Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:8][C:7]1=[O:18])C.[OH-].[K+]>CO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]2[CH2:10][N:6]([CH2:5][C:4]([OH:19])=[O:3])[C:7](=[O:18])[CH2:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CN1CC(c2ccc(Cl)cc2)CC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CC(c2ccc(Cl)cc2)CC1=O

Procedure:
95.6 g (340 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid ethyl ester are dissolved in 440 ml of methanol; 22.5 g (40 mmol) of potassium hydroxide (80% strength) are added and the whole is heated under reflux for 16 hours. Concentration by evaporation is carried out under reduced pressure at 70°, 200 ml of hydrochloric acid are added and the whole is extracted by shaking with 800 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, concentrated to 500 ml, and 200 ml of hexane are added. The crystalline precipitate is filtered off with suction and dried. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid having a melting point of 142°-43° is obtained. Additional product can be obtained by concentrating the mother liquor by evaporation, taking up the residue in 200 ml of ethyl acetate and crystallising it by the addition of 100 ml of hexane.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]1[NH:34][CH2:33][CH2:32][N:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH:30]12>>[CH2:29]1[N:34]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:33][CH2:32][N:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH:30]12
Reactant: C1CCN2CCNCC2C1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN4CCCCC4C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with octahydro-1H-pyrido[1,2-a]pyrazine via General Procedure E to give 24 mg of 284 following reverse phase purification. MS (Q1) 502.3 (M)+
Reaction SMILES: C[C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C=O>>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:8][NH:9][CH2:10][CH2:11][OH:12]
Reactant: Cc1cccc(CNCCO)n1
Agent: O=Cc1ccccn1
Product: OCCNCc1ccccn1

Procedure:
prepared as 2-[(6-methyl-pyridin-2-ylmethyl)-amino]-ethanol but reaction with pyridine-2-carboxaldehyde
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+].[S:24](Cl)([CH3:27])(=[O:26])=[O:25].C(N(CC)CC)C.Cl>O1CCCC1.CO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1-benzyl-5-nitro-1H-indole (50 mg, 0.19 mmol) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and ammonium formate of an excess amount and palladium/carbon (10%) of a catalytic amount were added. The solution was stirred at around 30° C. for 30 minutes to complete the reduction, filtrated through celite, concentrated under reduced pressure, dissolved again in dichloromethane (10 ml), and then washed with water and brine. After drying the resulting solution over anhydrous magnesium sulfate, dichloromethane solution containing amine compound (1-benzyl-5-amino-1H-indole) was obtained. Mesyl chloride (0.015 ml, 0.19 mmol) and triethylamine (0.028 ml, 0.20 mmol) were added to the above obtained solution and stirred at room temperature for 2 hours to complete the reaction. After adding 2N-hydrochloric acid solution (10 ml) to separate layers, dichloromethane solution was induced, washed by using water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then triturated with isooctane and isopropyleter. As a result, the present compound (34mg, productive yield 34%) was obtained as a solid.
Reaction SMILES: C(OCC)(=O)C.C(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:40])[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)[CH2:16][CH2:15]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>O>[Cl:36][C:32]1[CH:31]=[C:30]([C:29]2[C:28]3[C:23](=[N:24][C:25]([CH3:37])=[CH:26][CH:27]=3)[N:22]([CH2:38][CH3:39])[C:21](=[O:40])[C:20]=2[N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)[CH:35]=[CH:34][CH:33]=1
Reactant: CCn1c(=O)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(N2CCNCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a 10 ml ethyl acetate solution containing 570 mg of 3-(1-tert-butoxycarbonylpiperazin-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one was added a 10 ml 4M hydrogen chloride-ethyl acetate solution, followed by stirring at room temperature for 1 hour. After adding water, the reaction mixture was neutralized with 1M sodium hydroxide aqueous solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) and then recrystallized from diisopropyl ether to obtain 115 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperazin-1-yl)-1,8-naphthyridin-2(1H)-one as pale yellow crystals.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[F:12][C:13](F)([F:21])S(OC(F)F)(=O)=O>C(#N)C.O>[F:12][CH:13]([O:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[F:21]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(OC(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: FC(F)Oc1ccc(Cl)cc1Br
Reaction time: 0.08 h

Procedure:
36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory)
Reaction SMILES: [CH:1](Cl)(Cl)[C:2]([F:8])([F:7])[C:3]([F:6])([F:5])[F:4].FC(F)(C(F)(F)F)CO.[Cl-].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:7][C:2]([F:8])([C:3]([F:6])([F:5])[F:4])[CH2:1][O:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: FC(F)(F)C(F)(F)C(Cl)Cl
Agent: OCC(F)(F)C(F)(F)F
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1

Procedure:
Until HCFC-225ca becomes available in commercial quantities, HCFC-225ca may be prepared by a standard and well-known organic synthesis technique. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Br:11]C1C=CC(Cl)=CC=1O.C1C(=O)N(Br)C(=O)C1.BrC1OC2C=CC(Cl)=CC=2C1>C(#N)C>[Br:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[O:8][CH2:7][CH2:6][C:5]=2[CH:9]=1
Reactant: Oc1cc(Cl)ccc1Br
Reactant: Clc1ccc2c(c1)OCC2
Agent: Clc1ccc2c(c1)CC(Br)O2
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Clc1cc2c(cc1Br)CCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a similar way as described above, 6-chloro-2,3-dihydrobenzofuran (142) was prepared starting from 2-bromo-5-chlorophenol. NBS (155 mg, 0.87 mmol) was added to a solution of 2-bromo-5-chloro-2,3-dihydrobenzo[b]furan (142) (135 mg, 0.87 mmol) in 5 ml ACN. The reaction mixture was stirred 5 h at r.t. The yellow solution was poured into ice-water, extracted with EA. Org. phase was washed with aq. sodium bicarbonate and brine subsequently. After dried over sodium sulfate the org. phase was concentrated to give 204 mg (purity>90%, quantitative yield) title compound as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH3:22])[C:20]([C:19](=[O:24])[C:18]([F:26])([F:25])[F:17])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 50 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that heptane/ethyl acetate (10:1) was used. Yield: 50%; MS: m/z=392/394 (M).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[C:21]2[CH:22]=[CH:23]C=CC=2N=C1>>[O:17]1[CH2:21][CH:22]1[CH2:23][O:16][C:13]1[CH:14]=[CH:15][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1ccc2sc(-c3ccccc3)nc2c1
Product: c1ccc(-c2nc3cc(OCC4CO4)ccc3s2)cc1

Procedure:
Compound 59 was prepared in the manner of compound 6 substituting compound 29 for compound 8 in partC-5 of Example 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[NH2:35])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[CH2:32][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: CN1CCN(Cc2ccccc2N)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 2-(4-methylpiperazin-1-ylmethyl)aniline (32.0 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[2-(4-methylpiperazin-1-ylmethyl)anilino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (63 mg, 79%). NMR; δH [2H6]-DMSO includes 11.56,(1H, s), 9.94,(1H, s), 8.36-8.34,(2H, m), 8.02,(2H, d), 7-78,(1H, t), 7.68,(1H, dd), 7.64,(1H, d), 7.54,(2H, d), 7.35-7.25,(3H, m), 7.06,(1H, m), 6.98,(1H, m), 3.73,(2H, s), 2.22,(3H, s), 2.11, (3H, s). LCMS: retention time 2.60 min, MH+509.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC/N=C/c1c(F)cccc1CC

Procedure:
Prepared as described in Example 58(a) as by-product of reaction between butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine and ethylmagnesium bromide in tetrahydrofuran and ether. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: N1C=CC=C(CC2C(O)C3CCN2CC3)C=1.C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:43]([CH:50]1[CH:55]2[CH2:56][CH2:57][N:52]([CH2:53][CH2:54]2)[CH:51]1[CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1)[C:44]1C=CC=CC=1.N1C=CC=C(C=C2C(O)C3CCN2CC3)C=1.[H-].[Na+].CI>CCOCC>[CH3:44][O:43][CH:50]1[CH:55]2[CH2:56][CH2:57][N:52]([CH2:53][CH2:54]2)[C:51]1=[CH:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1
Reactant: c1ccc(OC2C3CCN(CC3)C2Cc2cccnc2)cc1
Agent: OC1C(=Cc2cccnc2)N2CCC1CC2
Agent: OC1C2CCN(CC2)C1Cc1cccnc1
Agent: [H-]
Solvent: Oc1ccccc1
Solvent: CCOCC
Solvent: CI
Product: COC1C(=Cc2cccnc2)N2CCC1CC2

Procedure:
The saturated alcohol intermediates, such as 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol, can also serve as templates for compound libraries. For instance, ethers can be generated from these alcohols, for example, using either Mitsunobu or Williamson conditions. Thus, by way of example, when 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol is reacted with phenol via Mitsunobu coupling with diethylazidocarboxylate and triphenylphosphine (Guthrie et al., J. Chem. Soc., Perkin Trans 145: 2328 (1981)), 3-phenoxy-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane results. Similarly, when 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol is treated with sodium hydride and methyl iodide, the unsaturated ether, 3-methoxy-2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octane, is formed. This gives the saturated ether, 3-methoxy-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (predominantly cis), upon catalytic hydrogenation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[CH3:22][C:23]([O:41][Si:42]([CH2:47][CH3:48])([CH2:45][CH3:46])[CH2:43][CH3:44])([CH3:40])[CH2:24][CH2:25][C:26]1[S:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:28]4[S:27][C:26]([CH2:25][CH2:24][C:23]([CH3:40])([O:41][Si:42]([CH2:47][CH3:48])([CH2:43][CH3:44])[CH2:45][CH3:46])[CH3:22])=[CH:30][CH:29]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC[Si](CC)(CC)OC(C)(C)CCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC[Si](CC)(CC)OC(C)(C)CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)s1
Temperature: 150 °C

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (90 mg, 0.24 mmol), ({1,1-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]propyl}oxy)(triethyl)silane (149 mg, 0.36 mmol, 1.5 eq), potassium carbonate (200 mg, 1.4 mmol, 6 eq), and palladium tetrakistriphenylphosphine (28 mg, 0.024 mmol, 0.1 eq) were diluted in dioxane (1.5 mL) and water (0.5 mL) in a 2-5 mL microwave vial. The mixture was degassed by bubbling argon through for 5 minutes, then heated in a microwave oven at 150° C. under high absorption for 40 minutes. The mixture was filtered through a thiol SPE cartridge, then concentrated to give the crude product as a brown oil. This material was purified by Isco Combiflash, 40 gram column, eluting with 0-15% methanol in dichloromethane. The desired product was obtained as a brownish tarry substance and was re-purified by ammonium hydroxide Gilson eluting with 20-95% acetonitrile in water. The product fractions were concentrated in a Genevac EZ2 evaporator to give the title compound as a light yellow solid (55 mg, 40%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]2[N:16]([CH:17]=1)[N:15]=[CH:14][N:13]=[C:12]2[OH:18])(=[O:4])=[O:3].O=P(Cl)(Cl)Cl.[F:25][C:26]1[C:34](O)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2.[H-].[Na+]>ClCCl.CN(C=O)C>[F:25][C:26]1[C:34]([O:18][C:12]2[C:11]3=[C:10]([CH3:19])[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2
Reactant: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(O)c12
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCS(C)(=O)=O)c(C)c34)ccc2[nH]1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 6-(3-methanesulfonyl-propoxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol (620 mg, 2.17 mmol) and POCl3 (10 mL) was heated at 85° C. for 3 h. POCl3 was removed in vacuo to give a yellow solid, which was dissolved in dichloromethane, and washed successively with cold NaHCO3 solution and brine. The organics were dried, filtered and concentrated to afford the crude chloroimidate intermediate (610 mg), which was added to a pre-mixed solution of 4-fluoro-2-methyl-1H-indol-5-ol (664 mg, 4.02 mmol) and NaH (60% in mineral oil, 160 mg, 4.02 mmol) in DMF at 0° C. The resulting mixture was stirred at RT for 30 min, and diluted with dichloromethane, washed with 10% LiCl aqueous solution, dried concentrated. The residue was purified by flash column chromatography (silica gel, eluting from 10% ethyl acetate/dichloromethane to 30% ethyl acetate/dichloromethane). The desired fractions were combined and concentrated in vacuo to give a solid, which was washed with MeOH to afford the title compound as a white solid (610 mg, 65% yield). HRMS (M+H)+ Calcd. For C20H21FN4O4S: 432.12675. Found: 433.1329. 1H NMR (d-DMSO) δ 11.36 (br, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 6.99 (m, 1H), 6.24 (s, 1H), 4.16 (t, 2H, J=6.16 Hz), 3.31 (t, 2H, J=5.7 Hz), 3.05 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 2.50 (m, 2H). Anal. Calcd. For C20H21FN4O4S: 0.4 H2O: C, 54.58; H, 4.84; N, 12.56; S, 7.29. Found: C, 54.61; N, 12.65; S, 7.33.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([OH:16])=O)=[CH:4][C:3]=1[Cl:17].[CH2:18]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]=[C:6]2[C:5]([C:14]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:4][C:3]=1[Cl:17]
Reactant: CCCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: CCCCN1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(CCC)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-propylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 16, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:14][CH:15]([CH2:17]O)O>>[CH:10]1([CH2:9][C:7]2[CH:6]=[C:5]3[C:3](=[C:2]([Br:1])[CH:8]=2)[N:4]=[CH:17][CH:15]=[CH:14]3)[CH2:11][CH2:12]1
Reactant: OCC(O)CO
Reactant: Nc1ccc(CC2CC2)cc1Br
Product: Brc1cc(CC2CC2)cc2cccnc12

Procedure:
2-bromo-4-(cyclopropylmethyl)aniline and glycerol can be combined to form 6-(cyclopropylmethyl)-8-bromoquinoline,
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
Into a reaction vessel were charged 31.2 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 0.83 part by weight of 4.5% palladium-0.5% platinum-carbon (ASCA-2, manufactured by N. E. Chemcat Corporation), thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 180° C. and an internal pressure of 0.3 MPa for 12.5 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 45 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 77.5 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The combined 1,1,3-trimethyl-4-aminoindane had an optical purity of 0.29% ee and a recovery rate of 97.7%.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23](NC)[N:24]=[CH:25]2)=CC=1>>[CH3:25][NH:24][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Reactant: CNc1cc2ccc(Br)cc2cn1
Product: CNc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromo-N-methylisoquinolin-3-amine. +ESI (M+H) 203.1; 1H NMR (400 MHz, CD3OD, δ): 8.87 (s, 1H), 8.51 (s, 1H), 7.98 (dd, J=8.88, 1.66 Hz, 1H), 7.58 (d, J=8.78 Hz, 1H), 6.60 (s, 1H), 2.93 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:23])[C:18]([NH:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N

Procedure:
A solution of 5 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-methyl-2-nitrobenzenamine in 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 4.64 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine as a residue.