63 g, 7.5 mmol), dioxane (10 mL), and 2-bromo-1-(3-trifluoromethyl-pyridin-2-yl)-ethanone hydrobromide (0.5 g) and stir at 100° C. for 2 hours. Cool the mixture and extract with EtOAc (4×10 mL). Wash the combined organic extracts with brine and dry over Na2SO4. Purify the residue by preparative HPLC to give the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 54 %

Procedure:
Prepared analogously to Example 17 from (S)—N-[4-(tert-butoxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)butyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 54%; Rf value: 0.21 (silica gel; dichloromethane/methanol=9:1); C24H28ClN5O2 (453.97); mass spectrum: (M+H)+=454/456 (chlorine isotope) and (M−H)-=452/454 (chlorine isotope).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)#[N:2].O1CCCC1>[Ni].CO>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Yield: 103.9 %

Procedure:
Combine 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g), raney nickel (350 mg), tetrahydrofuran (50 mL), and methanol (100 mL) then hydrogenated at 60 PSIG at 40° C. overnight. Filter off catalyst then concentrate on a rotary evaporator to yield 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH:29]=O)=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10](=[O:11])/[C:12](=[CH:29]/[C:25]3[CH:26]=[CH:27][C:28]4[N:16]([CH2:14][CH3:15])[C:17]5[C:22]([C:23]=4[CH:24]=3)=[CH:21][CH:20]=[CH:19][CH:18]=5)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(/C=C3\Oc4cc(C)ccc4OCC3=O)ccc21

Procedure:
Calone is reacted with 9-ethylcarbazole-3-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-4-[1-(9-ethyl-9H-carbazol-3-yl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45]([O:52][C:53]1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCNC1COC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:53][O:52][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1COC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1COC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]oxetan-3-yl-amide (421) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (125 mg, 0.28 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (98 mg, 0.42 mmol) (8 g) to get a white sticky solid (180 mg, 97%, mixture).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:20]N(C)P(N(C)C)(N(C)C)=O.CI>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH3:20])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt and 250 parts of hexamethylphosphoramide are added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). The whole is stirred at room temperature for one hour. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 140 parts of diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The residue is crystallized from 35 parts of diisopropylether at 0° C, washed with cooled ether and dried, yielding methyl p-(2-thenoyl)hydratropate; mp. 62° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=O)=[CH:5][CH:4]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:36]2)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[S:36])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3)C2=O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3)C2=S)cc1

Procedure:
Prepared by heating 1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulphide in xylene.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[C:16]([O:15][CH:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)O

Procedure:
8.2 g of benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate were hydrogenated in 50 ml of alcohol after the addition of 800 mg. of palladium-on-charcoal (5 percent) until the theoretical amount of hydrogen had been taken up. The catalyst was then filtered off and the filtrate evaporated under reduced pressure at 45°. The resulting oil was dissolved in excess sodium bicarbonate solution and extracted twice with 20 ml portions of ether and the bicarbonate solution adjusted to pH 2.5 with 3-N hydrochloric acid. The acidic solution was extracted twice with 70 ml portions of ethyl acetate. After being washed twice with 20 ml portions of 5 percent sodium chloride solution, the ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. The resulting oil was crystallized from ether/-petroleum ether to yield (RS)-2-(isonicotinoyloxy)-isocaproic acid; mp 98°-100°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3](C(O)=O)[CH2:2]1.S(O)(O)(=O)=O.[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17].[OH-:24].[Na+]>O.Cl>[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:17][C:4]1[CH2:3][CH2:2][NH:1][C:6](=[O:24])[CH:5]=1
Reactant: [OH-]
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(NC1=CC(=O)NCC1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-piperidinecarboxylic acid, 2,4-dioxo-, methyl ester (10.0 g) in industrial methylated spirits and water (1:1) (50 ml) and 5M aqueous hydrochloric acid (0.4 ml) was heated at 50°-55° for 30 min, and then heated at reflux for 1.5 h. The resulting mixture was cooled to room temperature and treated with 1-methyl-1-phenylhydrazine sulphate (2:1) (9.9 g) and 5M aqueous sodium hydroxide (11.6 ml). Water (5.5 ml) was added, and more water (33 ml) was added slowly over 45 min. The resultant solid was filtered off, washed with water (3×8 ml) and dried in vacuo at 43° to give the title compound (10.7 g), m.p. 180°-181°.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([CH2:53][OH:54])[CH:49]=[C:50]([NH2:52])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:51]=[C:50]([NH:52][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:49]=[C:48]([CH2:53][OH:54])[CH:47]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 68.8 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-difluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH2:35])[N:27]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CN(C=O)C>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH:35][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])[N:27]([CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CONC(=O)C2CC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). The cloudy mixture was stirred for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration, washed with dichloromethane and acetonitrile, and dried in a vacuum oven to provide 442 mg of N-{[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}cyclopropanecarboxamide as a hydrate, white crystals, mp 209-210° C.