Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-amine (7-3, 0.500 g, 1.68 mmol) in THF (8.4 mL) was added triethylamine (0.510 g, 5.03 mmol) followed by isonicotinoyl chloride hydrochloride (0.750 g, 4.21 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in toluene to give N-{4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (0.17 g) as yellow solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J=6.0 Hz, 2 H), 8.42 (d, J=1.0 Hz, 1 H), 8.28 (d, J=1.0 Hz, 1 H), 8.13 (m, 1 H), 7.67 (d, J=6.0 Hz, 2 H), 6.84 (s, 1 H), 6.68 (s, 2 H), 1.98 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][C:11]([O:13]C)=[CH:12][C:6]=2[CH:5]=1)(=[O:3])N.Br.C(O)(=[O:18])C>>[OH:13][C:11]1[CH:10]=[CH:9][C:7]2[S:8][C:4]([C:1]([OH:3])=[O:18])=[CH:5][C:6]=2[CH:12]=1
Reactant: CC(=O)O
Reactant: COc1ccc2sc(C(N)=O)cc2c1
Agent: Br
Product: O=C(O)c1cc2cc(O)ccc2s1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 2-Carbamoyl-5-methoxybenzo[b]thiophene (2.0 g), acetic acid (5 ml) and 48% hydrobromic acid (20 ml) was stirred for 16 hours at 110° C., and the mixture was poured into the ice-water. The resulting precipitate was collected by filtration, and dried to give 5-Hydroxybenzo[b]thiophene-2-carboxylic acid (1.66 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18]O)[CH2:15][O:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=2)[CH2:15][O:14]1
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC[C@@H]2COC(C)(C)O2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (150 mg, 1.0 mmol) and ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (132 mg, 1.0 mmol) in THF (10 mL) was added PPh3-resin (553 mg, 2.13 mmol/g) and DEAD (0.54 mL of a 40% solution, 1.2 mmol) and the suspension was stirred at ambient temperature overnight. The reaction mixture was filtered and partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (2:1) as eluent gave 4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylbenzaldehyde as a white solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].C1(C)C=CC=CC=1>C(O)C>[Br:1][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: BrBr
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(C(=O)CBr)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Bromine (1.25 ml; 25 mmol) is added dropwise to a solution of 4′-isobutylacetophenone (3.52 g; 20 mmol) in 60 ml of ethanol cooled down to approximately 5° C. After stirring the reaction mixture for 30 minutes at this temperature, stirring is continued for one hour at ambient temperature. The reaction medium, to which small portions of toluene are added, is concentrated to dryness. After purification on a silica column (eluent: ethyl-heptane acetate: 5-95), a colourless oil is obtained with a yield of 57%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].F[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](C)(C)[NH:9]2.C(N(CC)CC)C>C1COCC1>[C:1]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:6][CH:7]=2)[NH:12][C:11](=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
Acetyl chloride (0.36 ml) is added to 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.676 g) and triethylamine (0.76 ml) in THF (8 ml) at 0°. After stirring for 1 hr, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The layers are separated, the organic phase is filtered through sodium sulfate and concentrated. The concentrate is crystallized from methanomethylene chloride/hexane to give the title compound, mp 164°-165°; NMR (CDCl3) 2.28, 4.54, 7.00, 7.11, 7.21 and 9.19 δ.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:32]=2)O1>>[OH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[CH:32]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(Br)c1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(-c2ccnc(N3CCOCC3)c2)c1
Yield: 91 %

Procedure:
The method used to prepare example X was followed using 3-bromo-4-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)benzamide and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine to afford 4-(hydroxymethyl)-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide in a 91% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 3.61-3.73 (m, 4H), 3.83-3.90 (m, 4H), 4.63 (s, 2H), 7.09-7.15 (m, 1H), 7.39-7.47 (m, 2H), 7.53-7.60 (m, 1H), 7.75-7.82 (m, 1H), 7.91-7.99 (m, 2H), 8.04-8.13 (m, 2H), 8.14-8.19 (m, 1H). LC/MS (m/z)=458.1 (MH+), Rt=0.73 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[CH:7]=[N:6][CH:5]=1.[CH3:13][O:14][C:15](=[O:40])[CH2:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:22][CH:21]=[C:20](I)[N:19]=1>>[CH3:13][O:14][C:15](=[O:40])[CH2:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:22][CH:21]=[C:20]([C:11]#[C:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=2)[N:19]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1cncc(C(=O)OC)c1
Product: COC(=O)CCc1nc(C#Cc2cncc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 2.8 %

Procedure:
Under the conditions of example 5A, 184 mg of the crude 5-ethinylnicotinic acid methyl ester is reacted with 500 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate and for complete purification subjected to high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with acetonitrile/water=75/25. 15 mg of 3-{6-[2-(5-methoxycarbonyl-3-pyridyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:7]([CH2:16][N:17]([C@@H:25]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH:37]1[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]1>C(O)C.C(Cl)(Cl)Cl>[C:20]([O:19][C:18]([N:17]([CH2:16][C@@H:7]1[C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:37]2[CH2:47][CH2:46][CH:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38]2)[CH2:6]1)[C@@H:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(CCC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A mixture of 750 mg of tert-butyl {[(3R,4S)-1-acryloyl-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 8 ml of an ethanol:chloroform (4:1) mixed solvent was mixed with 487 mg of ethyl isonipecotate and stirred at 60° C. for 6Hours, and the reaction solution was concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 700 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}piperidine-4-carboxylate as a pale yellow amorphous substance. By carrying out the Boc-elimination from the thus obtained compound in the same manner as in Example 2, ethyl 1-{3-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3-oxopropyl}pyridine-4-carboxylate dihydrochloride was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)=[O:4].[OH-].[Na+].Cl>>[C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-73) (345 mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0 mL), stirred at 50° C. for 5 hours, cooled to room temperature, and neutralised with 1M HCl. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80° C. under vacuum to afford III-72 as an off-white solid (312 mg, 94%): mp 289-291° C. (dec.); 1H NMR (DMSO) δ 7.45 (1H, br s), 7.50-7.60 (5H, m), 7.80-7.88 (2H, m), 7.40-7.50 (2H, m), 8.60-8.70 (1H, d), 10.70 (1H, s), 13.00-13.80 (2H, br s); IR (solid) 1699, 1624, 1607, 1570, 1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CCCCO
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.081 ml of 4-(trifluoro-methoxy)-benzenamine in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for approximately 20 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 203 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:23]
Reactant: Clc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1

Procedure:
To a solution of 2-chloro-5-(4-phenoxyphenyl)pyrazine in 2 mL of ethanol was added hydrazine monohydrate (2 mL). The reaction mixture was heated at 110 C for 2 hours and evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over Na2SO4, and evaporated in vacuo to afford 2-hydrazinyl-5-(4-phenoxyphenyl)pyrazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and p-tolylboronic acid to give (1H-pyrazol-3-yl)-(1-p-tolyl-isoquinolin-3-yl)-amine. LC-MS m/e 301(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH:9]1[CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1COS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a stirred solution of the diol (344) (12.7 g, 58.5 mmol) and triethylamine (5 equiv., 41 mL) in CH2Cl2 (200 mL) at 0° C. was added methanesulfonyl chloride (NsCl) (2.4 equiv., 10.9 mL). The resulting suspension was removed from the ice bath and allowed to warm to room temperature with stirring at which point TLC analysis indicated complete consumption of the starting material and conversion to a single spot of higher Rf (5% MeOH/CHCl3, stained with K2MnO4). The reaction was quenched by the addition of water (20 mL) with vigorous stirring. NaHCO3 (sat., aqueous, 200 mL) was added and the organic layer was separated, washed with brine, dried (MgSO4) and purified by flash chromatography (1–10% MeOH/CHCl3) to yield the desired compound (345) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(NC(C)C)(C)C>O1CCOCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4.44 mL of p-fluoronitrobenzene, 6 gms. 3-(4-methyl-piperazin-1-yl)-propylamine and 6.65 mL N,N-diisopropylamine in 19 mL dioxane is heated at 105° C. for 2 days. The reaction mixture is cooled to room temperature, evaporated to dryness, and recrystallized from hot isopropanol yielding [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in the amount of 0.1385 gms.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)nc3)n(CC(=O)N(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N(C)C)cn1
Temperature: 60 °C
Yield: 90 %

Procedure:
Methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(6-methoxypyridin-3-yl)-1H-indole-6-carboxylate (from Step 1, 1 eq.) was dissolved in a mixture THF:MeOH (0.07 M, 1:1, v/v) then an aqueous solution of LiOH monohydrate (3 eq, 0.21 M) was added. The reaction mixture was heated at 60° C. for 4 h. It was allowed to cool to RT, and then hydrochloric acid was added. The precipitate that formed was collected by filtration and dried in vacuo to give the title compound (90%). 1H NMR (400 MHz; DMSO-d6, 300 K) δ 1.17-1.28 (m, 3H), 1.65-1.86 (m, 7H), 2.45-2.55 (m, 1H), 2.8 (s, 3H), 2.96 (s, 3H), 3.94 (s, 3H), 4.91 (s, 2H), 6.97 (d, J 8.4, 1H), 7.62 (d, J 8.8, 1H), 7.65 (d, J 8.8, 1H), 7.82 (d, J 8.4, 1H), 7.95 (s, 1H), 8.11 (s, 1H), 12.6 (bs, 1H); MS (ES+) m/z 436 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:13]1[CH2:14][CH2:15][CH:16]2[S:17][C:9](=[O:8])[CH2:10][C:11]2=[CH:12]1.[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(Cc1ccccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C1CC2=CN(Cc3ccccc3Cl)CCC2S1
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 8.23 g of 2-(tert-butyldimethylsilyloxy)-5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 4.31 g of p-toluenesulfonic acid monohydrate and 40 ml of methylene chloride was stirred at 40° C. for 2 hours to obtain precipitated crystals. The obtained precipitated crystals were filtered, washed with 20 ml of methylene chloride and dried under reduced pressure to obtain 7.85 g of 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydrothieno[3,2-c]-pyridin-2-one-p-toluenesulfonate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 16.4 g (75.0 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122°-124° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)(OC)=[O:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)=[O:2])[CH3:33]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Reactant: CCNCC
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Yield: 50 %

Procedure:
The crude 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one (1.50 g, 3.50 mmol), prepared in part A, is hydrolyzed as in Example 3, part F and then coupled with diethylamine as described in Example 1, part A to give after chromatography (50% ethyl acetate/hexanes) 17β-N,N-diethylcarbamoyl-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one as a white foam; yield: 1.07 g (65%). Anal. Calcd. for C28H42N2O4 ; C, 71.45; H, 9.00; N, 5.95. Found C, 71.38; H, 9.07; N, 5.90.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:13][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1cc(C)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.12 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 20 mL (0.24 mole) of n-propylamine was stirred, and 25 mL of ethanol was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. After this time, the reaction mixture was heated to reflux where it stirred for 2.5 hours. An additional five mL of n-propylamine was added to the reaction mixture, then it was allowed to stir at ambient temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 250 mL of 10% methanol in methylene chloride. The cloudy solution was filtered through 300 grams of basic alumina (deactivated with 18 mL of water) using 10% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 21 grams of 2-amino-4-propylamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Reactant: O=S(Cl)Cl
Product: ClCc1cc2c(cn1)[nH]c1ccccc12

Procedure:
The 3-(hydroxymethyl)-β-carboline was added to an excess (3 grams) of thionyl chloride and the mixture was refluxed for 1 hour. The excess thionyl chloride was then evaporated and the obtained residue was crystallized from hexane. 2.5 grams of 3-(chloromethyl)-β-carboline was obtained.