Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])[CH3:6])[CH2:2][CH2:3][CH3:4].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([N:5]([C:7]([NH:21][CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)=[CH:8][N+:9]([O-:11])=[O:10])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=C[N+](=O)[O-])SC
Reactant: NCc1cccnc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCN(C)C(=C[N+](=O)[O-])NCc1cccnc1
Yield: 55 %

Procedure:
A mixture of 5.2 g of 2-(N-n-butyl-N-methylamino)-2-methylthio-1-nitroethylene, 2.84 g of pyridin-3-ylmethylamine and 3.69 g of disodium hydrogen phosphate in 30 ml of ethanol is refluxed for 1 hour. After removing the salt by filtration, the solvent is evaporated from the solution under vacuum and the residue is chromatographed through a column of silica gel with a 95/5 mixture of ethyl acetate/methanol. The product is eluated with ethylacetate/methanol (85/15). The solvent is removed by evaporation, affording 3.7 g of 2-(N-n-butyl-N-methylamino)-2-(pyridin-3-ylmethylamino)-1-nitroethylene as a viscous oil (Compound 3.2, Table 3).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 15b as the starting material afforded the title compound (35 mg, 73% yield) as a white solid:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:13])[C:10]([OH:12])=[O:11])=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])#[N:2].[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:13])[C:10]([O:12][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:11])=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])#[N:2]
Reactant: COCCOCOc1c(C#N)ccc(C(Br)C(=O)O)c1OCOCCOC
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COCCOCOc1c(C#N)ccc(C(Br)C(=O)OC(c2ccccc2)c2ccccc2)c1OCOCCOC

Procedure:
The product of Step A was dissolved in 10 ml of methylene chloride and 470 mg of diphenyl diazomethane were added. Evaporation was carried out followed by chromatography on silica (eluant: cyclohexane-ethyl acetate (2-1)) to obtain 450 mg of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:7][C:8]=1[CH3:9])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:25])[N:5]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:26])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1c(C)nc(-c2ccccc2O)n(CCc2ccccc2)c1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(C)nc(-c2ccccc2OC)n(CCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of 5-ethyl-2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one (0.19 g, 0.50 mmol) was dissolved in THF (10 mL) that contained potassium carbonate (0.80 g) and iodomethane (3 mL). The mixture was refluxed for 40 h under an argon atmosphere. After cooling to room temperature, hexanes (100 mL) were added and the salts were filtered off. The filtrate was evaporated in vacuum, and the residue was purified by flash chromatography on silica gel (40 g) eluting with ethyl acetate-hexanes (2:3) to give 5-ethyl-2-(2-methoxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one (110 mg, 56%) as a white solid after final crystallization from hexanes.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C@@H:12]([OH:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CS(C)=O>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 5.9 %

Procedure:
To a stirred suspension of 3β-tert-butyldimethylsilyloxyandrostane-6α,17β-diol (EP 0825197 A2, 6.21 g) in DMSO (160 mL) IBX (16.45 g) was added at room temperature. After 1.5 h the mixture was quenched at room temperature by addition of H2O (300 mL). After 15 min the mixture was filtered and the cake was washed with H2O. The cake was extracted with Et2O (4×). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 3β-tert-butyldimethylsilyloxy-androstane-6,17-dione (0.36 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.54 (m, 1H), 2.47-1.08 (m, 20H), 0.84 (s, 9H), 0.77 (s, 3H), 0.66 (s, 1H), 0.01 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)(O)[O-].[Na+].C(#N)C>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.O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: Ic1ccc2nccn2c1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2nn3c(c2-c2ccc4nccn4c2)CCC3)nc1
Yield: 71.9 %

