Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][NH:14][CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 120a (1.14 g, 2.62 mmol), methylene chloride (10 mL) and trifluoroacetic acid (10 mL). The solution was stirred for 2 h at room temperature. After this time, the solution was concentrated under reduced pressure. The residue was partitioned between methylene chloride (100 mL) and 1 M aqueous dibasic potassium phosphate (30 mL). The aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The organic extracts were combined, washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to afford a 68% yield (600 mg) of 153a as an off-white solid: mp 170-171° C.; 1H NMR (300 MHz, DMSO-d6) d 9.30 (s, 1H), 7.62 (m, 2H), 7.31 (s, 1H), 6.97 (d, 1H, J=7.8 Hz), 4.10 (br s, 1H), 3.83 (s, 2H), 3.43 (s, 3H), 2.96 (t, 2H, J=5.7 Hz), 2.68 (t, 2H, J=5.7 Hz); MS (ESI+) m/z 334.0 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([N:8]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 14 h
Yield: 64 %

Procedure:
To 50 ml of a dichloromethane solution of 2.984 g (9.90 mmol ) of 1-benzyl-3-[(1R,2S )-2-t-butoxycarbonylcyclopropyl]pyrrolidine (isomer B1) was added 2.83 ml (19.82 mmol) of benzyl chloroformate at room temperature, and the mixture was stirred at the same temperature for 14 hours. To the reaction mixture was further added 1.98 ml (13.86 mmol) of benzyl chloroformate, followed by refluxing for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 2.188 g (64.0%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(OC([N:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[C@H:14]1[C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])=O)(C)(C)C.C(N(CC)CC)C>ClCCl>[CH3:23][O:22][N:20]([CH3:21])[C:19]([CH:14]1[CH:15]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][CH2:17][NH:13]1)=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CON(C)C(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1NCCC1OS(C)(=O)=O
Temperature: 0 °C
Yield: 138.8 %

Procedure:
Methane sulphonyl chloride (3.49 g) was added dropwise over 10 minutes to a mixture of compound 65 (7.6 g) and triethylamine (7.7 ml) in dichloromethane (350 ml) and cooled to 0° C. under an argon atmosphere. It was then stirred at 0° C. for another hour. The reation mixture was then applied directly to a silica flash column which was eluted with ethyl acetate to give (2S,3 S)-1-tert-butoxycarbonyl)-2(N-methoxy-N-methylcarbamoyl)-3-methansulfonyloxypyrrolidine (compound 66) as a gum (9.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc3n2C)CN1C(=O)OC(C)(C)C
Yield: 66.8 %

Procedure:
tert-Butyl 7-bromo-3,5-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.791 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (174 mg, 0.791 mmol) were reacted following the procedure for Example 2 (step f) to provide the title compound (275 mg, 67%) as a yellow oil: ESI MS m/z 521 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:33]C(=O)C)[C:26](=[O:37])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C[O-].[Na+]>CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C:26](=[O:37])[C@@H:27]([OH:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](OC(C)=O)C(=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α, 11α,25R)-3,11-di(acetoxy)spirostan-12-one was saponified with sodium methoxide in methanol and THF to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16]C)[CH:10]=[CH:9][CH:8]=3.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-chloro-5-methoxyxanthone (12.5 g.) [see Examples 32 and 33] in dry dichloromethane at 0° C. is slowly added boron tribromide (24 ml.). The mixture is stirred at room temperature for 24 hours, then poured into water. The resulting precipitate is filtered off and dried to give 3-chloro-5-hydroxyxanthone which is used without further purification.
Reaction SMILES: C([NH:5][C:6]([NH:8][C:9]1([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][C:6]([NH:8][C:9]1([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])=[O:7]
Reactant: CC(C)CCC1(NC(=O)NC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC1(NC(N)=O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of the product of Example 57 (8 mg, 0.013 mmol) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.3 mL). The solution was stirred at room temperature for 18 h and then concentrated in vacuo. Column chromatography on silica (5% methanol/dichloromethane) afforded the title compound as an off-white solid (7 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.67 (dd, J=6.43, 3.86 Hz, 6H), 0.83-1.07 (m, 2H), 1.17-1.31 (m, 1H), 1.46-1.62 (m, 1H), 1.66-1.83 (m, 1H), 2.99 (s, 3H), 5.40 (s, 2H), 6.51 (s, 1H), 7.23-7.33 (m, 2H), 7.34-7.43 (m, 3H), 7.46 (d, J=2.21 Hz, 1H), 7.97 (d, J=8.09 Hz, 1H), 9.86 (s, 1H), 15.47 (s, 1H); MS m/z 562.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35]([BH3-])#N.[Na+].Br>CC(O)C.CO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH3:35])[CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:20][CH2:21][CH2:22]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)NCC2
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)N(C)CC2

