Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=[C:9]1[C:26]#[N:27])(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:26]([C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)n3CC(=O)O)cc21
Temperature: 25 °C

Procedure:
A solution of tert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate (2.2 g, 5.8 mmol), and sodium hydroxide (1.6 g, 40 mmol) in ethanol (200 ml) was heated to reflux for 2 hours. After cooling to room temperature the mixture was acidified with diluted hydrochloric acid, and extracted with ethylacetate. The ethylacetate solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethylacetate/hexane afforded the title compound, m.p. 207-209° C. (1.2 g, 64%); 1H-NMR (DMSO-d6) δ 1.61 (s, 6H), 4.77 (s, 2H), 6.35 (d, J=4 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 10.43 (s, 1H), MS (APCI (−)) m/z 324 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]1[CH:24]=[CH:23][C:22]([CH:25]2[NH:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[CH:21]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][CH2:29][NH:30][CH:25]([C:22]5[CH:23]=[CH:24][O:20][CH:21]=5)[CH2:26]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1cc(C2CNCCN2)co1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccoc4)C3)c(F)cc2c1=O
Temperature: 120 °C
Yield: 24.3 %

Procedure:
A mixture of 365 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 593 mg of 3-(3-furanyl)piperazine and 10 ml of pyridine was heated in a pressure bottle at about 120° C. for 2 days, then allowed to cool and the solvent removed. The residue was purified by flash silica gel column chormatography eluting with chloroform:methanol:water:triethylamine (95:5:1:1). This product was then triturated with methanol-ether and the solid, washed with methanol, then ether and dried in vacuo, giving 125 mg of the desired product, mp 202°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH2:19]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH:19]2[C:8](=[O:10])[C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1ccsc1C(=O)O
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccsc1C(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Yield: 29 %

Procedure:
A 2.00 g (12.69 mmoles) sample of 3-methoxy-2-thiophenecarboxylic acid (prepared according to Gronowitz, S., Arkiv. for Kemi. 12:239 (1958)) was reacted with 10 ml of thionyl chloride according to Example 32. Evaporation of excess thionyl chloride left 2.17 g of 3-methoxy-2-thiophenecarbonyl chloride as a crystalline solid, m.p. 86°-88° C. The acid chloride was coupled to 2.16 g (10.24 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 3.30 g (27 mmoles) 4-(N,N-dimethylamino)pyridine according to the procedure in Example 32. Aqueous acid quench followed by filtration gave a yellow solid which was purified by recrystallization to give 1.04 g (2.96 mmoles, 29% yield) of 5-chloro-3-(3-methoxy-2-thenoyl)-2-oxindole-1-carboxamide as a yellow solid, m.p. 272°-274° C. (acetic acid).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:44]([OH:47])(=[S:46])[CH3:45]>O1CCCC1.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:46][C:44](=[O:47])[CH3:45])[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9]
Reactant: CC(O)=S
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N(C)C)N(C)C1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-Methyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (970 mg) was dissolved in dry tetrahydrofuran (11.1 ml), and triphenylphosphine (2.66 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.60 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 30 minutes. Thioacetic acid (1.45 ml) was added to the mixture under ice-cooling, and stirring was continued for 40 minutes under ice-cooling, followed by allowing to stand overnight. The reaction mixture was diluted with dichloromethane, washed with aqueous potassium carbonate solution and dried over magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]([F:15])([F:14])[C:7]1[O:11][C:10]([CH2:12]Cl)=[N:9][N:8]=1.C(O)C>CO>[NH:3]1[CH2:2][CH2:1][NH:4][CH2:12]/[C:10]/1=[N:9]/[NH:8][C:7](=[O:11])[C:6]([F:15])([F:14])[F:5]
Reactant: NCCN
Reactant: FC(F)(F)c1nnc(CCl)o1
Solvent: CCO
Solvent: CO
Product: O=C(N/N=C1/CNCCN1)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
The solution of ethylene diamine (89 g) in methanol (305 mL) is stirred and cooled to −20° C. over about 45 minutes. 5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (79 g) is added slowly to the solution over 90 minutes at −20° C. The resulting slurry is stirred for about 90 minutes at −20° C. Ethanol (482 mL) is added and the slurry is warmed to −5° C. After stirring for about 2 hours at −5° C., the solid is filtered, washed with ethanol (79 mL) and dried at about 55° C. to afford the title compound. (Yield: 46.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][S-:14].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:14][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[S-]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(SC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Methyl 2,6-dichloroisonicotinate (300 mg, 1.45 mmol) was dissolved in anhydrous DMF. Sodium thiomethoxide (102 mg, 1.45 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc and washed with water (×3), brine (×1) and dried over sodium sulfate and concentrated in vacuo to afford title compound (294 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 30.4 grams (0.116 mole) of triphenylphosphine in about 116 mL of methylene chloride is stirred, and 7.9 grams (0.116 mole) of imidazole is added. Upon completion of addition, the reaction mixture is stirred about one hour until the imidazole dissolves, then 29.4 grams (0.116 mole) iodine is added portionwise. After the iodine dissolves, the reaction mixture is cooled to 0° C., and a solution of 36.3 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol in about 77 mL of methylene chloride is added dropwise, while maintaining the reaction mixture temperature below 0° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then taken up in about 500 mL of acetonitrile and extracted with three 300 mL portions of hexane. The combined extracts are concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 17.8 grams of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (0.26 g, 0.51 mmol) in dichloromethane (5 mL) at ambient temperature was added trifluoroacetic acid (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The solution was concentrated and the residual glassy solid was redissolved in ethyl acetate (2 mL). Hexanes (10 mL) were added, and after mixing for a few minutes, the product solidified. The mixture was concentrated to afford the desired compound as a light brown powder (0.23 g, 99% yield).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].C([O:21][CH2:22][CH3:23])(=O)C>C(Cl)Cl>[OH:21][C:22]1[CH:23]=[CH:2][C:1]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:3][C:8]=1[CH2:7][CH2:6][CH3:5]
Reactant: CCOC(C)=O
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Product: CCCc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 4-iodo-2-propylphenyl under the conditions described in Example 1. The product was isolated by chromatography over the 40 fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. It was crystallized from ether/hexane to give off-white crystals with m.p. 154°-156°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M152) (377 mg, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (118 mg, 39%).
Reaction SMILES: Cl.C[N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][C:15]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14]3)[CH2:5][CH2:4]1.[Cl:28]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[ClH:28].[C:22]1([S:19]([C:15]2[CH:16]=[N:17][C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[N:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A stirred solution of 8-(4-methyl-piperazin-1-yl)-3-phenylsulfonylquinoline hydrochloride (D10) (0.148 g, 0.4 mmol), 1-chloroethyl chloroformate (0.093 ml, 0.85 mmol) and N,N-diisopropylethylamine (0.148 ml, 0.85 mmol) in 1,2-dichloroethane (9 ml) was heated at reflux for 1.25 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane, pooling fractions which contained the major component (Rf 0.9, methanol/dichloromethane 1:19). The purified material was redissolved in methanol (15 ml) and the solution was refluxed for 1 h under argon. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to a solid which was stirred with diethyl ether (5 ml) and filtered to afford the title compound (D11) (0.08 g, 0.21 mmol, 51%);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[P:20](=[S:28])(Cl)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C(#N)C>[P:20](=[S:28])([O:13][C:10]1[N:11]=[CH:12][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Oc1ncn(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1ncn(-c2ccc(Cl)nn2)n1
Temperature: 70 °C
Yield: 38.5 %

Procedure:
Into a 500-ml three-necked flask equipped with a stirrer and reflux condenser were placed 6.5 g (0.033 m) of 1-(6-chloro-3-pyridazinyl)-1H-1,2,4-triazol-3-ol, 5 g (0.033 m) of potassium carbonate, 0.5 g of mercuric chloride and 100 mls of acetonitrile. The mixture was stirred and heated to 70° C. for one hour and cooled. To this mixture was added 5.6 g (0.03 m) of O,O-diethyl phosphorochloridothioate and the mixture was heated at 60° C. for 6 hours and cooled. The insolubles which formed were removed by filtration and the solvent was then removed by evaporation at 60° C. under reduced pressure. The oil which remained was taken up in 250 mls of methylene chloride sequentially washed with 200 mls of water, 200 mls of a 2 percent sodium hydroxide solution and 200 mls of water and then separated, dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation under reduced pressure leaving 4 grams of an oil product. The O,O-diethyl O-(1-(6-chloro-3-pyridazinyl)-1H-1,2,4-triazol-3-yl) phosphorothioate product was crystallized from warm hexane in a yield of 1.7 grams (15 percent of theoretical). The product melted at 46°-49° C. NMR (60 MHz) (CDCl3, δ): 9.00 (s,1H); 8.18 (d, J=10.0 1H); 7.00 (d, J=10.0 1H); 4.35 (d of q, J=10.5, 6.5, 4H); 1.43 (t w/fine coupling, J=6.5, 6H). (Compound 5).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15](Cl)[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH-:30].[Na+].O>CO>[CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([SH:30])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(Cl)cc12
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(S)cc12
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658 and sodium hydrosulfide (26.7 mg, 0.48 mmol) in methanol (2 ml) was refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the resulting solid. The reaction mixture was stirred for 30 minutes and then filtered. The resulting solid was washed with water 3 times and then dried to give 68 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:17])[CH2:15][CH3:16]>>[CH2:14]([O:17][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH3:16]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (650 mg, 3.3 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 700 mg (96%) of the title compound.
Reaction SMILES: [CH3:1][Ge:2]([CH3:20])([CH3:19])[C:3]1[CH:4]=[C:5]([C:13]2([CH3:18])OCC[O:14]2)[CH:6]=[C:7]([Ge:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>CC(C)=O>[CH3:11][Ge:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:14])[CH3:18])[CH:4]=[C:3]([Ge:2]([CH3:19])([CH3:1])[CH3:20])[CH:8]=1
Reactant: CC1(c2cc([Ge](C)(C)C)cc([Ge](C)(C)C)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cc([Ge](C)(C)C)cc([Ge](C)(C)C)c1
Yield: 98 %

Procedure:
A mixture of 240 mg (0.60 mmol) of 2-[3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane, 23 mg (0.090 mmol) of PPTS, 10.6 ml of acetone (excess) and 540 mg (30 mmol) of water was refluxed for 2.5hours. The reaction mixture was evaporated and extracted with ether. The extract was evaporated to give 208 mg of pale yellow crystals, which were sublimed at 70° C., 0.5mmHg to give 189 mg of white prisms, m.p.56° C. (yield 89%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH:4](O)[CH:5]=[CH2:6].C=CCCC=C.S(Br)([Br:18])=O>ClCCCl>[Br:18][CH2:6]/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C=CC(O)CC(C)(C)C
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Solvent: ClCCCl
Product: CC(C)(C)C/C=C/CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of Example 35A (2.38 g, 18.56 mmol) and 1,5-hexadiene (1.65 mL, 13.9 mmol) in 1,2-dichloroethane (30 mL),stirring at 0° C., was added thionyl bromide (2.16 mL, 27.8 mmol). The reaction was stirred for 2 hours at 0° C. and then quenched with water. The mixture was extracted with diethyl ether and the diethyl ether layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound 3.15 g, 89%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 9 H) 1.94 (m, 2 H) 3.97 (m, 2 H) 5.74 (m, 2 H).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN1C(=O)N(C)CCC1.Cl[C:20]1[N:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:22][CH:21]=1>O1CCCC1>[CH:3]1([S:9][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH2:32][N:31]4[CH:39]=[CH:40][CH:41]=[C:30]4[CH2:29]3)=[O:27])=[CH:22][CH:21]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: SC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(c1ccc(SC2CCCCC2)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 35 mg of sodium hydride (60% in oil) in 3 ml of tetrahydrofuran is added under argon 0.10 g of cyclohexylmercaptan. A white precipitate forms and after 0.5 hour at room temperature, 1 ml of N,N'-dimethylpropyleneurea is added. To the mixture is added 0.13 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, quenched with water and ammonium chloride and concentrated under vacuum. The aqueous suspension is filtered and the solid washed with water and hexane. The solid is purified by chromatography on silica gel prep-plates with ethyl acetate-hexane (1:4) as eluent to give 0.13 g of white solid; mass spectrum (CI): 404 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:12][C@@H:13]1[CH:17]([O:18][CH3:19])[O:16][C@H:15]([CH2:20][OH:21])[C@H:14]1[OH:22].CO>CN(C)C=O>[F:12][C@H:13]1[C@H:14]([O:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH3:3])=[CH:5][CH:6]=2)[C@@H:15]([CH2:20][O:21][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([CH3:8])=[CH:6][CH:5]=2)[O:16][CH:17]1[O:18][CH3:19]
Reactant: Cc1ccc(CBr)cc1
Reactant: COC1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC1O[C@H](COCc2ccc(C)cc2)[C@@H](OCc2ccc(C)cc2)[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
In a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 2.5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added thereto. The reaction mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolane in the form of a colorless oily product.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Product: CNC(=O)c1ccc2[nH]cnc2c1
Yield: 67 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid and aqueous methylamine furnished the product in 67% yield.