Procedure:
Add tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) to a 2 L flask containing a solution of 6-iodo-imidazo[1,2-a]pyridine (6.16 g, 25.2 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 6.07 g, 26.5 mmol), and sodium bicarbonate (4.24 g, 50.5 mmol) in 2.5:1 acetonitrile:water (700 mL). Reflux the reaction mixture for 3 h, cool, concentrate to about one half of the volume, extract into dichloromethane (4×250 ml), and concentrate. Flash chromatography using a gradient from 100% hexanes to 100% ethyl acetate (10 min, 45 ml/min), followed by isocratic 100% ethyl acetate (2 L), removes most impurities. Elution with ethyl acetate/methanol mixtures followed by tituration in hot ethyl acetate affords the title compound as a white solid 5.46 g, (72%). MS ES+ m/e 301.9 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.39 (d, J=3.2 Hz, 1H), 7.87 (s, 1H), 7.81-7.76 (m, 2H), 7.51 (d, J=1.2, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.26 (m, 1H), 7.05 (dd, J=9.2, 2 Hz, 1H), 4.2 (t, J=6.6 Hz, 2H, 2.99 (t, J=6.6 Hz, 2H), 2.59 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1)C.O.[OH-].[Li+]>C1COCC1.O>[S:15]1[CH2:16][CH2:17][N:18]=[C:14]1[S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)CCc1ccccc1SC1=NCCS1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccccc1SC1=NCCS1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 250 mg of 2-(2-thiazolinylthio)hydrocinnamic acid ethyl ester, 36 mg of lithium hydroxide monohydrate and 5 ml of THF/water 9:1 is stirred at room temperature for 5 days and then concentrated to dryness by evaporation. The residue is taken up in water, washed with ethyl acetate, adjusted to pH 5 with 0.5N HCl and extracted with ethyl acetate. The extracts are washed with water, dried with sodium sulphate, concentrated by evaporation and chromatographed on silica gel with eluant R. Rf (R)=0.22.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:11])[S:5]([NH:8][O:9][CH3:10])(=[O:7])=[O:6].Cl[S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])=[O:14].Cl>CCCCCC.C1COCC1>[CH3:3][N:4]([CH3:11])[S:5]([N:8]([S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])=[O:15])[O:9][CH3:10])(=[O:7])=[O:6]
Reactant: CONS(=O)(=O)N(C)C
Reactant: O=C(NS(=O)(=O)Cl)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CON(S(=O)(=O)NC(=O)Oc1ccccc1)S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2.69 g (61.5 mmol) of 55% sodium hydride was washed with n-hexane and then suspended in 100 ml of dry THF. Then, 4.62 g (30 mmol) of N,N-dimethyl-N'-methoxysulfamide dissolved in 20 ml of THF was dropwise added thereto under cooling with ice. The mixture is heated to room temperature and then stirred at room temperature for one hour. Then, this reaction mixture was again cooled with ice, and 7.07 g (30 mmol) of phenyl N-chlorosulfonylcarbamate dissolved in 30 ml of dry THF was dropwise added thereto. The mixture was heated to room temperature and then stirred at room temperature for 30 minutes. The reaction mixture was poured into 500 ml of ice water containing 6.4 g of 35% hydrochloric acid and extracted three times with 80 ml of diethyl ether. The extract solution was washed three times with 100 ml of water and once with 100 ml of a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 10.1 g of phenyl N-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonyl]carbamate as slightly yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[C@H:20]([C@H:21]([OH:33])[C@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1cc(F)cc(F)c1)[C@@H](O)[C@@H]1CO[C@@H](CCC(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add acetic anhydride (25 μL, 0.264 mmol) to a solution of 5-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (107 mg, 0.240 mmol) and triethylamine (37 μL, 0.267 mmol) in tetrahydrofuran (5 mL) and stir at room temperature for 18 hours. Concentrate and purify (silica gel chromatography, eluting with 80:20 ethyl acetate:dichloromethane), to separate the two title compounds 5-(R)-[2-(S)-acetylamino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (0.141 g, 59%) and 5-(S)-[2-(R)-acetylamino-3-(3,5-difluorophenyl)-1-(R)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (25.1 mg, 22%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:28])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]3[CH:21]([CH2:25][CH2:26]O)[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH2:26][CH2:25][CH:21]1[C:19]2[NH:20][C:16]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:14]=3[N:15]=[C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([CH3:28])=[N:8]4)=[CH:17][C:18]=2[C:23](=[O:24])[NH:22]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(CCO)NC4=O)c2nc1NC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CCN=[N+]=[N-])NC4=O)c2nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a suspension of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(2-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (462) (149 mg, 0.39 mmol) in 5 mL of DCM at 0° C. was added TEA (0.27 mL, 1.96 mmol) followed by methanesulfonyl chloride (33.4 μL, 0.43 mmol). It was stirred at 0° C. for 30 min, diluted with 30 mL of DCM, washed sequentially with 5 mL of water, 5 mL of sat NaHCO3 and 5 mL of brine. The DCM solution was dried over Na2SO4 and concentrated. The brown residue was dissolved in 1 mL of DMF and treated with sodium azide (80 mg, 1.24 mmol). The mixture was heated in an oil bath at 70° C. for 45 min. It was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with 2×5 mL of water. The EtOAc solution was concentrated and purified on a silica gel column (2-8% MeOH in DCM) to give 6-(2-azidoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (463a, 97 mg, 0.24 mmol, 61% yield). m/z (ESI, +ve) 405 (M+H)+. To a solution of 6-(2-azidoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (463a, 97 mg, 0.24 mmol) in 3 mL of THF and water (43.2 μl, 2.39 mmol) at RT was added trimethylphosphine (0.36 mL of 1 M in THF, 0.36 mmol). It was stirred at RT for 30 min, then diluted with 50 mL of EtOAc, and washed with 5 mL of water. The organic layer was concentrated and the residue was purified on a silica gel column (5% MeOH in DCM followed by 5% of 2 M NH3 in MeOH in DCM) to provide 6-(2-aminoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (463) (68 mg, 0.18 mmol, 75% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (1H, dd, J=7.4, 1.4 Hz), 7.71 (1H, s), 7.57-7.67 (1H, m), 7.35 (1H, t, J=7.7 Hz), 6.84 (1H, s), 5.99 (1H, s), 4.57 (1H, dd, J=8.4, 4.1 Hz), 3.41 (3H, br.), 2.64-2.77 (2H, m), 2.56 (3H, s), 1.92 (1H, dd, J=13.3, 4.3 Hz), 1.57-1.65 (1H, m), 1.55 (9H, s). m/z 379.1 (ESI, +ve) (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:14][C@H:15]([O:17][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
To a solution of 2.8 g (7.8 mmol) (3R,5R)-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylic acid benzyl ester in 70 ml dry THF were consecutively added 1.0 g (8.5 mmol) benzoic acid, 1.7 g (8.5 mmol) diethyl azodicarboxylate and 2.2 g (8.5 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 2.8 g (78%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[OH:20][C:21]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:21]3([OH:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)CC1(O)CCCCC1
Product: O=C(CC1(O)CCCCC1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(1-hydroxycyclohexyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 9.29 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.52-8.57 (m, 1H), 7.82-7.93 (m, 2H), 7.70-7.72 (m, 1H), 7.62 (s, 1H), 7.50 (dd, J=5.0, 1.4 Hz, 1H), 2.62 (s, 2H), 1.79-1.90 (m, 3H), 1.65-1.74 (m, 2H), 1.52-1.65 (m, 5H), 1.28-1.38 (m, 1H)); MS (APCI+) M/Z 413 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Product: Oc1ncnc2cc(F)ccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
2-Amino-4-fluorobenzoic acid (1.55 g, 10 mmol) in formamide (5 mL) was heated to 150° C. for 6 h. The mixture was cooled to room temperature with stirring. The precipitate was filtered out and washed with ethyl ether to give 1.3 g of 7-fluoroquinazolin-4-ol (78%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:10]=2)[C:6]([CH3:14])([CH3:15])[C:7]1=[O:13])[CH3:12]
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(O)c1cccnc1
Product: CCN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-1-ethyl-3,3-dimethylindolin-2-one (G. Georges et al., US2006/142247 A1) and nicotinic acid. The title compound was obtained as white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.N1C=CC=CC=1>C(OCC)C>[C:6]12([NH:16][C:3](=[O:4])[CH2:2][Cl:1])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCl)NC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of chloroacetyl chloride (1.6 mL, 20 mmol) in anhydrous diethyl ether (10 mL) was added dropwise within 5 min to a solution of 1-adamantanamine (3.0 g, 20 mmol) and pyridine (1.63 mL, 20 mmol) in anhydrous diethyl ether (40 mL) at 0° C. The yellow suspension was stirred for 1 h at that temperature. The precipitate was removed by filtration and washed by diethyl ether (10 mL). The combined organic solution was washed with HCl (2 N, 2×15 mL), followed by sat. NaHCO3 (15 mL), sat. NaCl (15 mL) solutions and dried with Na2SO4. The solvent was removed at reduced pressure and the residue was recrystallized from diethyl ether-hexanes to afford N-(1-adamantyl)chloroacetamide (1.551 g, 34%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: Cc1ccccc1CC1(N)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccccc1CC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 161 mg (1 mmol) 1-(2-methyl-benzyl)-cyclopropylamine. Yield: 60 mg (16%, trifluoroacetate); mass spectroscopy: [M+H]+=369.
Reaction SMILES: [OH-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[N:37]=[C:26]3[CH:27]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH2:28][CH2:29][CH2:30][N:25]3[N:24]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:21]=[CH:22]/[C:23]2[N:37]=[C:26]3[CH:27]([CH:31]4[CH2:32][CH2:33][N:34]([C:3](=[O:5])[CH3:4])[CH2:35][CH2:36]4)[CH2:28][CH2:29][CH2:30][N:25]3[N:24]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C(C)=O)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A 1 N sodium hydroxide solution (0.5 ml) and acetyl chloride (14 ul) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (25 mg) in methylene chloride (0.5 ml), and the reaction solution was stirred at room temperature for 40 minutes. Chloroform was added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with chloroform twice. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 25 mg of racemic 1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethanone. Then, the racemate was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 27 minutes and positive optical rotation (7.4 mg; 100% ee) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (6.7 mg; 97% ee)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[Sn](C)(C)[C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=1>O1CCOCC1.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>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=1
Reactant: Clc1nc2ccccc2s1
Reactant: C[Sn](C)(C)c1ccc(C(N)=O)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2nc3ccccc3s2)cn1
Temperature: 160 °C
Yield: 29.1 %

Procedure:
A mixture of 2-chloro-1,3-benzothiazole (38 μL, 0.31 mmol), 5-(trimethylstannyl)pyridine-2-carboxamide (97 mg, 0.34 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in dry dioxane (2 mL) was heated under argon to 160° C. for 30 min in a microwave reactor. The precipitate was filtered off. Flash chromatography (DCM/MeOH 99:1→DCM/Acetone 1:1) gave the title compound (23 mg) as a white solid. 1H NMR δ 9.31 (dd, 1H) 8.63 (dd, 1H) 8.27 (br s, 1H) 8.26-8.19 (m, 2H) 8.16 (d, 1H) 7.83 (br s, 1H) 7.64-7.59 (m, 1H) 7.57-7.52 (m, 1H); MS m/z (M+H) 256.