Procedure:
A mixture of 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline. (1.89 g), 37% aqueous formaldehyde solution (3 ml), methanol (30 ml) and sodium cyanoborohydride (0.5 g) was stirred at ambient temperature for 24 hours. The mixture was poured onto water (100 ml) and extracted with dichloromethane (300 ml). The extract was washed with dilute aqueous ammonia solution to yield a residue which was dissolved in propan-2-ol and treated with 48% aqueous hydrobromic acid. The solvent was removed by evaporation to yield 7-benzyloxy-6-methoxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred brown solution of 1H-indole-6-carboxylic acid (2.68 g, 16.6 mmol) in THF (25 mL) was added CDI (2.97 g, 18.3 mmol) and stirred at room temperature for 2 hours. The mixture was then cooled to 0° C. and O,N-dimethyl-hydroxylamine hydrochloride (1.95 g, 20.0 mmol) was added and stirred at room temperature over night. Water (50 mL) was added to the reaction and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 1H-indole-6-carboxylic acid methoxy-methyl-amide as an oil (3.87 g, 114% crude yield): 1H NMR (CDCl3) δ 3.40 (s, 3H, NCH3), 3.59 (s, 3H, OCH3), 6.57-6.59 (m, 1H, Ar), 7.31-7.33 (m, 1H, Ar), 7.46-7.50 (m, 1H, Ar), 7.64 (d, J=8 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 8.60 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br.Br.[NH2:12][C:13]1[C:17]([NH2:18])=[CH:16][S:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:12][C:13]1[C:17]([NH:18][C:28]([NH:27][C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[S:29])=[CH:16][S:15][CH:14]=1
Reactant: Nc1cscc1N
Reactant: Cc1cccc(Cl)c1N=C=S
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1NC(=S)Nc1cscc1N

Procedure:
was obtained in a similar manner to the method specified in Example 6a) by reacting a mixture prepared from 0.74 g (=1.01 ml) of N-ethyl-N,N-diisopropylamine in 40 ml of THF, 0.8 g of 3,4-diaminothiophene dihydrobromide and 0.473 g of 2-chloro-6-methylphenyl isothiocyanate.
Reaction SMILES: [CH3:1][C:2]1(C)[CH:12]=CC=C[CH:3]1[O:4]CC(O)=O.B.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O1CC[CH2:22][CH2:21]1>>[CH3:1][C:2]([O:15][C:19]1[CH:22]=[CH:21][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH2:3][OH:4]
Reactant: C1CCOC1
Reactant: CC1(C)C=CC=CC1OCC(=O)O
Agent: B
Product: CC(C)(CO)Oc1ccccc1
Yield: 94 %

Procedure:
This compound was prepared in 94% yield by reduction of 2,2-dimethylphenoxyacetic acid with a 1 molar solution of borane-tetrahydrofuran in tetrahydrofuran (Aldrich Chemical Co.) using the procedure of N. M. Yoon et al, J. Org. Chem. 38, 2786 (1973).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:21][N:22]([CH3:24])[CH:23]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(-n2ncnc2-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(-n2ncnc2-c2ccccc2)cc1

Procedure:
A 1.5 g. portion of 1-(p-aminophenyl)-5-phenyl-1H-1,2,4-triazole in 10.0 ml. of dimethylformamide dimethylacetal and 4.0 ml. of dimethylformamide is heated at 90°-95° C. for 1.5 hours. The solution is concentrated to 10 ml., cooled and then evaporated at 60° C. to an oil. This oil is triturated with 50 ml. of ether. The solid is collected by filtration and recrystallized from chloroform-hexane giving 670 mg. of the desired product as yellow plates, mp. 109°-111° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[CH:21]=[C:20]1[OH:27])=[O:18].C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[C:21]([C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:5])=[C:20]1[OH:27])=[O:18]
Reactant: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 0.5 h

Procedure:
2.23 g of fresh 2-methyl-6-trifluoromethyl-nicotinoyl chloride are added to a mixture of 2.14 g of 2-hydroxy-1-methoxy-5-methyl-4-oxo-cyclohex-2-ene-carboxylic acid methyl ester and 2.02 g of triethylamine in 30 ml of acetonitrile. After about 30 minutes, 0.065 g of potassium cyanide is added and the batch is stirred for 18 hours. The batch is then extracted at pH 2 with water against ethyl acetate, dried over magnesium sulfate and concentrated by evaporation. By filtering over silica gel (mobile phase: ethyl acetate/methanol/triethylamine 85:10:5), pure 2-hydroxy-1-methoxy-5-methyl-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-4-oxo-cyclohex-2-enecarboxylic acid methyl ester is obtained in the form of a viscous oil.
Reaction SMILES: [Na].[CH:2]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.Cl>C(O)C>[CH:2]1([S:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: SC1CCCCC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(SC2CCCCC2)cc1
Yield: 67.9 %

