Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[CH2:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Yield: 97.7 %

Procedure:
Treatment of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.3 g, 10.37 mmol) with sodium azide (3.03 g, 46.68 mmol) generally according to the procedure described for Intermediate 98 gave 2.91 g (98%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.29 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.3 g (76%) of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 222-224° C.; Anal calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found C, 60.65; H, 4.76; N, 4.51.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCSc1ncccc1CCl
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: CCCSc1ncccc1COc1ccc(C2CC2C(=O)O)cc1Cl
Yield: 69 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (47 mg, 0.23 mmol) obtained in Step C of Preparation Example 14 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (61 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60 mg, 73%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Si:25]([O:32][CH:33](Br)[CH3:34])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Br)O[Si](C)(C)C(C)(C)C
Reactant: CNc1ccc(-c2cc3ccc(O)cc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: CNc1ccc(-c2cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3s2)cc1
Temperature: 80 °C
Yield: 43 %

Procedure:
2-[4-(N-Monomethylamino)phenyl]-6-hydroxybenzothiophene (113, 1.56 g, 4.52 mmol) and potassium carbonate (1.88 g, 13.57 mmol) were dissolved in dimethylacetimide (40 mL), 1-(t-butyldimethylsilyloxy)ethyl bromide (TBDMSO-CH2CH2Br) (114, 1.08 g, 4.52 mmol) was added thereto, and the reaction mixture was heated at 80° C. for 24 hours. To the reaction mixture was added an aqueous solution of ammonium chloride, and organic compounds were extracted with ethyl acetate. The recovered organic solvent was washed with a brine solution and dried over sodium sulfate. Purification was performed by column chromatography to give 2-[4-(N-monomethylamino)phenyl]-6-[2-(t-butyldimethylsilyloxy)ethoxy]benzothiophene (115, 804 mg, 43%) as a yellow solid. The obtained target compound 115 had a melting point of 118-119° C., and the following physical data;
Reaction SMILES: [CH:1]([N:3]1[CH:12]([C:13](O)=O)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=O.[C:16]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[CH:18]=C1>C(OC(=O)C)(=O)C>[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][C:12]1[N:3]([CH:1]=[C:18]3[C:13]=1[C:16](=[O:27])[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:19]3=[O:26])[CH2:4]2
Reactant: O=CN1Cc2ccccc2CC1C(=O)O
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2C(=O)c2c1cn1c2Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-formyl-3-carboxy-1,2,3,4-tetrahydroisoquinoline (20 g) and 1,4-naphthoquinone (30.8 g) in acetic anhydride (500 ml) was heated at 100° C. with stirring for 30 minutes. The reaction mixture was cooled, the solid collected by filtration, washed with acetic anhydride (50 g) with ether (2×100ml) and dried to give the title compound in Form B (26 g).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:27])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O)[CH3:12]>>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:1]([C:3]2[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:2]=1)=[O:27])[CH3:12]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Reactant: COc1ccc(NN)cn1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)nc2)n1

Procedure:
The general procedure of Referential. Example 3-2) was repeated through use of the 5-hydrazino-2-methoxypyridine (1.0 g) prepared in Referential Example 2 and the 4-(4-fluorophenyl)-2,4-dioxobutanoic acid ethyl ester (1.88 g) prepared in Referential Example 134, to thereby give the title compound as an oily product (2.12 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:5]2[CH2:11][CH:12]=1.[S].BrBr>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: BrBr
Agent: [S]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)OC2=O
Yield: 16 %

Procedure:
Various processes are known for preparing substituted phthalic anhydrides. In two such processes 4-methyl-1,2,3,6-tetrahydrophthalic anhydride is dehydrogenated either by sulfur or by bromine in acetic acid. Yields of 4-methylphthalic anhydride of 59%-87% are claimed for the former method, while the latter gives only a 16% yield [see IZV. Akad Nauk SSSR, Ser Khim, 6, 1315(1973) English trans. Pg. 1271 and D. Craig, Journal of Am. Chem. Soc., Vol. 72, Pg. 3732 (1950)].
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]1([C:21]2[N:22]=[C:23]([SH:32])[NH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:32][C:23]2[NH:24][C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)N1CCCc2ccccc21
Yield: 26 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4,5-diphenyl-1H-imidazole-2-thiol as the nucleophile to yield 19 as a off-white solid (26%): MS m/z: 426 (M+H)+. Anal. Calcd. For, C26H23N3OS.0.2H2O: C, 72.77; H, 5.50; N, 9.79; S, 7.47. Found: C, 72.58; H, 5.33; N, 9.74; S, 7.48.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]=[CH:12][N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:6]=1[OH:16].C(O)(=O)C>O1CCOCC1.C(O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:6]=1[OH:16]
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC[N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To sodium borohydride (4.3 g) suspended in a mixture of dioxane (85 ml) and ethanol (25 ml) at +10 to +15° C. is added 2-methoxy-4-(2-nitro-vinyl)-phenol in a mixture of dioxane (110 ml) and ethanol (50 ml). Thereafter the reaction mixture is stirred at room temperature for 2 hours. Acetic acid (4.5 ml) in water (130 ml) is then added carefully. The resulting mixture is evaporated to at about half of its volume. It is extracted with ethyl acetate (2×500 ml) washed with brine (2×100 ml) dried (MgSO4) and evaporated. 2-methoxy-4-(2-nitro-ethyl)-phenol is obtained as an oil which is purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[N:11]=[C:10]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:24][C:10]1[N:11]=[C:12]([NH:14][S:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(4-morpholinylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of step i) (0.34 g), THF (8 mL) and 2M lithium borohydride in THF (1 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and ammonium acetate/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 0.25 g
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([O:40][CH3:41])[C:26]([N:27]3[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:42])(C)(C)C>>[NH2:32][CH:29]1[CH2:30][CH2:31][N:27]([C:26]2[C:25]([O:40][CH3:41])=[CH:24][C:21]3[C:22](=[O:23])[N:13]([OH:12])[C:14](=[O:42])[C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)[CH2:28]1
Reactant: COc1cc2c3c(cccc3c1N1CCC(NC(=O)OC(C)(C)C)C1)C(=O)N(OC(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c3c(cccc3c1N1CCC(N)C1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
Following the procedure from Example 62, TFA (1.0 mL) and [1-(2-tert-butyloxy-1,3-dioxo-2,3-dihydro-5-methoxy-1H-benzo[de]isoquinolin-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester (0.2 g, 0.4 mmol, from Example N2) was stirred at room temperature overnight, concentrated, and the solid recrystallized from ethanol/ether to give 0.02 g of the title compound, mp 217-222° C.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([CH2:3][OH:29])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)ccc2c(=O)c3c(F)cccc3oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c2ccc3c(c2oc2cccc(F)c12)CC(CO)O3
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A mixture of 4-allyl-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (1.4 g), m-chloroperbenzoic acid (1.2 g) and chloroform (250 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. After addition of potassium carbonate (2 g) and water (50 ml), the mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 1.2 g of 7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene. m.p. 220°-221° C. This compound gave a mass spectrum having a molecular ion peak at m/e 286.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.[NH2:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:38][C@@H:39]4[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Reactant: N[C@@H]1CCC[C@H](O)C1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(N[C@@H]2CCC[C@H](O)C2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide and 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and (1S,3R)-3-aminocyclohexanol (152 mg, 1.32 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (230.2 mg, 0.73 mmol, yield 66%). 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (s, 1H), 3.91-3.89 (m, 1H), 3.69-3.62 (m, 1H), 2.50 (s, 1H), 2.29-2.25 (m, 1H), 2.20 (s, 6H), 1.97-1.83 (m, 3H), 1.41-1.21 (m, 4H); MS (ESI) m/z=318.2 [M+1]+.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[C:10]1(C)[CH:15]=CC=C[CH:11]=1>>[CH3:15][C:10]1[N:3]=[N:2][N:1]([CH2:4][C:5]([OH:7])=[O:6])[CH:11]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1ccccc1
Product: Cc1cn(CC(=O)O)nn1
Temperature: 120 °C
Yield: 18 %

Procedure:
To a solution of 2.0 g (18 mmol) of 1-(trimethylsilyl)-1-proyne in toluene (20 mL) was added 2.3 g (18 mmol) of ethyl azido-acetate. The reaction mixture was heated at 120° C. overnight then cooled to ambient temperature. All volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a 5-25% acetone in hexanes gradient to yield the title compound as a colorless oil (0.77 g, 18%). 1HNMR (500 MHz, CDCl3): δ 5.01 (s, 2H), 4.2 (m, 2H), 2.25 (s, 3H), 1.22 (m, 3H), 0.295 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([Cl:43])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([Cl:43])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (30 ml), and to the solution, triacetoxy sodium borohydride (0.31 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (0.22 ml) and triacetoxy sodium borohydride (0.31 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give crude crystals, which were recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 6) (0.2 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(OCc2ccccc2)c2cccnc12
Yield: 65.8 %

Procedure:
In a similar fashion using route 19 general procedure 29, 5-benzyloxy-8-nitro-quinoline 564 (572 mg, 2.04 mmol), SnCl2 (1.84 g, 8.16 mmol), and EtOH (15 ml) gave the title compound (336 mg, 66%) which was used in the next step without further purification.
Reaction SMILES: C[NH:2][C:3]1[O:4][C:5]([C:8]2[N:9]([CH3:16])[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][N:12]=2)=[N:6][N:7]=1.CN1C([N+]([O-])=O)=CN=C1C(NNC(NC)=O)=O>>[NH2:2][C:3]1[O:4][C:5]([C:8]2[N:9]([CH3:16])[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][N:12]=2)=[N:6][N:7]=1
Reactant: CNc1nnc(-c2ncc([N+](=O)[O-])n2C)o1
Agent: CNC(=O)NNC(=O)c1ncc([N+](=O)[O-])n1C
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)o1

Procedure:
In similar fashion, 2-(2-methylamino-1,3,4-oxadiazol-5-yl)-1-methyl-5-nitroimidazole (XIIB) is prepared from 1-(1-methyl-5-nitro-2-imidazolecarbonyl)-4-methylsemicarbazide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]C)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COCCn1ccc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCn1ccc2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of methyl 1-(2-methoxyethyl)-1H-indole-5-carboxylate (132 mg, 0.57 mmol, Step-1), 2M aqueous sodium hydroxide solution (2 mL), and methanol (2 mL) was stirred at 60° C. for 2 hours. The mixture was acidified with 2M aqueous hydrochloric acid solution, and the organic solvent was concentrated under reduced pressure. The precipitate was collected by filtration and dried to give 118 mg (95%) of the title compound as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[C-:10]#[N:11].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC>C(#N)C.O>[C:10]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)#[N:11]
Reactant: Cc1cc(CO)ccn1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CC#N)ccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 62 %

Procedure:
To a stirred mixture of 4-hydroxymethyl-2-methyl-pyridine [CAS No. 105250-16-6] (3.37 g, 27.4 mmol), potassium cyanide (3.56 g, 54.7 mmol) and 18-crown-6 (0.72 g, 2.74 mmol) in acetonitrile (75 ml) was added dropwise at 15-20° C. a solution of tributylphosphine (7.16 g, 30.1 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for 25 h, poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (3×100 ml), brine (100 ml) dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 4-cyanomethyl-2-methyl-pyridine (2.26 g, 62%) as a brown oil.
Reaction SMILES: C1(C2C=CC=C(OC)C=2)CCCCC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C@:23]23[O:29][C@H:28]2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C@@:23]23[O:29][C@@H:28]2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc([C@@]23CCCC[C@@H]2O3)c1
Agent: COc1cccc(C2=CCCCC2)c1
Product: COc1cccc([C@]23CCCC[C@H]2O3)c1

Procedure:
Prepared in a similar manner from 1-Cyclohex-1-enyl-3-methoxy-benzene as described for (S,S)-1-(3-Methoxy-phenyl)-7-oxa-bicyclo[4.1.0]heptane above using (S,S)—Mn(salen) as catalyst. The enantiomeric excess was 92.36%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][C:19]1[C:20]2[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:21]=2[S:22][CH:23]=1.COC(=O)CC1C2C=CC=C(OCC3C=C(C4C=CC(Cl)=CC=4)ON=3)C=2SC=1>>[CH3:28][C:26]1[C:25]([O:29][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[O:5][N:4]=2)=[CH:24][C:21]2[S:22][CH:23]=[C:19]([CH2:18][C:17]([OH:30])=[O:16])[C:20]=2[CH:27]=1
Reactant: COC(=O)Cc1csc2cc(O)c(C)cc12
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Agent: COC(=O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1cc(-c2ccc(Cl)cc2)on1

Procedure:
The title compound was prepared from commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and compound 78C in a manner analogous to compound 77C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60.6 %

Procedure:
To a cooled (0° C.) solution of 4-hydroxymethylpiperidine-1-carboxylic acid, 1,1-dimethylethyl ester (Example 36; 0.82 g, 3.8. mmol) and triethylamine (2.75 mL, 19.76 mmol) in dichloromethane (20 mL) was added sulfur trioxide pyridine complex (2.42 g, 15.2 mmol) in dimethylsulfoxide (10 mL) in three portions and the reaction was stirred at 0° C. for 3.5 h. Examination of the reaction by tlc indicated that some starting alcohol remained, so an additional quantity of sulfur trioxide pyridine complex (1.21 g, 7.6 mmol) in dimethylsulfoxide (5 mL) was added and the reaction was allowed to proceed for another 2 h at 0° C. The reaction mixture was partitioned between saturated sodium bicarbonate solution (60 mL) and diethyl ether/hexane (1:2, 125 mL) and the separated aqueous phase was re-extracted with diethyl ether/hexane (1:2, 2×50 mL). The combined organic extracts were washed with a 1M sodium dihydrogen phosphate solution (50 mL) and with brine (50 mL), then were dried (MgSO4), filtered and evaporated in vacuo. The resulting residual material was chromatographed over silica gel (25% ethyl acetate/petroleum ether) to give 4-formylpiperidine-1-carboxylic acid, 1,1-dimethylethyl ester (0.492 g, 61% yield) as a colorless oil.