Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH3:9])[CH:3]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:65]([CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH3:9])[CH:3]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC1CCCC(O)C1O[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1CCCC(N=[N+]=[N-])C1O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of racemic [1-Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51f, (2.5 g; 9.6 mmol) in 60 mL of dry THF at room temperature was added, triphenylphosphine (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) and diphenylphosphoryl azide (5.3 g; 19.2 mmol) and the reaction mixture was stirred at room temperature for 60 h. The solvent was concentrated in vacuo and the resultant oil was purified by silica gel chromatography (10% Et2O-Hexane to ether gradient) to afford 2.57 g of the desired product 51g.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 205 mmole) in a mixture of tetrahydrofuran (200 ml) and ethanol (300 ml), sodium borohydride (14 g) is added in several portions under ice cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is neutralized with conc. sulfuric acid, concentrated in vacuo to approximately a half volume, diluted with water, and extracted with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (58.7 g). Yield: 81.7%. NMR δ(CDCl3) ppm: 1.8 to 2.2(m, 1H), 2.3 to 2.5(m, 1H), 3.01(s, 3H), 3.57 (d, J=4.4 Hz, 1H), 3.64(d, J=4.4 Hz, 1H), 3.81(s, 3H), 3.82 to 4.3(m,3H), 5.09(s, 2H), 5.21(br s, 1H), 6.89(d, J=8.8 Hz, 2H), 7.31(d, J=8.8 Hz,2H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl:12][C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:13]([Cl:12])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCN(C(=O)Cl)c1ccccc1
Reaction time: 27 h
Yield: 191.2 %

Procedure:
To a solution of 6.72 g (45 mmol) of butylphenylamine in 50 ml of methylene chloride cooled to 10° C. was added slowly with stirring 6.67 g (22.5 mmol) of triphosgene in 40 ml of methylene chloride. The reaction was allowed to continue at room temperature for 27 hours. The solvent was evaporated and the residue extracted twice with n-hexane. The organic solution was concentrated in vacuo to yield 9.11 g (43.03 mmol) of a yellow oil (96%). 1H-NMR (CDCl3): δ 0.9 (m, 3H), 1.3 (m, 2H), 1.6 (m, 2H), 3.7 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[CH:8]1([NH:14][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCC(=O)O1
Reactant: NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
Succinic anhydride (2.59 g, 25.9 retool) was dissolved in pyridine (15 ml). Cyclohexylamine was added dropwise to the solution at 0°. Thereafter, the mixture was stirred at room temperature (20°-22°) for 6 h. The pyridine was removed under reduced pressure. The residue was poured into 10% aqueous citric acid. The resulting precipitate was collected, washed thoroughly with 10% aqueous citric acid and then water. The precipitate was dried under vacuum to give the title compound (3.81 g, 74%), mp 168°-170°. The structure of the product was confirmed by NMR.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].[H-].[Na+].[CH3:28]I>CN(C=O)C>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CI
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OC)c(OS(=O)(=O)C(F)(F)F)cc2C1

Procedure:
A solution of 5-trifluoromethansulfonyloxy-6-hydroxy-2-(di-n-propylamino)indan (Example 7) in DMF is added to a suspension of sodium hydride in DMF under nitrogen. The mixture is alkylated with methyl iodide to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.[C-:22]#N.[K+]>CC(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
285 mg (1 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 50 mg of potassium cyanide are stirred at 60° C. for 72 hours in 10 ml of 2-propanol. Then, the mixture is concentrated on a rotary evaporator, the residue is partitioned between water and chloroform, extracted twice with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. There is obtained isopropyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine 3-carboxylate of melting point 190°-192° C. This product is uniform according to thin-layer chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:22]I>>[F:1][C:2]1[CH:3]=[C:4]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F
Reactant: CI
Product: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from (3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250 mg, 0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 7.76 (d, J=8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H), 3.58 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:16][CH2:17][CH2:18][OH:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([NH:16][CH2:17][CH2:18][OH:19])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: NCCO
Reactant: Cc1cc(Br)cnc1C1=CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)cnc1C1=CCC(NCCO)CC1

Procedure:
To a solution of 4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-one (2.06 g) in dichloromethane (50 ml) was added 2-aminoethanol (0.463 ml) at room temperature with stirring. Then sodium triacetoxyborohydride (1.64 g) was added thereto, and stirred at the same temperature. After completion of the reaction, to the reaction solution was added 10% sodium carbonate aqueous solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (chloroform/methanol), and then suspended and washed with a mixed solvent of a small amount of diethyl ether and n-hexane to give 2-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]amino ethanol (860 mg) as a light brown solid.
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a water cooled (25° C.) solution of 10.0 g of (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 250 ml of dry methylene chloride is added in one portion 16.0 g of pyridinium chlorochromate, 36.0 g of dried, crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid. The resulting mixture is stirred at 25° C. for one hour. Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added, the suspension is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in diethyl ether and is passed through a short column of silica gel using diethyl ether as the eluant. The first two 500 ml fractions contain the desired aldehyde. The solvent is concentrated in vacuo to give 10.1 g of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:27]4=[O:34])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.CS(C)=O.[ClH:39]>O>[Cl:39][C:9]1[N:10]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:27]3=[O:34])[CH2:22][CH2:23]2)[C:11]2[C:16]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Reactant: Cl
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(Cl)n2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-Fluorophenyl)-5-methyl-1-[1-[2-[3-(2-propyl)imidazolidin-2-on-1yl]ethyl]-4-piperidyl)-1H-indole 4h (3.0 g), dimethylsulphoxide (0.51 g) and conc. aqueous HCl (1 ml) was heated to 60° C. for 0.5 h under stirring. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with 4N aqueous NaOH and brine. Evaporation of the solvent gave an oil which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3). This afforded the title compound which crystallized from diethyl ether. Yield 0.4 g, mp 127°-130° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C(O)C>[CH2:24]([NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH2:25][CH3:26]
Reactant: CCCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCNc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 9 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and n-propylamine (1.44 g) in ethanol (20 ml) yielded the title compound, 0.46 g, m.p. 185°-7° C. (recrystallised from ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[NH2:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A mixture of 3.2 g (0.0091 mole) of 4-[4-(2,4-diamino-6-propyl-5-pyrimidinyl]-1-piperazinyl]benzoic acid, 4.9 g (0.030 mole) of diethyl phosphorocyanidate and 4.2 ml (0.030 mole) of triethylamine in 200 ml of of N,N-dimethylformamide (dried over 4 Å molecular sieves overnight) was stirred at room temperature for two hours. To the resulting clear solution was added a mixture of 2.4 g (0.010 mole) of diethyl glutamate hydrochloride and 1.4 ml (0.010 mole) of triethylamine in 10 ml of N,N-dimethylformamide, and the solution was stirred for another hour. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 40° C. The gummy residue was poured into 100 ml of ice water. The solid was collected and recrystallized from N,N-dimethylformamide to give 1.9 g of the product as an off-white powder; mp 175°-180° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][C:10]([N:12]([CH2:14][CH:15](OC)OC)[CH3:13])=[O:11])[CH2:4][CH2:3]1.Cl.[H][H]>[Pt].CO.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:15][CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9]2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O
Temperature: 50 °C

Procedure:
82 g platinum on charcoal (5%) are added to a solution of 822 g (trans)-1-hydroxy-4-{[N-(2,2-dimethoxy-ethyl)-N-methyl-amino]-carbonylmethylamino}-cyclohexane in 4500 ml of methanol and 450 ml of water. After the addition of 499 ml concentrated hydrochloric acid hydrogenation with hydrogen is begun immediately. During the hydrogenation process the mixture is heated to 50° C. After 3 h it is filtered.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH:12]([Cl:16])[CH2:13][CH2:14][CH3:15]>C(O)C>[Cl:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: Sc1ccccc1Br
Reactant: CCCC(Cl)CBr
Agent: [Na]
Solvent: CCO
Product: CCCC(Cl)CSc1ccccc1Br
Reaction time: 1 h

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added, in about 0.5 hour, a solution of 173.0 g of o-bromothiophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0°, and treated, dropwise, with 185.5 g of 1-bromo-2-chloropentane. The addition requires about 1 hour. The mixture is stirred for about 2 hours at 0°, warmed slowly to reflux, and then heated under reflux for 2 hours. The mixture is filtered and the filtrate concentrated in vacuo at 40° to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH2:9][CH:10]3[CH:15]([C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1)[CH2:14][NH:13][CH2:12][CH2:11]3.Br[CH2:19][CH2:20][CH3:21]>>[CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH2:9][CH:10]3[CH:15]([C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1)[CH2:14][N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11]3
Reactant: Cc1cc(C)c2c(c1)C1CNCCC1CC2=O
Reactant: CCCBr
Product: CCCN1CCC2CC(=O)c3c(C)cc(C)cc3C2C1