Procedure:
Dissolve sodium metal (343 mg, 14.9 mmoles) in anhydrous ethanol (20 mL) at room temperature under nitrogen atmosphere. Then add cyclohexyl mercaptan (2 mL, 16.37 mmoles) and stir at room temperature for 30 min. Add then neat 4-fluoro-benzonitrile (1.8 g, 14.9 mmol) and heat the resulting solution at 80° C. overnight. Cool the reaction to room temperature and quench the reaction by adding 1N aqueous HCl (100 mL). Concentrate the mixture in vacuo and take up the residue with EtOAc (100 mL). Wash the organic layer with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over MgSO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with cyclohexane/EtOAc (98:2 to 80:20 gradient) to afford the desired intermediate (2.2 g, 68%). GC-MS m/z: 217 (M+).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.O1CCCC1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Cl-].[Na+].O>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CC1CCC(F)(F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCC(F)(F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
A mixture of the crude product of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0° C., tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3 mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at mom temperature for eight hours. Brine was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:9]2[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][C:11]=3[C:12](=[O:13])[N:7]([OH:6])[C:8]2=[O:21])=[CH:38][CH:39]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: CC(C)(C)c1ccc(Cn2c(=O)n(O)c(=O)c3sc4ccccc4c32)cc1

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione (50 mg, 0.13 mmol) was alkylated with 4-tert-butyl benzyl bromide and subsequently deprotected to provide the title compound as a white solid (ret.=3.32 min., m/z=381.0): 1H NMR (d6-DMSO, 300 MHz) δ 1.20 (s, 9H); 5.64 (s, 2H); 7.17 (d, J=8 Hz, 1H); 7.25-7.60 (m, 5H); 7.95 (d, J=8 Hz, 1H); 8.08 (d, J=8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CSc1ccccc1Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1Cl
Reaction time: 12 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2-chlorothioanisole (3.0 g) in 120 ml dichloromethane, were added slowly first 2.8 g of aluminum chloride and 3.0 g of phenylacetyl chloride at 0° C. The reaction mixture was stirred at the temperature for 12 hours. Then the reaction solution was poured onto ice and aqueous hydrochloric acid. The quenched solution was stirred for 30 minutes and extracted with dichloromethane (80 ml×3). The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated in vacuo. The resulting residue was recrystallized from hexane and dichloromethane to give 3.6 g of 1-{3-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone. mp: 101-102° C. NMR: δ2.51 (s, 3H), 4.22 (s, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 7.87 (J=8.4, 1.8 Hz, 1H), 7.97 (d, J 1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N+:7]([O-])=[C:6]([CH3:9])[C:5]([F:10])=[CH:4][CH:3]=1.C([O-])([O-])=[O:12].[K+].[K+].O>C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:9][OH:12])[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: Cc1c(F)ccc(Br)[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: OCc1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
6-bromo-3-fluoro-2-methylpyridine 1-oxide (2.89 g, 14.02 mmol, 1 eq.) was dissolved in neat TFAA (10 ml) and stirred 30 min at room temperature and refluxed for 2 hrs. The solvent was evaporated and the residue diluted with DCM and basified with sat. aqueous Na2CO3. The organic layers was separated and washed with sat. aqueous Na2CO3, dried with MgSO4 and concentrated. The crude was dissolved in THF and MeOH (1 ml) was added followed by K2CO3 (4.8 g, 35.07 mmol, 2.5 eq.). After 30 min of stirring, water was added and the reaction was extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. (6-bromo-3-fluoropyridin-2-yl)methanol (2.54 g, 79% yield) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([OH:15])[C:9](C(O)=O)=[C:8]2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O>[CH:1]1([N:7]2[C:8]([CH3:19])=[CH:9][C:10]([OH:15])=[C:11]([CH3:14])[C:12]2=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(O)c(C(=O)O)c(C)n(C2CCCCC2)c1=O
Agent: Cl
Solvent: O
Product: Cc1c(O)cc(C)n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 158.6 %

Procedure:
A solution of 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.57 mmol) in concentrated HCl (5 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with water and washed with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 1-cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one as a white solid (0.2 g, 77%): 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 5.73 (s, 1H), 3.95-3.75 (m, 1H), 2.80-2.55 (m, 2H), 2.25 (s, 3H), 1.85-1.40 (m, 5H), 1.72 (s, 3H), 1.38-1.05 (m, 3H).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:3]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH:22]=[N:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:4]2[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]2)[C:10](=[O:11])[N:12]=1)[CH3:21]
Reactant: Nc1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)n1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Previously dried 2',3'-dideoxy-3'-fluorocytidine (300 mg, 1.3 mmoles) was treated with dimethylformamide dimethylacetal (0.45 g, 3.8 mmoles) in anhydrous DMF (5 mL) under a nitrogen atmosphere. The contents were stirred overnight and the solvents removed by rotary evaporation. The syrupy residue remaining was crystallized from ethanol to give white crystals (276 mg, 75%) of the product N4 -dimethylaminomethylene-2',3'-dideoxy-3'-fluorocytidine which were shown to have the following properties: