Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH:4]([CH3:23])[CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH:4]([CH3:23])[CH2:3]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC1CC(N)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of 1-[2-(4-amino-2-methylpiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) was heated over 3 Å molecular sieves at 80° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (299 mg, 1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH˜10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (4×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (17:3) gave 195 mg (69%) of the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][Cl:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24](O)=[O:25])=[CH:18]2)([O-:14])=[O:13].CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[NH:1][C:24]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:25]
Reactant: Nc1cc(O)ccc1CCCl
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(O)ccc1CCCl)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 14 %

Procedure:
2-(2-Amino-4-hydroxyphenyl)ethyl chloride was coupled with 5-nitroindole-2-carboxylic acid with EDCI at 0-50° C., preferably at room temperature, in DMF to give 4-(2-chloroethyl)-3-(5-nitroindole-2-carboxamido)phenol in 14% yield. Subsequent catalytic hydrogenation of 4-(2-chloroethyl)-3-(5-nitroindole-2-carboxamido)phenol at 0-50° C., preferably at room temperature, with 5% Pd-C in THF gave an amine which was directly reacted with at 0-50° C., preferably at room temperature, benzoic acid mustard (p-N,N-bis(2-chloroethyl)aminobenzoic acid) and EDCI to give the desired compound 4-(2-chloroethyl)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol in 24% yield. Reaction of 4-(2-chloroethyl)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol at 0-50° C., preferably at 5° C., with 4-nitrobenzyl chloroformate and triethylamine gave the prodrug 4-(2-chloroethyl)-O-(4-nitrobenzylcabonato)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol in 13% yield, after purification by silica gel column chromatography. The structures of all the compounds prepared were confirmed using IR, 1H-NMR (1H and 13C) spectroscopy, and FAB mass spectrometry including accurate mass measurements.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: CNC
Reactant: O=c1[nH]ccc2cc(F)ccc12
Solvent: CCO
Product: CN(C)c1ccc2c(=O)[nH]ccc2c1
Temperature: 150 °C

Procedure:
6-Fluoro-2H-isoquinolin-1-one (54 mg, 0.33 mmol) was deposited in a sealed tube with 5 mL 33% dimethylamine in ethanol. This was heated at 150° C. for 3.5 hours. This was concentrated in vacuo and purified by flash chromatography (gradient elution 50 to 100% ethyl acetate/hexanes) to yield 6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol). MS (ESI) 189.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[CH3:24][C:25]([CH3:45])([O:27][C:28]([NH:30][CH2:31][CH2:32][C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34])=[O:29])[CH3:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[CH3:23][C:6]1[C:7](=[O:22])[N:8]2[C:20](=[CH:21][C:5]=1[CH:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][NH:30][C:28]([O:27][C:25]([CH3:26])([CH3:24])[CH3:45])=[O:29])[CH2:3][CH3:4])[C:11]1=[N:12][C:13]3[C:18]([CH:19]=[C:10]1[CH2:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC(OC(=O)CCNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reaction time: 312 h

Procedure:
A mixture containing (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-dichloroethane (5 mL) under an argon atmosphere was heated at reflux for 5 d. Thin layer chromatographic analysis at this time indicated that the reaction was incomplete, so the mixture was transferred to a pressure bottle and heated at 90°-95° C. for 1 d. Afterwards, additional 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) were added, and heating was continued for 13 d. The mixture was then purified by flash chromatography eluting with a solvent gradient of 0-3% MeOH/CH2Cl2. The material that was isolated was recrystallized from Et2O and dried in vacuo to afford the title compound, mp 155°-8° C. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.32 (s, 1H), 5.90 (dd, J=7.7, 6.1 Hz, 1H), 5.26 (s, 2H), 5.02 (br s, 1H), 3.44 (m, 2H), 2.66 (q, J=5.8 Hz, 2H), 2.02-1.80 (m, 2H), 1.38 (s, 9H), 0.98 (t, J=7.4 Hz, 3H). Anal. Calcd for C27H31N3O5.1/5 H2O: C, 67.40; H, 6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:21]([OH:24])[CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][O:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:23][CH2:22][CH2:21][OH:24])=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Reactant: OCCO
Product: OCCOc1ccc(C(F)(F)C(F)(F)c2ccc(OCCO)cc2)cc1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
700 ml of ethylene glycol and 65 g of 1,2-bis(4-fluorophenyl)-1,1,2,2-tetrafluoroethane* are heated to 110° C. in a stirred flask. 57 g of potassium tert.-butylate are added in portions and the mixture is then stirred at 150° C. for 7 hours. The mixture is cooled, poured onto 4 liters of ice-water and mixed thoroughly with a homogenizer (Ultraturax). The crystals which have precipitated are filtered-off with suction, stirred again with 2 liters of water filtered-off with suction again, dried and recrystallized from toluene.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
The mixture of 2-[3-methyl-2-((Z)-pent-1-enyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (124) (69 mg, 0.18 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 5 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (125) as white solid (42 mg, 64%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.Cl.[C:31]1([CH2:41][CH2:42][NH2:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1>>[C:31]1([CH2:41][CH2:42][NH:43][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:9]4)[CH2:10]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1
Reactant: NCCC1=CCCc2ccccc21
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: Cl
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCC1=CCCc2ccccc21

