Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:26]/[C:27](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:28]\[CH2:29][OH:30]>[N+](C)([O-])=O>[CH3:26]/[C:27](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:28]\[CH:29]=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: C[N+](=O)[O-]
Product: CC(C)=CCC/C(C)=C/C=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
6.1 mg (0.02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.37 g (0.6 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 154 mg (1 mmol) of (E)-3,7-dimethylocta-2,6-dien-1-ol were added to 5 ml of nitromethane, and the mixture was heated at 70° C. while being stirred under a nitrogen for two hours. The later treatment was carried out in the same way as in Example 1, and then (E)-3,7-dimethylocta-2,6-dienal was obtained. The yield of the obtained (E)-3,7-dimethylocta-2,6-dienal was determined and the result is shown in Table 2. (Yield: E:Z=16:1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[OH-:18].[Na+]>C(O)C>[OH:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CCCCCCCO)c1ccc(Cl)cc1

Procedure:
To 8-bromo-1-(4-chlorophenyl)octan-1-one (4.0 g) in ethanol (170 ml) was added 3% aqueous sodium hydroxide (70 ml). The mixture was heated at reflux for 3 h, cooled and evaporated to one third volume. Water (50 ml) and dichloromethane (100 ml) were added. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (2×50 ml). The combined extracts were washed with water (30 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was crystallised from 40-60° C. petroleum ether to give 8-hydroxy-1-(4-chlorophenyl)octan-1-one (1.0 g). 1H-NMR (CDCl3) δ 1.25-1.9 (10H, m), 2.94 (2H, t), 3.64 (2H, t), 7.43 (2H, m) and 7.89 (2H, m). (EI) Found M+=254. C14H19ClO2 requires 254.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.Br[CH2:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[O:41][C:40](=[O:45])[CH:39]=[CH:38]2.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[O:41][C:40](=[O:45])[CH:39]=[CH:38][C:37]=3[CH:36]=2)[C:13](=[O:21])[CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[N:11]=1
Reactant: O=c1ccc2cc(CBr)ccc2o1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1ccc2oc(=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a suspension of sodium hydride (0.11 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (20 ml) was added gradually (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. The mixture was cooled in an ice-bath and a solution of 6-bromomethyl coumarin (0.66 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto. The mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture was added acetic acid (0.5 g) under cooling in an ice-bath. The resultant mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) under stirring. The mixture was adjusted to pH 7.5 with sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with a brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel (eluent : CHCL3) to afford (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-one as a colorless crystalline solid (1.30 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.FC(F)(F)C(O)=O.N1C=CC=CC=1.C(O)(=O)C(O)=O>CS(C)=O.C1C=CC=CC=1.CCOCC.CO.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH:12]=[O:13])[CH:3]=1
Reactant: Cc1cn(CCO)c2ccccc12
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CO
Product: Cc1cn(CC=O)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-dicyclohexylcarbodiimide (9.0 g) is added to a cooled, stirred solution of 3-methylindole-1-ethanol (3.0 g) in 30 ml of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid (0.6 ml) and pyridine (1.12 ml). The reaction is stirred at room temperature under nitrogen for 5 hours. The reaction mixture is now diluted with 300 ml of ether, followed by the dropwise addition of a solution of oxalic acid (3.78 g) in 11 ml of methanol. After 30 minutes, water (300 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2 X) and water (2X). After drying (MgSO4) the organic phase is evaporated to yield 3-methylindole-1-acetaldehyde. The latter compound is then converted to its corresponding gem-dithiol with hydrogen sulfide and reduced with lithium aluminium hydride according to the method of T. L. Cairns et al., J. Amer. Chem. Soc., 74, 3982 (1952), to yield the title compound, γ maxCHCl3 2570 cm-1.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[N:11]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:10](=[O:35])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:42]=1[CH3:43].CC1C=C(C)C(P(C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)=CC=1S([O-])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.CC(O)=O.CC(O)=O.[Pd].O>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][C:42]=5[CH3:43])[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:10](=[O:35])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccncc1Br
Reactant: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(B(O)O)c3)CC2)N1c1cccc(F)c1
Agent: [Pd]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])cc1P(c1cc(S(=O)(=O)[O-])c(C)cc1C)c1cc(S(=O)(=O)[O-])c(C)cc1C
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1ccncc1-c1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 120 °C

Procedure:
To a solution of 0.100 g (0.209 mmol) 3-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}phenylboronic acid (7-1) in 1 mL CH3CN:H2O was added 0.030 g (0.174 mmol) 3-bromo-4-methylpyridine and 0.007 g (0.011 mmol) Tris(4,6-dimethyl-3sulfonatophenyl)phosphine and 0.001 g (0.004 mmol) palladium II acetate and 0.037 g (0.349 mmol) sodium carbonate. The reaction was heated in the microwave at 120° C. for 20 mins. Purification by preparative HPLC (5-95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 PRO YMC 20×150 mm) afforded 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-[3-(4-methylpyridin-3-yl)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one as a white solid. NMR 1H NMR (CD3OD) δ 8.37 (d, J=5.04 Hz, 1H), 8.29 (s, 1H), 7.42 (m, 3H) 7.19 (m, 6H), 3.76 (m, 1H), 3.47 (s, 2H), 2.77 (m, 2H), 2.29 (s, 3H), 2.14 (m, 6H), 1.95 (m, 2H), 1.77 (m, 2H), 1.66 (m, 1H), 1.36 (m, 4H), 1.18 (m, 1H). High resolution mass spec (FT/ICR) calc M+H=526.2977 found 526.3012.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][NH2:24]>>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:24][CH3:23])[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Reactant: CN
Product: CNCc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1

Procedure:
In a manner analogous to Example 70, 0.8 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-y]-2,6-bis(1,1-dimethylethyl)phenol is reacted with excess monomethylamine gas to give 0.2 g (31%) of analytically pure 2,6-bis(1,1-dimethylethyl)-4-[3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl]phenol, mp 120°-122° C.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Cc1cc(C(=O)O)cc(N)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (413 mg, a brown solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (422 mg, 1.6 mmol, Amine-1, single enantiomer) and 2-amino-6-methylisonicotinic acid (250 mg, 1.6 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31]O)[CH:8]=2)[N:3]=1.S(Cl)([Cl:35])=O>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31][Cl:35])[CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of thionyl chloride are added to 2 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone, and the mixture is stirred at 25° C. for 1 h. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up a further twice with 50 ml of dichloromethane each time, and the mixture is again evaporated to dryness in vacuo.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC2C=CC=CC=2)[C:5](=[O:23])[CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:22])[C:5](=[O:23])[CH2:4]1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Product: CS(=O)C1CC(=O)N1CC(=O)c1ccccc1
Yield: 80 %

Procedure:
Substituting 4-methylthio-1-phenacyl-azetidin-2-one (0.53 g, 2.25 mmol) for 4-methylthio-1-(9-phenyl-2-oxononyl)azetidin-2-one and using corresponding molar quantities of mCPBA as for Examples 5 and 6 gave 4-methylsulphinyl-1-phenacylazetidin-2-one (Example 8) as a waxy white solid (0.45 g, 80%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:26]#[N:27]>ClCCl>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCOCC1
Reactant: COc1ccc(C#N)cc1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C#N)cc1OCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g 3-Morpholine-4-yl-propan-1-ol was dissolved in dichloromethane, cooled to 0° C., 3.25 mL methanesulfonylchloride was added and the mixture was stirred for 2 h at ambient temperature. Then 7 g potassium carbonate and 3-hydroxy-4-methoxybenzonitrile were added and the reaction was stirred at 45° C. for 3 h. The mixture was concentrated and 70 mL dimethylacetamide was added and stirred at 120° C. for 3 h. After this time, the mixture was diluted with dichloromethane and extracted with water, the organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][CH3:24])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC=O
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Solvent: CCOC(C)=O
Product: CCCCC(O)C(C(=O)OCC)c1nsc(NC(=O)OC(C)(C)C)n1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 1.1 g (~10 mMol) of n-pentanal for 9 days in the manner described in Example 29 and, after aqueous work-up, the product was isolated from the ethyl acetate extract. A 1:1 mixture of the erythro and threo forms resulted.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1>>[Cl-:2].[Cl-:2].[CH3:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: COc1ccc(C(=O)c2ccccc2)cc1
Product: [Cl-]

Procedure:
The reaction was proceeded by the method described in Example 1. 10.4G of PCl5 was reacted with 10.6 g of 4-methoxybenzophenone to give 10.6 g(purity 89%, yield 70%) of 4-methoxybenzophenone dichloride as a tan liquid.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([C:8]1[O:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1coc(Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1coc(Cc2ccccc2)n1

Procedure:
Hydrolysis of this ester with a solution of sodium hydroxide in methanol at 15° C. gives 20.5 of 2-benzyl-oxazole-4-carboxylic acid, melting point 155°-156° C., which, when decarboxylated with copper powder at 210°-220° C., gives 12.5 g of 2-benzyloxazole, boiling point 134°-136°/25 mm Hg; nD25 1.5395.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]1C(=O)C1C=CC=CC=1)#N.[CH2:28]([C:32]1[CH:39]=[CH:38][C:35](CCl)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]>O>[CH2:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]
Reactant: N#CC1c2ccccc2C=CN1C(=O)c1ccccc1
Reactant: CCCCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ccc(Cc2nccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a dimethylformamide (1.8 ml) solution of 60% sodium hydride (16 mg, 0.40 mmol), a dimethylformamide (3.6 ml) solution of 1-cyano-2-benzoyl-1,2-dihydroisoquinoline (100 mg, 0.38 mmol) synthesized according to the literature of Org. Synth., VI, 115(1988), and 4-n-butylbenzylchloride (70 mg, 0.38 mmol) was added dropwise under nitrogen atmosphere at −16° C., and was further stirred at room temperature for 30 minutes. Water was added, this was concentrated, and toluene and water were added to this residue. The toluene layer was washed with water, dried over potassium carbonate, and concentrated. To an ethanol (1.6 ml) solution of the residue, 50% aqueous sodium hydroxide solution (0.63 ml) was added, and this was refluxed for 2 hours. After concentration, toluene and water were added. The toluene layer was washed with water, then dried over calcium carbonate, and then concentrated. The residue was purified by silica gel column chromatography to give 18 mg of the aforementioned compound of the formula (Ia).
Reaction SMILES: [CH3:1][S:2]Cl.[Na].[OH:5][C:6]1[CH:11]=[C:10]([CH3:12])[O:9][C:8](=[O:13])[CH:7]=1>C(Cl)Cl>[OH:5][C:6]1[CH:11]=[C:10]([CH3:12])[O:9][C:8](=[O:13])[C:7]=1[S:2][CH3:1]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CSCl
Agent: [Na]
Solvent: ClCCl
Product: CSc1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
Methanesulfenyl chloride (21.6 g., 0.261 mol) dissolved in methylene chloride (100 ml.) was added to a rapidly stirred slurry of the monosodium salt of 4-hydroxy-6-methyl-2-pyrone (38.6 g., 0.261 mol) in methylene chloride (500 ml.) over a period of 35 minutes. The reaction temperature was maintained at 25°C. with cooling during the addition; then stirring was continued at ambient temperature for 4 hours. The methylene chloride was removed by distillation in vacuo and the residue triturated with water (200 ml.) to remove the by-product sodium chloride. The crude product was removed by filtration, 26.0 g., m. 127°-134°C., 58 percent yield; after recrystallization from 2-propanol, 17.2 g., m. 139°-140.5°C., 38 percent yield
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]([CH2:12][O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH2:12][O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: COC[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COC[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-serinamide (736 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (766 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:15][C:16]([CH3:24])=[CH:17][C:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:15][C:16]([CH3:24])=[CH:17][C:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1

Procedure:
5-Chloro-1,3-dihydroindol-2-one (61 mg, 0.36 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (66 mg) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([NH:20][C:21](=O)[CH3:22])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:20][CH2:21][CH3:22])([CH3:19])[CH3:18])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)NC(C)(C)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(C)(C)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)propan-2-yl)acetamide (417 mg, 1.1 mmol) was dissolved in THF (40 ml). This solution was refluxed and 10 M borane dimethyl sulfide complex (165 μl, 1.65 mmol) was added slowly to the refluxing mixture. The reaction mixture was refluxed for 2.5 hr. Next, 0.5 ml 6 M hydrochloric acid solution was added and after stirring at reflux for 5 min it was cooled to room temperature. Next 3M sodium hydroxide solution was added, followed by water and the material was extracted with ethyl acetate. It was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography 0-10% MeOH in DCM to give 5-Bromo-3-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-1H-pyridin-2-one (73 mg, 18%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.18 Hz, 3 H) 1.70 (s, 6 H) 2.67 (m, 2 H) 3.52 (s, 3 H) 7.44 (d, J=9.06 Hz, 1 H) 7.58 (d, J=2.27 Hz, 1 H) 7.86 (dd, J=8.69, 2.64 Hz, 1 H) 8.45 (d, J=2.64 Hz, 1 H) 8.73 (d, J=2.64 Hz, 1 H) 8.76-8.88 (m, 1 H) 8.99 (s, 1 H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@H](C)N3C(C)=O)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(N)cn2)C[C@H](C)N3C(C)=O)nc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a flask charged with ethyl 6-((2S,4R)-1-acetyl-2-methyl-4-((5-nitropyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (for a preparation see Intermediate 25)(780 mg, 1.640 mmol), ammonium formate (1034 mg, 16.40 mmol) and palladium on carbon (10% Pd/C) (160 mg, 1.503 mmol) was added ethanol (15 ml) and the resulting mixture was refluxed for 45 min. The reaction was cooled to room temperature, filtered through Celite™, the residue washed with EtOH and the combined filtrate and washings concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with a MeOH/DCM gradient; which gave ethyl 6-((2S,4R)-1-acetyl-4-((5-aminopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (450 mg, 1.010 mmol, 61.6% yield) as a pink foam. LCMS (HpH, 2 min), Rt=0.93 min, MH+=446.
Reaction SMILES: Br[CH2:2][C:3]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][OH:14]>F[B-](F)(F)F.[Ag+]>[Cl:12][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH2:2][O:14][CH3:13])[N:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: N#Cc1c(Cl)cc(Cl)nc1CBr
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COCc1nc(Cl)cc(Cl)c1C#N
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dichloronicotinonitrile (378.9 mg, 1.425 mmol) in MeOH (5.0 ml) was charged with silver(I) tetrafluoroborate (360 mg, 1.849 mmol) and stirred at 50° C. for 17 hr. LCMS showed conversion to the desired mass. The mixture was concentrated in vacuo and purified via flash chromatography (15-60% Et2O/Hexane) to provide 4,6-dichloro-2-(methoxymethyl)nicotinonitrile. MS ESI calc'd for C8H7C12N2O [M+H]+ 217. found 217.