Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6][CH:7]=[CH:8][C:9]([OH:11])=O.[C:12]1(SC=CC(O)=O)[CH:17]=[CH:16][CH:15]=[CH:14]C=1>>[N:1]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:12]1)[C@@H:4]([NH:3][C:9](=[O:11])/[CH:8]=[CH:7]/[S:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:5]2
Reactant: O=C(O)C=CSc1ccccc1
Reactant: O=C(O)C=CSc1ncc[nH]1
Product: O=C(/C=C/Sc1ncc[nH]1)N[C@H]1CN2CCC1CC2

Procedure:
Employing essentially the same procedure as that described in Example 1 above but substituting 3-(2-imidazolylthio)acrylic acid for the 3-(phenylthio)acrylic acid and purifying by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent resulted in formation of the title compound; MS (ES−) 279. (MH−).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH:5]([C:11](OCC)=[O:12])[C:6](OCC)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][CH:5]([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CCOC(=O)C(CC(OC)OC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COC(CC(CO)CO)OC
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
Diethyl (2,2-dimethoxyethyl)malonate (115.0 g, 0.46 mol) was added to a suspension of lithium aluminum hydride (38.0 g, 1.00 mol) in 400 ml of dry ether at a rate to maintain a gentle reflux. After stirring for 15 min. 40 ml of water, 40 ml of 15% aqueous NaOH, and 120 ml of water were added and stirring was continued until a white suspension was obtained. The inorganic salts were filtered off and extracted with several 200 ml portions of tetrahydrofuran (THF). The combined organic extracts were evaporated and distilled twice in vacuum to yield 50.23 g (66.5%) of the title compound. B.p. 116°-125° (0.02 mm Hg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.[C:14](#[N:18])[CH:15]([CH3:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[F:12][C:10]1[CH:11]=[C:2]([C:15]([CH3:17])([CH3:16])[C:14]#[N:18])[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(F)cc(F)c21
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(F)c2c(c1)CCNC2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsilyl)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsilyl)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[C:75]1([SH:81])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=[C:16]3[S:81][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Sc4ccccc4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was benzenethiol. Yield: 36 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 61.2 %

Procedure:
In 40 ml of ethanol is dissolved 26 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate, and 6.2 g of acetic acid is added to the solution. Sodium cyanoborohydride (4.4 g) is added to the mixture under ice-cooling, and the mixture is stirred for 1 hour and allowed to stand at room temperature overnight. Water (500 ml) is added to the reaction solution, followed by extraction with methylene chloride. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown viscous material is purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give 16 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate as a colorless oily material.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7])C.[Li+].CC([N-]C(C)C)C.Cl[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:7][CH:6]([CH3:8])[CH:5]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]([OH:9])=[O:3]
Reactant: CCOC(=O)CC(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(COCC[Si](C)(C)C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbutyric acid ethyl ester (1.3 g, 10 mmol) in THF (50 mL) is added dropwise LDA solution (2 M in THF/hexane/ethylbenzene, 6 mmol) at −78° C., and the mixture is stirred at −78° C. After 0.5 h, to the reaction mixture is added (2-chloromethoxyethyl)trimethylsilane (2.65 mL, 15 mmol) at −78° C. The reaction mixture is allowed to warm to 0° C. 2 h and then quenched by addition of 100 mL of 5% aqueous KHSO4 and extracted with Et2O (200 mL). The organic phase is successively washed with 5% aqueous KHSO4, 5% aqueous NaHCO3, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. A mixture of the residue and 1M aqueous NaOH in MeOH is stirred at 70° C. After 5 h at 70° C., the reaction mixture is quenched by 5% aqueous KHSO4 (100 mL) and extracted with Et2O (200 mL). The organic phase is successively washed with H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C(O)C.[Ni]>[NH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=1[NH:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1NC1CCCCC1
Yield: 103.7 %

Procedure:
41.6 g (0.16 mol) of 4-chloro-N-cyclohexyl-2-nitroaniline were dissolved in 400 ml of ethanol, 4.2 g of Raney nickel were added, and the mixture was hydrogenated at 25° C. under 1 bar. The mixture was then filtered and the filtrate was concentrated under reduced pressure. 37.3 g (100%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:28][CH2:27][C:29](=[O:30])[CH3:31])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C=CC(C)=O
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Product: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)nc1C

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide was prepared using the method of the previous Example starting from (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide and methyl vinyl ketone. 1H NMR (400 MHz, CDCl3): 1.21 (3H, d), 2.17 (3H, s), 2.44 (3H, s), 2.89 (2H, t), 4.13 (2H, t), 4.29 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.44 (1H, s), 7.48 (1H, d), 7.58 (1H, d), 7.66 (1H, distorted d), 7.85 (1H, distorted dd), 8.00 (1H, d).
Reaction SMILES: Cl.[C:2]([CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[C:2]([CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:11]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: O=C(c1ccccc1)C1CNCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC(C(=O)c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 101.5 %

Procedure:
A solution of 2-benzoylmorpholine hydrochloride (269 mg, 1.17 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (320 mg, 1.41 mmol) and triethylamine (0.49 ml, 3.51 mmol) in tetrahydrofuran (10 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing ethyl acetate and diethyl ether to give the title compound (447 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:26]3[S:25][CH:24]=[N:23][C:22]=3[CH3:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: Cc1ncsc1C=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1ncsc1CNc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 4-methylthiazole-5-carbaldehyde using decaborane yielded the title compound as a white solid. MS (ESI): m/z=390.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and 2-amino-2-ethyl-N-methyl-butyramide as starting materials, MS (LC/MS): 374.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12](OC)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([Se:23][CH3:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Se]C1C=CC(B(O)O)=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](N2C(=O)C(OC)=C(C3C=CC(SC)=CC=3)C=N2)=[CH:39][CH:38]=1.FC1C=CC([Mg]Br)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([Se:23][CH3:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: COc1c(-c2ccc([Se]C)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: C[Se]c1ccc(B(O)O)cc1
Agent: Fc1ccc([Mg]Br)cc1
Product: C[Se]c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 228, substituting 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone (prepared according to the method of Example 194C, substituting 4-(methylseleno)benzeneboronic acid from Example 1 in place of 4-(methylthio)benzeneboronic acid) in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium chloride (yield: 44 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 6.98 (dd, J=8.8, 8.8 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.17 (dd, J=8.7, 8.7 Hz, 2H), 7.23–7.31 (m, 2H), 7.32 (d, J=8.7 Hz, 2H), 7.65–7.72 (m, 2H), 8.00 (s, 1H). MS (APCI+) m/z 455 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1ccnc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (164 mg), ethyl 3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (99 mg) and triphenylphosphine (248 mg) in THF (1.5 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (430 μL), and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (72 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CC(=O)C)[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH:35](C1C=CC(C(O)=O)=CC=1)=[O:36]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:23]=[CH:24][C:25]([CH:35]=[O:36])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C=O)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using 4-formylbenzoic acid in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C24H30N5O3+ 436.2. found m/z=436.2 (M+H)+.
Reaction SMILES: [CH2:1](CN)C=C.[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13]C>>[CH3:13][N:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH2:7][NH:6][CH3:1]
Reactant: C=CCCN
Reactant: CCN1CCC[C@H]1CN
Product: C=CCN(C)CCNC

Procedure:
By using N-allylmethylamine (821.5 mg) as a starting material, the title compound (246 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:20]1[O:21][C:9]2([CH2:8][CH:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]2=3)[O:18][CH2:19]1
Reactant: OCCO
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C1(CC(c3sccc3Cl)C2)OCCO1
Yield: 89.1 %

