Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]=[C:21]4[NH:31][CH:32]=[CH:33][C:20]=34)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.C=O.[BH3-][C:42]#N.[Na+].CN.C([O-])(O)=O.[Na+]>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([C@@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[CH3:42])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]=[C:21]4[NH:31][CH:32]=[CH:33][C:20]=34)[CH2:17][CH2:18]2)=[O:12])=[CH:8][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C([C@@H](c1ccc(Cl)cc1)[C@@H]1CCCN1)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Agent: C=O
Agent: CN
Agent: Cl
Solvent: CO
Product: CN1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 194.7 %

Procedure:
(S)-2-(4-Chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.060 g, 0.105 mmol, see Example 20) in MeOH (0.5 mL) was cooled to a temperature of about 0° C. to about 5° C. Formaldehyde (0.0234 mL, 0.314 mmol) and NaCNBH3 (0.0132 g, 0.210 mmol) were added. The mixture was stirred at a temperature of about 14° C. to about 16° C. for 45 minutes. Methyl amine (2 mL, 2.0M in THF) was added, and the reaction was stirred for 30 minutes. Saturated NaHCO3 (5 mL) was added, and the aqueous phase was extracted with DCM (20 mL). The combined organic phases were washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was dissolved in DCM (0.5 mL), and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.060 g, 98%). MS ESI (+) m/z 514 detected.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)=O.Cl.[OH:21][NH2:22]>C(O)C.O>[OH:21][N:22]=[CH:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a solution of 0.50 g of 4-formyl-2-methyl-N-(2-pyridylmethyl)benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.18 g of hydroxyamine hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 12 hours. After the completion of the reaction, solid was filtered off, ethanol was distilled off under reduced pressure, and 30 ml of saturated sodium hydrogen carbonate aqueous solution was added in the remaining aqueous solution. The precipitated crystal was filtered off, washed with water and dried to obtain 0.45 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:9][N:10]([C:19]2[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=2)[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(CNC2CCCC2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CCC1

Procedure:
Reaction of 1-cyclopentylaminomethyl-cyclobutanecarboxylic acid methyl ester with 2,4-dichloro-5-nitropyrimidine and K2CO3 in acetone gave 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclobutanecarboxylic acid methyl ester
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COS(OC)(=O)=O>CC(C)=O>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:1])[CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
K2CO3 (621 mg, 4.5 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (988 mg) in acetone (30 mL). Me2SO4 (105 μl, 1.6 mmol) was slowly added at 0° C. The mixture was stirred at rt for 6 h, then concentrated and purified by reverse phase column chromatography (gradient elution 0-80% of acetonitrile in water) to give (2S,5R)-6-(benzyloxy)-2-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (198 mg, 33% for two steps) as a yellow solid. ESI-MS (EI+, m/z): 398.3 [M+H]+.
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>CO>[CH2:18]([NH:19][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCCCCCCN
Reactant: CCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (50 g.) and hexamethylenediamine (18.6 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxydecylamine] (I: R = CH3 (CH2)7, R' = H, X = (CH2)6, Z = H) (25.4 g., m.p. 118.0°-126.8° C.).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[N:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.O.Cl[Sn]Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>CCO.O>[NH2:31][C:28]1[CH:27]=[N:26][C:25]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:1]34[CH2:2][CH:3]5[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]5)[CH2:10]3)[CH2:8]4)[CH:12]=2)=[N:30][CH:29]=1
Reactant: O=[N+]([O-])c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 34.8 %

Procedure:
A solution of 2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-nitropyrimidine (163 mg, 0.37 mmol) and SnCl2.2H2O (418 mg, 1.85 mmol) in anhydrous EtOH (1.7 mL) was heated at 90° C. (oil-bath) for 3.3 h, cooled to room temperature and diluted with H2O (2 mL). After adjustment of the pH to 7-8 by addition of 2 N NaOH (1.6 mL) and 5% NaHCO3 (3 mL), the resulting mixture was stirred for 40 min and extracted with EtOAc (3×30 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (25% EtOAc/hexane) to give 53 mg (35%) of 5-amino-2-[3′-(1-adamantyl)-4′-benzyloxyphenyl]pyrimidine as a light-purple solid, mp 216-219° C. IR 3424, 2900, 1182 cm−1; 1H NMR (CDCl3) 1.76 (bs, 6H, AdCH2), 2.08 (bs, 3H, AdCH), 2.24 (m, 6H, AdCH2), 3.74 (bs, 2H, NH2), 5.21 (s, 2H, C6H5CH2), 7.04 (d, J=8.7 Hz, 1H, 5′-ArH), 7.34-7.56 (m, 5H, C6H5), 8.13 (dd, J=8.7 Hz, 2.4 Hz, 1H, 6′-ArH), 8.28 (d, J=2.4 Hz, 1H, 2′-ArH), 8.43 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd C27H29N3O [M+H]+ 412.2389. found 412.2391.
Reaction SMILES: [CH2:1]([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S:24]=[C:25]([C:27](=[S:29])[NH2:28])[NH2:26]>>[CH2:1]([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[S:24][C:25]2[N:26]=[C:14]([C:10]3[S:11][CH:12]=[CH:13][C:9]=3[CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[S:29][C:27]=2[N:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC(=S)C(N)=S
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1C=O
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1-c1nc2sc(-c3sccc3CC(CCCCCC)CCCCCCCC)nc2s1
Temperature: 200 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, 3-(2-hexyldecyl)-2thiophenaldehyde (3.00 g, 8.91 mmol) (A3) and rubeanic acid (375 mg, 2.97 mmol) were added to a flask equipped with Dean-Stark, then heated to 200° C., and stirred for five hours. Then, the reaction mixture was extracted with chloroform, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and chloroform was used as a mobile phase, 2,5-bis(3(2-hexyldecyl)thiophene-2-yl)thiazolo[5,4-d]thiazole (A4) was obtained as a yellow solid (630 mg, 28% yield). The product (A4) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.34 (d, J=5.4 Hz, 1 H), 6.95 (d, j=5.4 Hz, 1 H), 2.93 (d, J=7.4 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:33])=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>O1CCOCC1>[Cl:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([Cl:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (4.87 g, 21 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (5.50 g, 20 mmol) and dioxane (200 mL) and stirred at rt for 2 h and at reflux for 8 h. The mixture is concentrated, diluted with DCM and filtered over silica gel. The filtrate is concentrated to give the sub-title compound.
Reaction SMILES: [C:1]([CH2:8][N:9]1[C:13]([SH:14])=[N:12][N:11]=[N:10]1)([C:3]([O:5]CC)=[O:4])=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH2:8][N:9]1[C:13]([SH:14])=[N:12][N:11]=[N:10]1)([C:3]([OH:5])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Cn1nnnc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)Cn1nnnc1S
Reaction time: 0.67 h
Yield: 59.9 %

Procedure:
To a solution of 1-ethoxalylmethyl-1H-tetrazole-5-thiol (18.6 g) in methanol (186 ml) was added 1N aqueous solution of sodium hydroxide (172 ml) at room temperature and the mixture was stirred for 40 minutes. After adjusting to pH 7.5 with 10% hydrochloric acid, the solution was evaporated in vacuo to remove methanol and the remained aqueous solution was washed with ethyl acetate (100 ml). The aqueous solution was adjusted to pH 4.0 and washed again with ethyl acetate to remove impurities. The aqueous solution was adjusted to pH 2.5, and extracted with ethyl acetate, dried over magnesium sulfate and evaporated to give pale yellow powder of 1-oxalomethyl-1H-tetrazole-5-thiol (9.7 g), mp 140° to 150° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[N:17][CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:18]=[N:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccc(F)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To the solution of 4-chloro-2-nitro-phenylamine (862 mg, 5.0 mmol), 5-bromo-2-fluoro-pyridine (924 mg, 5.25 mmol) in dioxane (15 mL) was added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (289 mg, 0.5 mmol), Pd2(dba)3 (457.5 mg, 0.5 mmol), followed by cesium carbonate (3.26 g, 10.0 mmol). After degassed and refilled with nitrogen for three times, the reaction mixture in vessel was stirred at 110° C. for overnight till all starting material has been consumed. The reaction mixture was quenched with ice water, the solid was filtered and collected, washed with water, and dried over oven to yield the nitro product about 800 mg as crude solid (yield: 60%). To the solution of (4-chloro-2-nitro-phenyl)-(6-fluoro-pyridin-3-yl)-amine (800 mg, 3.0 mmol) in methanol (10 mL) was added Raney Ni (slurry in water, 100 mg), followed by hydrazine (2 mL), the reaction mixture was stirred at RT for 30 min, till all starting material has gone. The mixture was filtered and the filtrate was combined. After evaporated under reduced pressure, about 600 mg of the residue was obtained as crude product (yield: 90%). The cyclization step is as the same as previous description in Example 2-1. MS obsd. (ESI+) [(M+H)+], 296.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.O>FC(F)(F)C(O)=O>[F:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([CH2:18][C@H:15]1[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH2:17][CH2:16]1)[CH:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1ccc2c(ccn2C[C@@H]2CC[C@H]3CNCCN3C2)c1
Yield: 89.8 %

Procedure:
A solution of 3.0 g (7.75 mmol) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 200 mL of 70:30 trifluoroacetic acid:water was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, basified with 15% sodium hydroxide and extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered and evaporated to give 2.0 g (90%) of (7R,9aS)-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH2:28])=[N:22][C:23]([CH3:27])=[N:24]2)=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[NH2:28][C:21]1[C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=[C:23]([CH3:27])[N:22]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Cc1nc(N)c2ccc(F)cc2n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)c2ccc(-n3cc(C)c4c3CC(C)(C)CC4=O)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To 3,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.3 g, 1.2 eq) in dimethylacetamide (50 mL) is added slowly sodium hydride (50.8 mg, 1.5 eq). The resulting mixture is stirred at RT for 0.5 h. To that 7-Fluoro-2-methyl-quinazolin-4-ylamine (0.25 g, 1 eq) is added and the mixture is stirred at 150° C. for overnight. The mixture is poured into sat'd NaHCO3 aq. solution (300 mL), and extracted by EtOAc (3×100 mL). The combined organic layers are dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography, eluted by 50% EtOAc in Hexane to EtOAc to give 1-(4-Amino-2-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.135 g, 29% yield). LC/MS m/z=335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a stirred solution of ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g, 69 mmol) in CCl4 (270 mL), bromine (11.1 g, 69 mmol) was added slowly (dissolved in 140 mL of CCl4) at −10° C. over a period of 30 min. The reaction mixture was stirred for another 1 h at −10° C. Upon completion of the reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with saturated Na2S2O3 solution, water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by re-crystallization using hexane to yield compound ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (7 g, 7 g starting material recovered) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:3][C:2]#[CH:1])[CH2:8][CH2:7]1
Reactant: C#CCBr
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(C)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
At 0–5° C., propargyl bromide (12.01 g) was added dropwise with stirring to a suspension of 4-methylpiperidine (10.0 g) and potassium carbonate (13.96 g) in dry acetone (80 ml). The mixture was stirred at 50° C. for 6 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water (3×15 ml), dried with sodium sulfate and concentrated under reduced pressure. Distillation of the residue under reduced pressure gave 12.73 g of an oil of boiling point 60° C./16 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCOCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCO)ccc21
Reaction time: 6 h
Yield: 80 %

Procedure:
3-[-5-(2-benzyloxy-ethoxy)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester (2.5 g, 5.6 mmol) was dissolved in 70% ethyl acetate/methanol (50 mL) and added under an argon atmosphere to a suspension of 10% palladium on carbon [10% w/w] (3.0 g) in the same solvent (50 mL). The reaction was placed in a Parr Hydrogenator for 6 h. The reaction was filtered through celite and the solvent was evaporated under vacuum. Purification of the crude mixture via column chromatography with silica gel, eluting with hexane/ethyl acetate gave the title compound (80% yield). 1H NMR (CDCl3), δ 7.14-7.32 (m, 7H), 6.82 (dd, 1H, J=2.3, 8.8 Hz), 6.45 (d, 1H, J=3.0 Hz), 6.07 (d, 1H, J=2.1 Hz), 6.01 (t, 1H, J=7.4 Hz), 4.03 (m, 4H), 3.91 (m, 2H), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[OH:24][C@@H:16]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:15][N:14]1[CH2:13][CH2:12][CH2:11][C:10]2[NH:9][CH:8]=[C:7]([CH3:32])[C:6]=2[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(CCCNC[C@H](O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
(S)-5-[3-(2-Hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2 and 4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 78d (580 mg, 1.28 mmol) were dissolved in 6 ml of toluene under an argon atmosphere, the reaction mixture was cooled in an ice-water bath, meanwhile a solution of trimethylaluminum in toluene (1.9 ml, 2 mol/L, 3.84 mmol) was added to the solution. Upon the completion of the addition, the ice-water bath was removed, and the reaction solution was heated to reflux for 24 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent, added with 20 ml hydrochloric acid (6 mol/L) and stirred for 20 minutes, adjusted to about pH 12 with sodium hydroxide solution (12 mol/L) in an ice-water bath. The resulting mixture was extracted with dichloromethane (50 ml×2), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 78e (300 mg, yield 57.6%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:22]2[C:21]3[NH:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15](=[O:23])[N:14]([CH2:24][O:25][CH3:26])[C:13]=2[CH:12]=[C:11]([C:27](OCC)=[O:28])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[OH:28][CH2:27][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[C:22]2[C:21]3[NH:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15](=[O:23])[N:14]([CH2:24][O:25][CH3:26])[C:13]=2[CH:12]=1
Reactant: CCOC(=O)c1cc(OC)c2c3c(c(=O)n(COC)c2c1)CCCN3
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCn1c(=O)c2c(c3c(OC)cc(CO)cc31)NCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Tetrahydrofuran (10.0 ml) was added to lithium aluminum hydride (125 mg, 3.30 mmol) and cooled to 0° C. The compound (457 mg, 1.32 mmol) prepared in step 7 was dissolved in tetrahydrofuran (10.0 ml) was added dropwise slowly at 0° C. and the resulting mixture was stirred at the same temperature for 1 hour. After completion, ammonium chloride aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:methanol=10:1) to obtain the title compound (399 mg, yield: 99.2%, ivory solid).
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)C.C[O-].[Na+].[C:19](#[N:21])[CH3:20].Cl>O.C1(C)C=CC=CC=1>[O:10]=[C:8]1[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][CH:4]=[C:20]1[C:19]#[N:21]
Reactant: COC(=O)c1ccccc1N=CN(C)C
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c[nH]c2ccccc2c1=O

Procedure:
A stirred mixture of 1.03 g of methyl 2-(dimethylaminomethyleneamino)benzoate, 0.54 g of sodium methoxide, 1.04 ml of acetonitrile, and 10 ml of toluene was refluxed for 18 h. The mixture was cooled, treated with water, and brought to pH 3 by addition of dilute HCl. The resulting solid was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethanol to give a solid, mp 290-300° C.