Procedure:
Following the procedure of Example 70, the title compound was prepared from 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.29 g (1.38 mmol) of 3,4-dihydro-1-naphthaleneethanamine hydrochloride. The purified product after chromatography was obtained as a white foam, 0.41 g (59%); 1H NMR (CDCl3) δ1.48-1.99 (17H, m), 2.39-2.50 (2H, m), 2.67-2.82 (3H, m), 3.23-3.57 (3H, m), 3.99 (2H, t, J 5.0 Hz), 4.84 (1H, br s), 5.24 (1H, br s), 5.73 (1H, m), 6.16 (1H, m), 7.00-7.63 (9H, m), 8.12 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl.[C:15](OCC)(=O)C.Cl.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]3[CH2:8][CH2:9][NH:10][CH2:15][C:6]=3[NH:5]2)=[CH:12][CH:13]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Temperature: 25 °C
Yield: 68 %

Procedure:
6-Fluorotryptamine (0.71 g) was dissolved in tetrahydrofuran (30 ml), a 4N hydrochloric acid-ethyl acetate solution (1.2 ml) was added dropwise, and the mixture was stirred at room temperature. The solvent was evaporated under reduced pressure. Glyoxylic acid monohydrate (Aldrich Co., 403 mg), a 1N potassium hydroxide solution (3.98 ml) and water (80 ml) were added to the obtained residue, and the mixture was stirred with heating at 80° C. for 1.5 hr. After ice-cooling, the precipitate was collected by filtration and washed with water to give a pale-brown solid. Water (80 ml) and concentrated hydrochloric acid (2 ml) were added to the obtained solid, and the mixture was stirred with heating at 80° C. for 1 hr. Concentrated hydrochloric acid (2 ml) was further added, and the mixture was heated under reflux for 1 hr. The insoluble material was hot filtrated, and the filtrate was adjusted to pH 12 or above with a 6N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water, and dried to give 7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline (516 mg, yield 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 4-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.13 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.25 (d, 2H, J=7.9 Hz), 7.15 (d, 2H, J=7.8 Hz), 4.50 (s, 2H), 2.28 (s, 3H). [M+H] calc'd for C14H14N2O2, 243. Found 243.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCCCC3)n2)cc1
Yield: 81.4 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (100 mg, 0.46 mmol) was acylated in CH2Cl2 using cyclohexane carbonyl chloride (85 μL, 0.57 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 123 mgs cyclohexanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(F)ccc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
2-Amino-6-fluoro-3-methoxyquinoxaline (580 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 756 mg of the titled compound (yield, 95%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][N:1]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[N:2]=2)[CH:7]=1
Reactant: c1cncc(-c2cc[nH]n2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
15.45 g of 3-(1H pyrazol-3-yl)-pyridine prepared as indicated in CA 68 P 95812 g (1968) is introduced dropwise over 1 hour while maintaining the temperature below 30° C. or equal to 30° C. into a mixture of 20 ml of DMF and 6.13 g of sodium hydride. A solution of 29.90 g of 2-(4-bromobutyl)-1H -isoindole-1,3(2H)-dione and 110 ml of DMF is added dropwise. The reaction medium is agitated for 30 minutes at ambient temperature, followed by concentrating, pouring into 300 ml of water cooled down to 10° C., extracting with ethyl acetate, washing with water, drying, filtering and concentrating. The residue is taken up in methylene chloride, followed by drying, filtering and concentrating. 35.87 of a product is obtained which is crystallized from ethyl ether, dried, washed with water and dried. 22.93 g of sought product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27]OS(C)(=O)=O)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:33])[N:11]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([N:11]2[CH:12]([CH3:33])[C:13]3[C:14](=[N:15][C:16]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][N:47]5[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]5)[CH:21]=4)=[N:17][CH:18]=3)[N:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[O:42])=[CH:39][CH:38]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester (0.10 g; 0.16 mmol) (from Example 5a supra) and 1-methylpiperazine (0.25 mL; 2.23 mmol) (Aldrich) and heated at 110° C. for 1 hour. Upon cooling, the mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (Biotage 12S; 100:0 to 40:60 ethyl acetate-methanol gradient) and then crystallized from ethyl acetate-hexanes to give (±)-3-(3-(4-methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzonitrile. (Yield 60.6 mg; 64.1%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>CO>[C:18]1([CH2:17][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to literature (ref. JOC, 1990, 55(1), 111-122) starting from (D)-serine methyl ester hydrochloride (98%, from Aldrich) (D)-serine methyl ester hydrochloride (10 g, 0.065 moles) was suspended in 50 ml of anhydrous methanol and cooled to 0° C. under nitrogen. Triethylamine (9 ml, 0.065 moles) was added dropwise, followed by benzaldehyde (6.6 ml, 0.065 moles). The reaction mixture was then warmed up and stirred at room temperature for 2 hours. Sodium borohydride (4.85 g, 0.13 moles) were added in small portions over 2 hours. The resulting mixture was stirred at room temperature overnight. The mixture was then slowly added to 50 ml of HCl (20% solution) at 0° C. and the resulting solution was washed with diethyl ether (50 ml). The aqueous layer was then brought to basic pH by adding solid potassium carbonate and extracted with diethyl ether (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum to afford the title compound as colourless oil (10.95 g).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S-2:24].[Na+].[Na+].O>CS(C)=O>[SH:24][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)OCc1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1cc([N+](=O)[O-])ccc1S)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 44.6 %

Procedure:
To a partially dissolved mixture of 6A (7.00 g, 20.91 mmol) in DMSO (40 mL), was added sodium sulfide (3.26 g, 41.8 mmol). The mixture was stirred at 50° C. for 45 min. The reaction mixture was cooled to rt, poured into water (500 mL). The mixture was extracted with EtOAc (3×). The combined organic phase was washed with water and brine, filtered though a pad of SiO2 and concentrated to a red oil. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 100% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give 6B (3.10 g, 9.33 mmol, 44.6% yield) as an orange solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (d, J=7.15 Hz, 2H) 7.27-7.48 (m, 6H) 5.20 (br. s., 2H) 4.56 (br. s., 2H) 2.96 (br. s., 3H); MS (ESI) m/z: 333.1 [M+1]+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:3][CH:2]=1.[N+:17]([O-])([O-])=O.[NH4+].N>>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[NH2:17])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)C2CCCCC2=O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: [NH4+]
Product: Cc1ccc(C(=O)C2=C(N)CCCC2)cc1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Ammonia gas was bubbled into a cooled flask containing a suspension mixture of 2-p-toluoylcyclohexanone (21.6 g, 0.1 mole) and 8.8 g (0.11 mole) of ammonium nitrate until 17 g (1 mole) of ammonia was absorbed. The flask was stoppered and the mixture stirred for 30 min when a solution resulted. The flask and its mixture was allowed to stand overnight and the resulting brown solution was evaporated. The residue was extracted with boiling diethyl ether, 4×250 ml portions, filtered, and the extract was concentrated until crystallization began in the hot, and the mixture was allowed to cool. A total of 10 g of pale yellow needle crystals was obtained, mp 130°-131° C. A second crop of 6.35 g, mp 129°-130.5° C., for a total of 76% yield was obtained. The UV, mass spectrum and NMR spectra were consistent with the sub-titled intermediate amine.
Reaction SMILES: I.[NH:2]([C:4](SC)=[NH:5])[NH2:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO>[N:8]1([C:4](=[NH:5])[NH:2][NH2:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CSC(=N)NN
Reactant: C1COCCN1
Agent: I
Solvent: CO
Product: N=C(NN)N1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of methyl hydrazinecarbimidothioate hydroiodide (0.100 g, 0.429 mmol) in MeOH (2 mL) was added morpholine (0.075 mL, 0.858 mmol) and refluxed overnight. Reaction was cool to RT and concentrated to get morpholine-4-carboximidhydrazide as a white solid in quantitative yield.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[C:3]=[CH:4][CH2:5][C:6](=[O:8])[CH3:7]>[Pd]>[CH3:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:7])=[O:8])[CH3:1])[CH3:13]
Reactant: CC(=O)CC=C=C(C)CCC=C(C)C
Agent: [Pd]
Product: CC(=O)CCCC(C)CCCC(C)C

Procedure:
Using the apparatus and procedure described in Example 1 but employing a 0.5% (wt./wt.) Pd on Al2O3 catalyst (DEGUSSA, E257H/D) 6,10-dimethyl-undeca -4,5,9-triene-2-one (DUTO) was hydrogenated to produce hexahydropseudoionone. The process parameters were as stated below: