Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26](Cl)[O:27][CH3:28])(=[O:24])=[O:23]>O1CCCC1.CCCCCC>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]([O:27][CH3:28])[NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)(=[O:24])=[O:23]
Reactant: COC(Cl)=NS(=O)(=O)c1ccccc1C
Reactant: Cc1cc(C)nc(N)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1ccccc1C)Nc1nc(C)cc(C)n1
Reaction time: 0.25 h

Procedure:
To 1.2 g of 2-amino-4,6-dimethylpyrimidine in 50 ml of tetrahydrofuran is added 6.85 ml of 1.6 molar n-butyl lithium in hexane at 0°. The mixture is stirred for 15 minutes. To this solution is added dropwise, a solution of 2.1 g of methyl N-(2-methylphenylsulfonyl)carbonimidochloridate in 5 ml of tetrahydrofuran at 0°-10°. This reaction mixture is stirred for 30 minutes at 0°-10° and 30 minutes at ambient temperature. The reaction mixture is filtered and the solvent is stripped from the filtrate under reduced pressure to yield a crude product. The crude product is further purified via dry column chromatography on silica gel with ethyl acetate as the eluent. Pure N'-(2-methylphenylsulfonyl)-N-(4,6-dimethylpyrimidin-2-yl)carbamimidic acid, methyl ester is obtained.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl.CO>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:3]([C:5]2[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][N:6]=2)=[O:4])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(O)c(OCc2ccccc2)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2cc(O)c(OCc3ccccc3)cn2)CC1
Temperature: 100 °C
Yield: 17.4 %

Procedure:
To a suspension of 2-methoxycarbonyl-4-hydroxy-5-benzyloxypyridine (18.15 g) in N-methylpiperazine (21.04 g) was heated to 100° C. for 3.5 hours. The resulting viscous solution was cooled to room temperature, diluted with a mixture of chloroform (270 ml) and methanol (30 ml) and subjected to column chromatography on silica gel (800 g). The eluate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (600 g). The pure fractions were evaporated in vacuo and the residue was pulverized with diisopropyl ether to give 1-methyl-4-(4-hydroxy-5-benzyloxy-2-pyridylcarbonyl) piperazine (3.99 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:20][CH:19]=1.[OH-].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1

Procedure:
3.1 g of the compound obtained in stage 16F) and then 800 mg of sodium hydroxide pellets are added to 30 ml of methanol and 1 ml of water. The reaction mixture is brought to reflux for 2 hours. It is concentrated to dryness, the residue is taken up in 500 ml of buffer solution at pH 2, extraction is carried out with ether and the extract is dried and concentrated to dryness. 3 g of the expected compound, crystallized from pentane, are obtained.
Reaction SMILES: [C:1]([C:3]([CH3:23])([CH2:20][S:21][CH3:22])[C:4]([N:6]([C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[N:11][N:12]=1)[CH3:7])=[O:5])#[N:2].[H][H]>C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]([CH3:23])([CH2:20][S:21][CH3:22])[C:4]([N:6]([C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[N:11][N:12]=1)[CH3:7])=[O:5]
Reactant: CSCC(C)(C#N)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CSCC(C)(CN)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1

Procedure:
A suspension of 2-cyano-N-[5-(5-fluoro-3-pyridyl)-1,3,4-thiadiazol-2-yl]-N,2-dimethyl-3-methylsulfanyl-propanamide (157 mg, 0.4 mmol) and platinum oxide (131 mg, 0.6 mmol) in glacial acetic acid (8 mL) was reduced under 45 psi of hydrogen at room temperature for 16 hours, filtered through Celite and concentrated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×50 mL). Organic extracts were concentrated under reduced pressure and purified by reversed phase silica chromatography eluting with an aqueous acetonitrile mobile phase. Yield 33 mg (21%): mp 154-157° C.; IR (KBr thin film) 1656, 1383 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.17 (br, 1H), 9.02 (t, J=1.6 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.11 (ddd, J=9.8, 2.8, 1.8 Hz, 1H), 3.87 (d, J=2.9 Hz 1H), 3.48 (s, 3H), 3.47 (d, J=2.9 Hz, 1H), 2.99 (d, J=12.7 Hz, 1H), 2.78 (d, J=13.6 Hz, 1H), 2.20 (s, 3H), 1.41 (s, 3H); ESIMS (m/z) 356 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
NaH (60% in mineral oil, 1.2 g, 30 mmol) was added to an ice-cooled solution of (4-hydroxy-phenyl)-phenyl-methanone (5 g, 25.2 mmol) in DMF (25 mL). The resulting mixture was stirred for 20 minutes at room temperature (r.t.). Benzyl bromide (6.1 mL, 50 mmol) was added at 0° C. The reaction temperature was raised to r.t. after 1 h and thereafter stirred for additional 2 h. Water (20 mL) was added and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phase was concentrated and purified by flash chromatography (eluent: 100% dichloromethane). Yield: 7.0 g, 96% of 1. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.2 Hz, 2H), 7.58-7.52 (m, 1H), 7.50-7.32 (m, 7H), 7.03 (d, J=8.4 Hz, 2H), 5.17 (s, 2H).
Reaction SMILES: ClC1C([F:20])=C(C(C2C=CC=CC=2)C2NC=NC=2)C=CC=1.Cl[C:22]1[C:23](C)=[C:24]([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)[CH:25]=[CH:26][CH:27]=1>>[F:20][C:22]1[CH:23]=[C:24]([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1c(Cl)cccc1C(c1ccccc1)c1cnc[nH]1
Reactant: Cc1c(Cl)cccc1C(c1ccccc1)c1cnc[nH]1
Product: Fc1cccc(C(c2ccccc2)c2cnc[nH]2)c1

Procedure:
1H NMR (CD3OD, 300 MHz) 7.61 (s, 1H), 6.8-7.38 (m, 10H), 6.51 (s, 1H), 5.42 (s, 1H). 5-[(3-Chloro-2-fluoro-phenyl)-phenyl-methyl]-1H-imidazole: 1HNMR (CD3OD, 300 MHz) 7.61 (s, 1H), 6.95-7.38 (m, 9H), 6.51 (s, 1H), 5.71 (s, 1H). 5-[(3-Chloro-2-methyl-phenyl)-phenyl-m ethyl]-1H-imidazole: 1HNMR (CD3OD, 300 MHz) δ 7.96 (s, 1H), 7.01-7.96 (m, 9H), 6.40 (s, 1H), 5.92 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7]([O:9]C(C)(C)C)=O.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([O:16][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH3:15])[CH2:7][OH:9]
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(CO)Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 76.3 %

Procedure:
1.14 g of tert-butyl (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-hydroxybutanoate obtained in Example 123 was dissolved in 10 ml of dimethylformamide, and 0.65 g of tert-butyldimethylchlorosilane and 0.37 g of imidazole were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of toluene, and then a 1M toluene solution of diisobutylaluminum hydride was added thereto with stirring under cooling to -78° C. The mixture was stirred at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution with stirring under cooling to -78° C., and the temperature was raised to room temperature. Then, 1N hydrochloric acid and ethyl acetate were added thereto for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.99 g (yield: 76%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-(tert-butyldimethylsilyloxy)butanol.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1.CCN(CC)CC>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=2)=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: COc1cc(N)ccn1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C#N)cc2F)ccn1
Yield: 66.3 %

Procedure:
A solution of 4-cyano-2-fluoro-benzoic acid (6.7 g, 40.58 mmol), HATU (15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) and Et3N (22.62 mL, 162.3 mmol) in dichloromethane (60.3 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-50%) to yield 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) as a white solid. ESI-MS m/z calc. 271.07. found 272.1 (M+1)+; Retention time: 1.17 minutes (3 minutes run).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[OH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:47][CH2:46]1
Reactant: OCCOCCN1CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCN(CCOCCO)CC3)c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
To the solution of N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (450 mg, 0.76 mmol) in anhydrous DMF (5 mL) was added dropwise 1-[2-(2-hydroxyethoxy)ethyl]piperazine. The resulting reaction solution was stirred and heated at 80° C. for 30 min. It was then partitioned between saturated aqueous NaHCO3 and EtOAc. The EtOAc layer was separated and washed with brine (1×). The aqueous NaHCO3 layer was extracted with CHCl3 (1×) and the extract was washed with brine (1×). The organic layers were combined and dried over anhydrous sodium sulfate. The organic solution was decanted, concentrated, and wrapped with silica gel. Column chromatography (MeOH-EtOAc from 1:10 to 1:6) rendered the title compound as white foam in amount of 500 mg (96%).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].C(O[C:25](=O)[CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])C>CO>[CH2:26]([N:27]([CH2:30][C:31]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH2:28][CH3:29])[CH3:25]
Reactant: CCOC(=O)CN(CC)CC
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 80 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 6.37 g. of diethylamino acetic acid ethylester and 80 cm3 methanol are stirred for 10 hours at 100° C. in a closed system under pressure. 5.2 g. (80% yield) of 7-[(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. m.p.: 69°-70° C. (cyclohexane).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:24][CH:23]3[C:25](=[O:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19][C:18]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C(Cl)Cl>[N:50]1([CH2:49][CH2:48][O:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:24][CH:23]4[C:25](=[O:26])[CH:20]([CH2:21][CH2:22]4)[CH2:19][C:18]=3[CH:27]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: OCCN1CCOCC1
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1C2CCC1Cc1cc(OCCN3CCOCC3)ccc1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Diethyl azodicarboxylate (1.07 g, 6.16 mmol) in DCM (5 ml) was added at a dropwise rate to a stirred solution of 2-hydroxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (J. Org. Chem. 1982 4329, 829 mg, 4.10 mmol), triphenylphosphine (1.61 g, 6.16 mmol) and 4-(2-hydroxyethyl)morpholine (806 mg, 6.16 mmol) in DCM (45 ml). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The crude product was purified by column chromatography on silica eluting with 40:1 DCM: 2M ammonia in methanol. The chromatographed material was taken up in the minimal volume of ethyl acetate and diluted with diethyl ether. 1M HCl in diethyl ether was added. The precipitate was filtered washing the solid with ethyl acetate and diethyl ether. The white solid was taken up in DCM and washed with 1M sodium hydroxide (aq). The organic phase was dried over sodium sulphate, filtered and concentrated to dryness to give 5-(2-morpholin-4-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one as a colourless oil 740 mg (57%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:7]=[CH:6][CH:5]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(/C=C/C(=O)OCc3ccccc3)cccc2[nH]1
Reactant: O=Cc1cccnc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2cccc(/C=C/C(=O)OCc3ccccc3)c2c1Cc1cccnc1
Reaction time: 0.75 h
Yield: 35.1 %

Procedure:
A solution of benzyl (E)-3-[2-methyl-1H-indol-4-yl]-2-propenoate (4.75 g) and pyridine-3-carboxaldehyde (2.10 g) in dry dichloromethane (45 ml) was added dropwise to a stirred solution of triethylsilane (7.82 ml) in trifluoroacetic acid (40 ml) at 0° C. The solution was stirred, allowing the temperature to rise to room temperature, for 45 minutes and then evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonia solution. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave impurity,and further elution with dichloromethane/methanol (19:1) gave pure product.The product fractions were evaporated and the residue was triturated with ether to give the title compound (2.19 g), m.p. 180°-182° C., Rf. 0.35(SS1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[C:24](F)=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:20]=1[F:29]>C1COCC1>[Cl:18][C:19]1[C:20]([F:29])=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[C:24]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
LiHMDS (1.0M in THF, 10.3 mL, 10.3 mmol) was added dropwise to a stirred solution of aniline (505 mg, 5.43 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 2-chloro-1,3-difluoro-4-nitrobenzene (1.0 g, 5.17 mmol) in THF (5 mL) was added and stirring at −78° C. was continued for 30 min. The reaction mixture was quenched by addition of water then extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-70% EtOAc in cyclohexane) to afford the title compound (1.28 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 8.70 (1H, s), 8.15 (1H, dd, J=9.44, 5.61 Hz), 7.36-7.28 (2H, m), 7.12 (1H, t, J=7.44 Hz), 6.98-6.86 (3H, m).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)c2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([O:15][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of Boc-Pro(4-cis-OH)-OBn (8.45 g, 26.3 mmol) in pyridine (65 mL) at 0° C., was added methanesulfonyl chloride (3.4 mL, 44 mmol) dropwise over 7 min. The reaction mixture was allowed to warm to room temperature over 2 h, then stirred overnight. A solution of 10% water in pyridine (20 mL) was added over 15 min and the reaction mixture was concentrated. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×50 mL) saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated. The resulting residue was dissolved in toluene (100 mL) and concentrated to remove traces of pyridine. The residue was dried in vacuo for 30 min to afford the title compound (10.7 g, 102%), then used in the next step without purification.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=2)([CH3:5])[CH3:4].CC(C)=O>CO>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][OH:17])[CH:10]=2)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc2cc(C=O)cc-2cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)c1ccc2cc(CO)cc-2cc1
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Sodium borohydride (0.26 g) was added to a solution of 6-isopropylazulene-2-carboaldehyde (1.4 g) in methanol (30 ml) at 0° C. and the mixture was stirred for one hour. Acetone was added to the reaction mixture and the mixture was stirred for 15 minutes. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (6-isopropylazulen-2-yl)methanol (1.15 g).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].F>>[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:2]([NH2:3])=[S:1])[CH3:6]
Reactant: N#C[S-]
Reactant: CCc1ccccc1
Agent: F
Agent: [NH4+]
Product: CCc1ccccc1C(N)=S
Reaction time: 20 h
Yield: 80 %

Procedure:
In a polyethylene vessel having a capacity of 1 liter, at -20° C and with agitation, 46 g of ammonium thiocyanate (0.6 mol) and subsequently 53 g of ethylbenzene (0.5 mol) are added in portions to 0.5 l of 98% hydrofluoric acid. Subsequently, agitation is continued for 20 hours at room temperature, and the reaction mixture is then poured onto ice, thus causing the separation of a precipitate which slowly crystallizes. The precipitate is suction-filtered and washed with water. By steam distillation, about 10 g of ethylbenzene are recovered from the precipitate. After drying, 66 g (0.4 mol) of ethyl-thiobenzamide having a slightly yellow color and a melting point of 115 - 117° C are obtained, which corresponds to a conversion rate of 80% relative to the ethylbenzene used. The yield, relative to converted ethylbenzene, is 95% of the thoeretical yield. The product can be recrystallized from toluene or chlorobenzene. The gas chromatogram shows that substitution by the thioamide group has occured in p-position at a rate of more than 95%. The 4-ethylbenzonitrile may be obtained from the thioamide in known manner using alkali, thereby splitting off H2S.