Procedure:
A mixture of 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (7.07 g), ethyleneglycol (6.2 g) and p-toluenesulfonic acid (6.9 g) in toluene (200 ml) was refluxed for 15 hours, with separating water, and to the reaction solution were added ethyl acetate (150 ml) and saturated sodium hydrogen carbonate solution (200 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-ethyleneacetal(7.3 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[CH2:22]([Sn]12CCCN(CCC1)CCC2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(C[Sn]23CCCN(CCC2)CCC3)cc1
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(Cc3ccccc3)=C1c1ccc(OC)cc1C2
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (29.6 mg, 0.0847 mmol), 5-benzyl-1-aza-5-stanna-bicyclo[3.3.3]undecane (38.5 mg, 85% weight pure, 0.0935 mmol), and Pd(PPh3)4 (9.8 mg, 0.00848 mmol) in anhydrous toluene (1.3 mL) was degassed, placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 100° C. After heating 4 hours, the cloudy, dark brown reaction mixture was cooled in an ice bath and filtered through a pad of celite. The filtrate was evaporated under vacuum to an orange gum (57 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, using 9:1 hexanes-EtOAc as developing solvent. The major UV visible band at Rf 0.18-0.26 was removed and eluted with EtOAc to afford 4-benzyl-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (29 mg) as a pale yellow gum.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([OH:30])=[O:29]>>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:29]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(Cl)(Cl)Cl)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and trichloroacetic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 3.99-4.19 (2H, m), 3.61-3.94 (2H, m), 2.30-2.61 (2H, m), 1.58-2.03 (2H, m).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:11][C@H:10]([NH2:12])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3].[C:19](O)(=[O:23])[C@H:20]([CH3:22])[OH:21]>>[C:2]([N:5]1[CH2:11][C@H:10]([NH:12][C:19](=[O:23])[C@@H:20]([OH:21])[CH3:22])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C)c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)O)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 53 c), the condensation of (S)-5-acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride with L-(+)-lactic acid yielded the title compound as a yellow foam; MS: m/e=306 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[S:6](=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH-].[NH4+:17]>>[NH2:17][C:2]1[CH:15]=[CH:14][C:5]2[S:6](=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: O=S1c2ccccc2-c2cc(Br)ccc21
Agent: [OH-]
Product: Nc1ccc2c(c1)-c1ccccc1S2=O

Procedure:
A mixture of 150 g. of crude 2-bromodibenzothiophene-5-oxide, 160 g. of cuprous bromide and 1700 ml. of ammonium hydroxide is heated at 200° C. in a pressure reactor for about 12 hours. The mixture is then filtered, and the residue is washed with water, then heated in methanol and filtered hot. The product is recrystallized by cooling and separated by filtration to give 2-aminodibenzothiophene-5-oxide, m.p. 169°-172° C.
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]C)[CH3:3].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]([CH3:14])([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:3]
Reactant: COc1ccccc1CCC(C)(C)N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(N)CCc1ccccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of 986 mg (5.1 mmol) of 2-amino-2-methyl-4-(2-methoxyphenyl)butane in 20 ml of dry methylene chloride, a solution of 2.5 ml of a 1M BBr3 solution in 10 ml of methylene chloride is slowly added. The reaction mixture is stirred at 0° C. for two hours and then at room temperature for 3 hours. The reaction is quenched with methanol and concentrated. Pure product may be obtained by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12](O)([C:14]([CH3:17])([OH:16])[CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:16][C:14]([CH3:17])([CH3:15])[C:12]([CH3:13])([CH3:11])[O:8]2)[C:5]([F:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Cl)cnc1F
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)OC(c2cc(Cl)cnc2F)OC1(C)C

Procedure:
A flask fitted with a Dean-Stark trap was charged with a solution of 5-chloro-2-fluoronicotinaldehyde, 27, (8.95 g, 56.10 mmol) and 2,3-dimethylbutane-2,3-diol (8.00 g, 67.70 mmol) and p-toluene sulfonic acid mono hydrate (0.54 g, 2.81 mmol) in toluene (250 mL) and heated to vigorous reflux for 3 hr. The mixture was cooled, diluted with EtOAc, washed with NaHCO3 (2×) and brine (1×). The organic phase was dried over Na2SO4, filtered through a silica plug and concentrated in vacuo. A crystalline solid formed on standing (14.47 g): 1H NMR (300.0 MHz, CDCl3) δ 8.12 (s, 1H), 7.97 (dd, J=2.7, 7.8 Hz, 1H), 6.08 (s, 1H), 1.33 (s, 3H) and 1.26 (s, 3H) ppm.