Procedure:
In an analogous manner to that described in Example 49 b), from (+)-7,9-dimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with bromopropane there was obtained (+)-7,9-dimethyl-2-propyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with fumaric acid into the fumarate (1:1) with m.p. 220.5-226.50°, [α]589=+33.7 (c=0.5, H2O).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])O.C1(C=CC(O)=CC=1)O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O>[N:16]1([CH2:1][NH:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: C=CC(=O)NCO
Agent: Oc1ccc(O)cc1
Solvent: O
Product: C=CC(=O)NCN1CCOCC1

Procedure:
In a 300 cc capacity round bottom flask equipped with a stirrer were put 50.5 g (0.5 mole) of N-methylolacrylamide and 50 cc of water and, as a polymerization-inhibitor, 500 mg of hydroquinone. On the other hand, 43 g (0.5 mole) of morpholine were gradually added thereto while stirring. Afterwards, the entire contents were stirred for 1 hour at 50° to 60°C. The reaction product was concentrated and then recrystallized from ethyl acetate. m.p.; 91°-92°C. In addition, the resulting product was further distilled under reduced pressure to obtain 34.5 g of fraction of 140°-160°C/0.01 mmHg (45.7%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[NH3:17]>>[NH2:17][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CCCC(=O)CC(=O)OCc1ccccc1
Reactant: N
Product: CCCC(N)=CC(=O)OCc1ccccc1

Procedure:
A mixture of benzyl butyrylacetate (22.0 g, 0.10 mol) and 10 g of 4 Å molecular sieves was treated with ammonia gas which was bubbled through the mixture for 38 hrs at 50° C. After filtration, benzyl 3-amino-2-hexenoate was obtained as a yellowish oil (21 g, 95%).
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Reactant: CC(C)N
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 20728 %

Procedure:
To a solution of NaBO3.4H2O (10 g, 0.026 mol) in H2O (180 g) was charged isopropylamine (30 g, 0.25 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.3-10.5 by 6M HCl. PLP (1 g, 6.4 mmol) and ATA-412 (25 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 36 (50 g, 4.7 mmoL) in DMSO (250 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (100 mL), and then partitioned with water and IPAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 37 (16.5 g, 40% yield). 1H (DMSO-d6, 400 MHz): δ 7.83 (s, 1H), 7.18-7.13 (m, 4H), 4.06 (br, 1H), 3.67-3.51 (m, 2H), 2.30 (d, 3H), 1.99 (t, 1H), 1.36 (s, 9H), 0.82 (m, 3H); MS (ESI) m/e [M+H]+: 319.2
Reaction SMILES: O.Cl[C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1.[I-:27].[Na+].Cl>C(#N)C>[I:27][C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 25 °C

Procedure:
A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 7-chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (120 g, 346 mmol), as prepared above, sodium iodide (1.04 kg, 6.92 mmol), and 3 L of acetonitrile. To the yellow suspension is added concentrated hydrogen chloride (59.7 mL, 726 mmol) over 5 min. The white slurry is refluxed for 15 hr. The solvent is mostly removed by short-path distillation in vacuo. The resultant thick slurry is cooled to ambient temperature and treated with 2.5 L of water and 2.5 L of methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, concentrated and dried in vacuo at 30° C. yielding 7-iodo-9-(4-methyl-piperazin-1-ylmethyl)- 2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2 -MeOH (1:1) gave an analytical sample as an off-white solid: 198°-200° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ2.30 (s, 3H), 2.43, 2.57 (m, 8H), 3.93 (s, 2H). 4.40(s, 4H), 7.47 (s, 1H), 7.50 (s, 1H), 10.1 (s, 1H). Elemental analysis: Calculated for C18H20IN3O3 : C 47.70, H 4.45, N 9.27. Found: C 47.78, H 4.45, N 9.26.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:5]([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:16]([N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:22]=[N:21][NH:20][C:19]=3[CH3:18])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17]
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN1c2cc(Br)sc2C(=O)NC12CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A flask was charged with 6′-bromo-1′-ethyl-1′H-spiro [cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (158 mg, 0.50 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (463 mg, 1.5 mmol), sodium carbonate (150 mg, 2.5 mmol), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.050 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 1 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 100° C. for 1 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (86 mg, 54%) as a yellow solid: