Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.Cl[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>>[CH:21]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1)([CH3:23])[CH3:22]
Reactant: OC1CCCC2Oc3ccccc3OC12
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: CC(C)N(CCOC1CCCC2Oc3ccccc3OC12)C(C)C
Yield: 82.2 %

Procedure:
Working as described in Example 3, but starting with 12.4 g (0.06 mole) of the alcohol of Example 1 and 10 g (0.05 mole) of 1-chloro-2-diisopropylaminoethane hydrochloride, there were obtained 13.7 g of the title-compound of melting point 63.4° C., having the elementary analysis:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:2].CCO>[Fe].CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[NH:17][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=2)=[O:21])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(C(C)(C)C)cc2[nH]1

Procedure:
A mixture of 3-(4-tert-butyl-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (prepared in Example XX; 9.1 g, 31 mmol), iron powder (15.3 g, 274 mmol), EtOH (70 mL), and glacial AcOH (70 mL) was refluxed for 2 hours. After cooling, the resulting mixture was evaporated. THF (100 mL) was added to the residue, and the suspension was filtered on florisil, eluting with a large amount of THF. The solvents were evaporated, and the residue was purified by flash silica gel chromatography (5%-30% EtOAc in hexanes as eluents). MS(APCI): 246 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1sc2c(c1C)CNC(Cl)=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN1Cc2c(sc(C)c2C)N=C1Cl
Reaction time: 4 h

Procedure:
A mixture of 6.0 g of 2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, 5.52 g of ethyl bromoacetate and 12.5 g of powdered potassium carbonate in 300 ml of methyl ethyl ketone was heat-refluxed with stirring under a nitrogen atmosphere for 4 hours. After cooling, an insoluble inorganic salt was filtered off and the filtrate was concentrated in vacuo to give a crude oil of 2-chloro-3-ethoxycarbonylmethyl-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine. Because of the instability of the resulting compound, the crude oil was used in the subsequent reaction.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH:21][C:28]([NH2:29])=[NH:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N=C(N)n1cccn1
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C
Yield: 33.1 %

Procedure:
C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (1.0 g, 3.5 mmol), 1H-pyrazol-1-carboxamidine hydrochloride (0.5 g, 3.5 mmol) and 1.2 mL of diethyl isopropylamine (7.0 mmol) were dissolved in 10 mL of DMF. The reaction mixture was heated to 100° C. for three hours and then cooled and diluted by addition of 75 mL of water. The aqueous mixture was extracted twice with 100 mL of EtOAc, and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure, and the resulting oil was purified by medium pressure chromatography (silica gel, MeOH/CHCl3/NH4OH 10:89:1) to yield 0.4 g (1.16 mmol, 33%) of N-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-guanidine, MS: 344 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (5.0 g, 10 mmol) and (4-formylphenyl) boronic acid (2.35 g, 15.8 mmol) in dioxane/water (30 mL/10 mL) was added Na2CO3 (4.01 g, 37.9 mmol). The solution was purged with argon for 15 min., Pd(PPh3)4 (1.21 g, 1.05 mmol) and the mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with 10% MeOH/CH2Cl2. The combined organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The resulting crude material was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (3.5 g, 66%).
Reaction SMILES: N[C:2]1C=C(C2C=CC=CC=2)C=C[C:3]=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O.[NH2:33][C:34]1[CH:58]=[C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:56]=[CH:55][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[C:41]([O:53][CH3:54])[CH:40]=1)=[O:37]>>[CH3:54][O:53][C:41]1[CH:40]=[C:39]([N:38]2[C:36](=[O:37])[C:35]3[C:34](=[CH:58][C:57]([O:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)=[CH:56][CH:55]=3)[N:33]=[C:2]2[CH3:3])[CH:44]=[CH:43][C:42]=1[O:45][CH2:46][CH2:47][N:48]1[CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2c(C)nc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
Using 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide [Example C5] in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C4, gave the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([N+:19]([O-])=O)[CH:12]=3)=[O:5])[CH3:2].[ClH:22].[H][H]>C(O)C.[Pt](=O)=O>[ClH:22].[ClH:22].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([NH2:19])[CH:12]=3)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cc([N+](=O)[O-])ccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cc(N)ccc12

Procedure:
0.1 g of 7-nitro-β-carbolin-3-carboxylic acid ethyl ester is suspended in 30 ml of ethanol and, after the addition of 1 ml of 5N hydrochloric acid, is hydrogenated at normal pressure over 25 mg of platinum dioxide until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and washed well with warm ethanol. The filtrate is treated with active carbon and concentrated until turbidity commences. After cooling, 95 mg of 7-amino-β-carbolin-3-carboxylic acid ethyl ester dihydrochloride of melting point 270° C. (decomposition) is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[NH:10]1>C1(C)C=CC=CC=1>[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:10]1[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Clc1ncccn1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1c1ncccn1

Procedure:
A solution of 820 mg 2-chloropyrimidine and 1.6 g cis-2,6-dimethylpiperazine in 25 mL toluene was heated at reflux temperature for 12 hours. The solvent was evaporated, the residue was basified with 5% sodium hydroxide and extracted with 2×100mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give cis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used to prepare 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]-imidazole (Compound 140), m.p. 130°-135° C., according to the procedures described in Example VIII.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[NH:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:11])[NH:34][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:33][C:14]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: N=C(N)CCCCc1ccccc1
Reactant: CCOC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccc(C)cc1
Product: O=c1[nH]c(CCCCc2ccccc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)-propionate (293 mg, 1.02 mmol), 4-phenylbutanecarboxamidine (315 mg, 1.79 mmol) and pyridinium p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous removal of water. After 16 h, the solvent was evaporated and the product purified by column chromatography on silica gel (3% methanol/dichloromethane) followed by recrystallization from acetone. MS (m/z): 400.3 (M+H)+; C25H22FN3O requir. 399.5.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH:15][C:16](=[O:23])[C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19]O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:15]4[CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[C:16]4=[O:23])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)C1=O
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide (Intermediate 58-1, 89 mg, 0.213 mmol), diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) in THF (1 mL) was stirred at rt for 1 h. More diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) were added, and these additions repeated again after 1 h more. The mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide), then by preparative HPLC. The appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide 4-bromo-7-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide as a yellow solid (44 mg, 52%). 1H NMR (400 MHz, methanol-d4) δ 8.66 (1H, d, J=8.58 Hz), 7.94 (1H, d, J=1.54 Hz), 7.73 (1H, d, J=8.36 Hz), 7.55 (1H, dd, J=8.80, 1.98 Hz), 7.39 (1H, d, J=8.14 Hz), 3.97 (2H, t, J=6.93 Hz), 2.11 (2H, t, J=6.93 Hz), 1.28 (6H, s). Mass spectrum m/z 400, 402 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCOc2cc(O)ccc2C1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C1CCOc2cc(OCc3cccc(Oc4ccccc4)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of ethyl 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (0.189 g, 0.800 mmol), 3-phenoxybenzyl alcohol (0.240 g, 1.20 mmol) and tributylphosphine (0.299 mL, 1.20 mmol) in toluene (8 mL) was stirred under ice-cooling. 1,1′-(Azodicarbonyl)dipiperidine (0.279 g, 1.20 mmol) was added by small portions, and the mixture was stirred under nitrogen atmosphere at room temperature for 8 hr. Hexane (4 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-20% ethyl acetate/hexane) to give the title compound (0.20 g, yield 60%) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[CH3:19]O>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:19])=[O:12])=[CH:5][CH:4]=1)=[O:2]
Reactant: CO
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 5 °C
Yield: 86 %

Procedure:
A suspension of (E)-3-(4-formylphenyl)acrylic acid (2 g, 10.5 mmol) in methanol (30 mL) was cooled to 5° C. and then concentrated H2SO4 (3 mL) was added under stirring and heated at 60° C. for 2 hours. The solvent was removed by evaporation and the obtained compound was stirred with water (100 mL) for 15 minutes. The precipitated white solid was filtered, washed with water (300 mL) and dried to get the pure product (1.9 g, 86% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10][NH:38][CH3:39])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: O=C1N([C@H](CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
1′-[(1R)-1-(3-fluorophenyl)-3-hydroxypropyl]spiro [cyclohexane-1,3′-indol]-2′(1′H)-one (0.26 g, 0.74 mmol) was dissolved in pyridine (4 mL) and toluenesufonyl chloride (0.21 g, 1.1 mmol) was added. Stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 30 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1′-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one as a colorless oil (0.26 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.71 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 203 mg (51% over three steps) 1′-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CC(C)CCN
Product: CC(C)CCNc1nc2ccccc2cc1[N+](=O)[O-]

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99°-100° C. Analysis: Calculated: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 64.8; % H, 6.6; % N, 16.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (2.75 g, 8 mmol) in CH2Cl2 (5 ml) was added TFA (5 mL), and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and made basic with sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, evaporated to give 1.95 g (q.y.) 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ1.38 (3 H, t, J=6.8 Hz), 1.82-2.16 (4 H, m), 3.01-3.48 (2 H, m), 4.00-4.11 (1 H, m), 4.37 (2H, q, J=6.8 Hz), 4.54-4.77 (1 H, m), 7.44-7.46 (2 H, m), 7.95-7.97 (2 H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:4]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCN1CCOCC1)c1cc(Cl)ccn1
Reaction time: 20 h
Yield: 95.4 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf 0.50.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16](Cl)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:32])[CH2:28][N:29]([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:31][N:29]([CH3:30])[CH2:28][CH:27]([NH:32][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: O=C(Cl)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COc1ccccc1C(N)CN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(CN(C)C)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Yield: 14.4 %

Procedure:
To a 40-mL vial with magnetic stir bar at 25° C. under a nitrogen atmosphere was added 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl chloride (0.26 g, 0.94 mmol) and anhydrous DCM (8 mL). 1-(2-Methoxy-phenyl)-N*2*,N*2*-dimethyl-ethane-1,2-diamine (0.2 g, 1.0 mmol) was then added followed by the diisopropylethylamine (0.6 g, 0.8 mL, 4.7 mmol) and stirring continued×16 hours. The solvent was evaporated under a nitrogen stream and the resulting residue purified via preparative HPLC (0.1% triethylamine/1% acetonitrile mixture in water and methanol) afforded the desired product as a white solid (59.1 mg, 14% yield). LCMS m/e 436 (M+H). 1H NMR (400 MHz, DMSO-d6) ppm 2.12 (s, 6H) 2.25 (dd, J=12.38, 4.27 Hz, 1H) 2.60 (dd, J=12.34, 9.78 Hz, 1H) 3.77 (s, 3H) 5.44-5.52 (m, 1H) 6.41 (dd, J=3.36, 1.18 Hz, 1H) 6.66 (d, J=5.44 Hz, 1H) 6.84 (td, J=7.42, 0.71 Hz, 1H) 6.92-6.97 (m, 1H) 7.16-7.22 (m, 1H) 7.24 (dd, J=7.57, 1.56 Hz, 1H) 7.26-7.28 (m, 1H) 7.39 (d, J=5.39 Hz, 1H) 7.81 (d, J=5.38 Hz, 1H) 7.98 (d, J=5.41 Hz, 1H) 8.23 (d, J=7.92 Hz, 1H) 9.89 (s, 1H) 11.49 (br s, 1H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2C=C[C:17]([NH2:20])=[C:16]([N+:21]([O-])=O)[CH2:15]2)=[CH:10][CH:9]=1)#[N:7].[CH2:24](O)[CH3:25]>Cl.O>[NH2:21][C:16]1[CH:17]=[N:20][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: CCO
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)-aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][NH:32][CH3:33].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:33][N:32]([O:31][CH3:30])[C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: O=C(O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-tritylpiperidine-4-carboxylic acid (7.0 g), O,N-dimethylhydroxylamine hydrochloride (2.0 g) and triethylamine (2.9 ml) in dichloromethane (70 ml) was added WSC (3.97 g), and the mixture was stirred at room temperature for 1 hour and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, dried (MgSO4) and concentrated. The resulting crystals (6.3 g) were washed with isopropylether.