Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[N+:4]([C:7]1[C:12]2[N:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(#N)C>[N+:4]([C:7]1[C:12]2[NH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:1]#[N:2])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1cccc2c1N=C(c1ccccn1)CO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium cyanide (500 mg, 7 mmol) was added to a solution of 5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine (1 g, 4 mmol) (Example 70, Step 1), in acetonitrile (20 mL), and was stirred overnight at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The product was crystallized from methylene chloride to give 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile as a dark yellow powder (0.60 g. 60%). LCMS calculated for C14H11N4O3 (M+H)+: m/z=283.1. found: 282.9.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O1CCCC1>[C:26]1([O:25][C:23](=[O:24])[NH:1][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=2[C:13](=[O:14])[NH2:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCSc1nsc(N)c1C(N)=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide (2.2 g, 9.0 mmol) in 36 mL of tetrahydrofuran was added pyridine (0.90 g. 11 mmol) and phenyl chloroformate (1.7 g, 11 mmol). After stirring for 3 hours, additional pyridine (0.15 g, 1.9 mmol) and phenyl chloroformate (0.29 g, 1.9 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with water and extracted 2× with CH2Cl2 1× with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated for 12 hours with ether-hexane, and the resulting solids were collected and dried in vacuo, affording 2.6 g (79%) of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.41 (t, 2H, J=7.3 Hz), 7.29-7.20 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.50-1.30 (m, 4H), 0.90 (t, 3H, J=7.1 Hz) ppm; MS (APCI, m/z): 366 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O[CH2:10][C:11]1[CH:16]([C:17]([OH:19])=[O:18])[N:15]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]2[S:13][CH:12]=1)(=O)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:25]1([CH2:24][C:23]([NH:22][CH:21]2[C:20](=[O:32])[N:15]3[CH:16]([C:17]([OH:19])=[O:18])[C:11]([CH2:10][C:5]4[S:1][CH:2]=[CH:3][CH:4]=4)=[CH:12][S:13][C@H:14]23)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: c1ccsc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 3.4 g of thiophene in 200 ml of trifluoroacetic acid is mixed with 4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature and then mixed with an equal quantity of toluene, and the mixture is evaporated under reduced pressure. The residue is triturated with acetic acid ethyl ester and the solid material is twice crystallised from a mixture of methanol and acetic acid ethyl ester. 7-(N-Phenylacetyl-amino)-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid is thus obtained as colourless crystals, melting point 189°C; thin layer chromatogram (silica gel): Rf = 0.72 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.81 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.50 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol):λmax = 233 mμ (ε = 15400); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.73μ, 5.82μ and 6.05μ. A further quantity of the desired product can be obtained by concentrating the mother liquor and recrystallising the crystalline material.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[C:11]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(C)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a solution of methyl 3-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (103 mg, 0.25 mmol) in methanol (10 ml) was added NaOH (48 mg, 1.27 mmol). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (20.8 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH3:25][CH2:26][CH2:27][CH2:28]CC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (123.2 mg) was dissolved in tetrahydrofuran (3 ml), and the solution was then cooled to −78° C. A 1.56 M n-hexane solution (0.35 ml) of n-butyllithium was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (59.5 mg, yield 41%).
Reaction SMILES: C[Si](C)(C)[S:3][Si](C)(C)C.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:25]1[C:29]([NH:30][CH3:31])=[C:28]([CH:32]2[S:36][CH2:35][CH2:34][S:33]2)[C:27]([C:37]#[N:38])=[N:26]1>CN(C)C=O.CCOCC.O>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=[C:14]([Cl:13])[C:15]=1[N:25]1[C:29]([NH:30][CH3:31])=[C:28]([CH:32]2[S:33][CH2:34][CH2:35][S:36]2)[C:27]([C:37](=[S:3])[NH2:38])=[N:26]1
Reactant: CNc1c(C2SCCS2)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C[Si](C)(C)S[Si](C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c(C2SCCS2)c(C(N)=S)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To 1,1,1,3,3,3-hexamethyldisilathiane (0.157 g, 0.9 mmol) in dimethylformamide (4 mL) was added sodium methoxide (0.049 g, 0.9 mmol) and the resulting mixture was sonicated to provide a homogeneous blue colored solution. This resulting solution was added to the solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,3-dithiolan-2-yl)-5-(methylamino)-1H-pyrazole-3-carbonitrile (0.08 g, 0.2 mmol) in dimethylformamide (5 mL) at room temperature under nitrogen. This mixture was stirred at room temperature for one and half hour. It was then diluted with ether (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ether. The ethereal layers were combined and washed twice with water (2×20 mL), dried (Na2SO4), and concentrated to provide a yellow solid. Upon chromatographic purification via silica gel eluting with heptane:ethyl acetate (4:1 to 2:1), a yellow solid (0.048 g, 55%) was obtained. 19F-NMR: −63.634.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]=2)[CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([C:4]#[C:5][C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(C#CC2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C(#CC1CC1)C1=CCNCC1

Procedure:
To a rt solution of tert-butyl 4-(cyclopropylethynyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.344 g, 1.391 mmol) in 1,4-dioxane (4.0 mL) was added hydrogen chloride, 4.0 m solution in 1,4-dioxane (4.0 mL, 16.00 mmol) dropwise via syringe resulting in a dark brown solution. After 2 h the solvent was removed in vacuo and the residue was dissolved in DCM and washed with satd. NaHCO3. The organic solution was dried over MgSO4, filtered and concentrated to dryness to give 4-(cyclopropylethynyl)-1,2,3,6-tetrahydropyridine as a brown tar (186 mg, 91%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:30]=[N:31][C:32]([CH3:36])=[C:33](Br)[CH:34]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:8]5[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][CH:7]=5)[C:32]([CH3:36])=[N:31][CH:30]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: CNC(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cnc2C)cc1

Procedure:
4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)-N-methylbenzamide was prepared from 4-(methylcarbamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-])=O)=[C:7]([NH2:15])[CH:6]=[CH:5]2>C(O)C.[Ni]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:15])[C:8]=2[NH2:12])[CH:3]=1
Reactant: Nc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2cc(Br)ccc2c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a mixture of 6-bromo-1-nitronaphthalen-2-amine (11.6 g, 43.4 mmol) in ethanol (430 mL) under argon was added Raney Nickel (˜5 g, NOTE: no effort was made to remove the water from the nickel). Hydrogen gas was bubbled through the reaction mixture for 2 minutes. The reaction was stirred under an atmosphere of hydrogen at room temperature. After 16 hours, the Raney Nickel was removed by filtration over Celite and rinsed with ethyl acetate. The filtrate was thoroughly concentrated to yield 6-bromonaphthalene-1,2-diamine (9.2 g, 88% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:22]=[CH:21][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]O)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33][NH2:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:22]=[CH:21][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:34][CH2:33][C:32]4[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=4)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)ncn2-c1cccc(CO)c1
Reactant: NCc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)ncn2-c1cccc(CNCc2ccc(F)c(F)c2)c1

Procedure:
Compound 27 was prepared from compound 7 by the method described in Example 2. To a solution of compound 27 (3 g, 1.01 mmol) in DMF (30 ml) was added potassium carbonate (2 g; 1.45 mmol) and 3,4-difluorobenzylamine (1.43 ml; 1.2 mmol) and the resultant mixture was stirred at ambient conditions over night. Aqueous work-up followed by column chromatography afforded compound 28a (0.9 g). LC-ESI-HRMS of [M+H]+ shows 422.1697 Da. Calc. 422.167925 Da, dev. 4.2 ppm
Reaction SMILES: O[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.BrN1C(=O)CCC1=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>C(O)C>[NH:6]1[C:7]2[S:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:2]=2[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(O)c(=O)[nH]1
Reactant: Nc1ccccc1S
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: O=c1[nH]c2c(c(=O)[nH]1)Nc1ccccc1S2

Procedure:
Then, to a solution or suspension of a 5-hydroxypyrimidine-2,4(1H,3H)-dione derivative of formula (IV) in a reaction inert solvent is added N-bromosuccinimide portion-wise at room temperature. A preferred solvent is ethanol. The reaction mixture is stirred until the derivative of formula (IV) disappears. Then, a 2-aminobenzenethiol derivative of formula (V) is added and the mixture is heated at reflux. Certain 2-aminobenzenethiol derivatives of formula (V) are commercially available and, further, the derivatives of formula (V) can be prepared from the corresponding 2-aminobenzothiazoles by hydrolysis as described by Mital, R. L., et al., J. Chem. Soc. (c), 2148 (1969). When a precipitate results after reflux of the reaction mixture, the precipitate is collected to give a 1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione derivative of formula (I). When no precipitate is obtained after reflux, the derivative of formula (I) is obtained by chromatographic separation on silica gel. The foregoing method for reacting derivatives of formula (IV) with derivatives of formula (V) to yield derivatives of formula (I) is analogous to the method described by Sako, M., et al., Chem. Pharm. Bull., 32, 2474 (1984).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[CH:25][C:26]([CH:29]=O)=[N:27][CH:28]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:22][C:23]5[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(C=O)cn1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 5.16-5.05 (m, 1H), 4.02 (d, J=14.1 Hz, 1H), 3.74 (d, J=14.1 Hz, 1H), 3.45-3.41 (m, 1H), 3.38 (t, J=8.3 Hz, 1 Hz, 1H), 3.08 (d, J=9.9 Hz, 1H), 2.84-2.83 (m, 1H), 2.62-2.54 (m, 1H), 2.52 (s, 3H), 2.47-2.40 (m, 1H), 2.14-1.89 (m, 6H), 1.71-1.64 (m, 2H), 1.24-1.16 (m, 3H). MS: (M+H m/z=394.1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[CH:17](SC)[CH2:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([NH:2][CH2:4][CH2:5][O:9][CH3:8])=[CH:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(C[N+](=O)[O-])SC
Solvent: CC#N
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 55.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and 1,1-bis(methylthio)-2-nitroethane (1.65 g) were refluxed in acetonitrile for 8 hr. Solvents were removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) added. After refluxing for a further 8 hr, removal of solvents gave an oil. This was purified by column chromatography to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine (1.0 g). NMR τ(CDCl3) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH2:14][O:15][CH2:16][CH2:17][CH3:18])[N:10]=2)[C:6]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:21][C:5]=2[C:4](=[O:28])[N:3]1[CH:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:22]1([C:20]2[S:21][C:5]3[C:4](=[O:28])[N:3]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:2](=[O:1])[N:7]([CH2:8][C:9]4[O:13][N:12]=[C:11]([CH2:14][O:15][CH2:16][CH2:17][CH3:18])[N:10]=4)[C:6]=3[CH:19]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCOCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
To a solution of tert-butyl 4-[2,4-dioxo-6-phenyl-1-{[3-(propoxymethyl)-1,2,4-oxadiazol-5-yl]methyl]-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (500 mg, compound B69) in DCM (10 ml) is added trifluoroacetic acid (10 ml). After 1 h at RT all volatile materials are removed in vacuo. The residue is taken up in diethyl ether, the resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: FC(F)(F)C1C=C(C2ON=C([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)N=2)C=CC=1OC(C)C(F)(F)F.[H-].[Na+].C([Si](OCCI)(C)C)(C)(C)C.O>CN(C=O)C>[NH:25]1[C:26]2[C:22](=[CH:21][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[Si](C)(C)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 325.5 %

Procedure:
In a 50 ml reaction vessel, to a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) in DMF (1 ml) was added 60% NaH (10.9 mg) at 0° C. The solution was warmed to room temperature, followed by stirring for 0.5 hour. Further, tertiary-butyl (2-iodoethoxy)dimethylsilane was added thereto at 0° C., followed by stirring at room temperature for 15 hours. Completion of the reaction was confirmed by LC-MS, and then the reaction solution was added with water (30 ml). It was extracted three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. It was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=100:0 to 90:10) to obtain 1-(2-{[tertiary-butyl(dimethyl)silyl]oxy}ethyl)-4-{5-[3-(trifluoromethyl)-4-2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (86.4 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=C1CCc2cccc(O)c2N1
Product: O=C1CCc2cccc(OCCCCSc3ccccc3)c2N1

Procedure:
Prepared analogous to Example 4 from 8-hydroxy-3,4-dihydro-carbostyril (see J. D. Loudon et al., J. Chem. Soc. 1955, 743-744) and 4-phenylmercapto-butyl bromide (bp. 96°-103° C. at 0.02 mm Hg).
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:8])=[O:7])([CH3:5])[CH3:4].F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[CH:3]([S:6]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: COc1ccc(CNS(=O)(=O)C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cc(F)ccc2[N+](=O)[O-])S(=O)(=O)C(C)C)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
Suspend sodium hydride (60% in mineral oil, 0.85 g, 21.2 mmol) in tetrahydrofuran (100 mL). Add 1 N-[isopropylsulfonyl]-4-methoxy-benzylamine (4.73 g, 19.45 mmol) in tetrahydrofuran (400 mL) and heat to 70° C. Stir 10 minutes, then add 2,4-difluoronitrobenzene (3.2 mL, 29.2 mmol) in one portion and stir 18 hours at 70° C. Cool to ambient temperature and remove solvents under reduced pressure. Dissolve in ethyl acetate and wash twice with 1 N HCl aq., three times with saturated sodium hydrogen carbonate, saturated sodium carbonate, 1 N HCl aq., dry magnesium sulfate, filter and remove solvents under reduced pressure. Purify on silica gel with dichloromethane/hexane mixtures to give 5.395 g (72%) of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[CH:14]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1.O>C(Cl)Cl>[CH:14]1([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:10][O:11][CH3:12])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1
Reactant: COCCl
Reactant: Oc1ccc(C2CC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C2CC2)cc1
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (77.6 mL) and chloromethyl methyl ether (33.7 mL) were added to a solution of 4-cyclopropylphenol (24.0 g) in methylene chloride (250 mL) to form a reaction solution. This reaction solution was stirred for 15 minutes under ice cooling, and then left overnight at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with a 1 mol/L sodium hydroxide aqueous solution, water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure to obtain the target product (27.6 g) as a colorless oil.