Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:22](Cl)([Cl:24])=[S:23]>C(Cl)(Cl)Cl.O>[Cl:24][C:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1)=[S:23]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-(2,4,5-Trichlorophenyl) 4-(hydroxy)thiobenzoate (5.4 g) in dry chloroform (70 ml) at -20° C. was treated sequentially with sodium hydroxide (0.78 g) in water (3 ml) and thiophosgene (1.85 ml). The solution was allowed to warm to room temperature and was stirred for a further 2 hours. The reaction mixture was then dried over calcium chloride and the filtered solution evaporated to give a crude solid. Purification by chromatography on silica gel using ethyl acetate/hexane mixtures as eluants afforded 3.4 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:16])[C:5]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([F:8])[CH:7]=1.[Li]CCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C(OC)(C)(C)C>[CH2:11]([O:10][CH:9]([O:13][CH2:14][CH3:15])[C:5]1[C:4]([F:16])=[CH:3][C:2]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:7][C:6]=1[F:8])[CH3:12]
Reactant: CCOC(OCC)c1c(F)cc(Br)cc1F
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CCOC(OCC)c1c(F)cc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene (14.7 g, 0.05 mol) in t-butylmethylether (290 mL) was added n-BuLi (21 mL of 2.5 M in hexanes, 0.052 mol) at −78° C. under argon. The reaction was then stirred at −78° C. for 1 hour. Acetone (4.9 mL, 0.065 mol) was added dropwise to the reaction mixture. The reaction solution was then slowly warmed to 0° C. and stirred for 30 min. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to afford the title compound. No further purification was performed. 1H NMR (300 MHz, CDCl3): δ 10.34 (s, 1H), 87.03 (d, 2H), 5.74 (s, 1H), 3.85-3.71 (m, 2H), 3.60 (q, 2H), 1.52 (s, 6H), 1.24 (t, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 3-bromoaniline (0.806 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(3-bromo-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.65 g, 100%).
Reaction SMILES: C([CH:3]([C:24]([OH:26])=[O:25])[N:4]([C:14](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])=[S:7])C.Br.[CH3:28]COCC>C(O)(=O)C>[CH2:14]([N:4]([CH2:5][P:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])=[S:7])[CH2:3][C:24]([OH:26])=[O:25])[CH3:28]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(C(C)C)C(C)C)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(C(C)C)C(C)C

Procedure:
Ethyl N-carbobenzoxy-N-(diisopropylthiophosphinylmethyl)glycine (2 g., 0.0044 mole) was reacted with 36% hydrogen bromide (8 ml) in glacial acetic acid. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diisopropylthiophosphinylmethyl)glycine (0.7 g., 0.0022 mole) as an oil, ND22 =1.5066.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32](O)=O)[N:17]=1>>[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:19]=[C:18]([C:32]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:17]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C(=O)O)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2nc(-c3cccc(S(N)(=O)=O)c3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.8) (0.14 g, 0.50 mmol) according to the general procedure V. Obtained as a white solid (0.097 g, 42%). MS (ISP) 462.1 [(M+H)+]; mp 240.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: N#Cc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-cyanopyridine (0.500 g, 4.2 mmol) was suspended in dry dichloromethane (10 mL) and triethylamine (0.635 g, 6.3 mmol) was added to it under stirring at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.800 g, 6.3 mmol) was added dropwise under stirring at 0° C. and stirring was further continued for about 10 minutes at about 0° C. and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent) and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:13][CH3:14].C([O-])(=O)C.[Na+].Cl>>[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][NH:19][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CCCCN(CCCC)CCCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCN(CCCC)CCCNc1ccccc1[N+](=O)[O-]

Procedure:
15 g. of o-nitrobromobenzene and 13 g. of 3-dibutylaminopropylamine are agitated with 15 g. of anhydrous sodium acetate for 7 hours at 135° C. The reaction mixture is taken up in 70 ml. of 6N hydrochloric acid and 80 ml. of water, the unreacted o-nitrobromobenzene is subjected to steam distillation, the distillation residue is rendered alkaline with potassium hydroxide solution, and extracted with ether. After distilling the residue of the ether extract, 12 g. of 2-(3-dibutylaminopropylamino)-nitrobenzene is obtained, b.p. 140°-160° C. at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[C:20]([CH:25]=O)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][N:28]1[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:14]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2cccc(-c3ccccc3CN3CCc4ccccc4C3)c2)c2ccccc2n1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 100 (166 mg, 0.49 mmol) and 40 (0.06 mL, 0.473 mmol) in dichloroethane (4.9 mL) were sequentially added NaBH(OAc)3 (155 mg, 0.73 mmol) and HOAc (0.03 mL, 0.52 mmol). The reaction was stirred for 48 hours and then extracted with dichloromethane (2×30 mL). The dichloromethane extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give desired product as a yellow solid (51 mg, 23.7%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[O:38])=[CH:33][CH:32]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)=[O:38])=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)nn12
Yield: 38.2 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.191 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 73.56 mg of {4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone as a lyophilized powder. (M+H)=443.8. 1H NMR (400 MHz, DMSO, d6) δ 9.74 (s, 1H), 9.00 (s, 1H), 7.76 (m, 3H), 7.48 (m, 1H), 7.33 (d, 2H, J=8.64 Hz), 7.23 (d, 1H, J=8.28 Hz), 7.13 (t, 1H, J=7.48 Hz), 6.97 (m, 2H), 3.81 (s, 3H), 3.06 (m, 4H), 3.26 (m, 2H), 3.07 (m, 2H), 2.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N1C=CC=[CH:18][CH:17]=1>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:18][CH2:17]2
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: c1ccncc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(F)ccc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 30 g of 4-fluorophenylacetic acid and 48.9 g of thionyl chloride in 60 ml of 1,2-dichloroethane was added a catalytic quantity of pyridine, and the solution was then refluxed for 5 hours under an atmosphere of nitrogen. Following removal of the 1,2-dichloroethane, the product was added dropwise to an ice cooled suspension of 48.6 g of aluminum chloride in 200 ml of dichloromethane. Following stirring for 30 minutes, ethylene gas was blown into the reaction vessel, and after a further 5 hours of stirring, dilute hydrochloric acid was added, and following separation of the organic layer, the aqueous layer was extracted with toluene. The toluene extract was combined with the organic layer and washed subsequently with water, a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate and the solvent removed by evaporation, and subsequently purified by distillation (75° C., 2 Torr) to obtain 19.4 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1cc(O)c(-c2ccccc2)cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccccc3)cn1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
An amount of 40.0 mg (0.154 mmol) of (4E)-6-t-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (based on a sample that is 39% pure by weight), is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 31 mg (0.154 mmol) of 2-aminomethyl-5-phenyl-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 44 mg of the title compound as a pink solid (66% yield); mp 195-218° C. dec, MS data ES(+) 428.4 m/e.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:26]1([CH:25]=[C:24]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=2)[C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC#Cc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 99.3 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.70 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (302 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C25H26N2O3S [M+H]+ 435.56, observed 435.0.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C@H:24]([OH:26])[CH3:25])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>CN(C=O)C>[OH:26][C@H:24]([CH3:25])[CH2:23][C@H:20]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:10][CH:7]4[CH2:6][CH2:5][CH:4]([N:3]([CH3:2])[CH2:34][C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])[CH2:9][CH2:8]4)[C:22]=3[C:21]1=2
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)CC(=O)N5CCCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.1 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (170 mg, 0.38 mmol, 1.0 equiv) in 5.5 mL of dichloromethane cooled to 0° C. Then hydrochloric acid (12 M, 0.5 mL) was added and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure to give (2R)-1-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propan-2-ol hydrochloride (130 mg, crude) as a light yellow oil. The resulting hydrochloride (130 mg, crude) was dissolved in DMF (5 mL). Potassium carbonate (359 mg) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (125 mg) were added at room temperature and the resulting mixture was stirred for 14 h at 25° C. After completion of the reaction, the product was extracted with DCM, washed with brine and concentrated in vacuo. The crude product (160 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.1% HCOOH) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254/220 nm. The product containing fractions were collected and evaporated to remove the water and CH3CN to give 2-[(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (52.7 mg) as a white solid. MS (ES): m/z 473 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.46 (1H, s), 5.32-5.18 (1H, m), 3.94-3.92 (1H, m), 3.57 (2H, t), 3.45 (2H, t), 3.36 (3H, m), 3.08-3.10 (1H, m), 2.96-2.98 (1H, m), 2.67-2.62 (2H, m), 2.41-2.29 (6H, m), 2.070-1.97 (5H, m), 1.95-1.87 (2H, m), 1.64-1.52 (5H, m), 1.30 (3H, d).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].O1CCOCC1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirred solution of L-asparagine (Aldrich) (10 g, 76 mmol), NaOH (3.4 g, 85 mmol), H2O (50 mL), and dioxane (50 mL) at 0° C. was added PhSO2Cl (10.6 mL, 84 mmol). After 1 min, NaOH (3.4 g) in H2O (50 mL) was added and the reaction mixture stirred for 30 min. The reaction mixture was then concentrated to remove the dioxane then washed with EtOAc. The aqueous phase was then cooled to 0° C. and acidified to pH 3 with conc. HCl to effect product precipitation. The resulting solid was collected by filtration, washed with H2O (20 mL) and dried at 50° C. under vacuum to give 22-1 as a white solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][SH:5].[OH-].[K+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CO.C(O)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Reactant: CC(C)=CCC/C(C)=C/CS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CSC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 54.6 %

Procedure:
To a stirred solution of (E)-3,7-dimethylocta-2,6-dienylmercaptan (1.00 g=5.9 mmol) in methanol (40 ml) was added potassium hydroxide (0.33 g=5.8 mmol) and 1-chloro-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethane (1.62 g=5.9 mmol) in ethanol at room temperature, and then the reaction mixture was refluxed for 90 minutes. After cooling, the methanol was evaporated, and then the residue was diluted with chloroform. The chloroform layer was washed with water, followed by drying over anhydrous sodium sulfate. Concentration followed by column chromatography on silica gel (ethyl acetate:hexane=2:3) gave 1.32 g of Compound 10 as a colorless oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:10]([OH:12])=[O:11].CCOCC>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccc(O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(O)c([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
Dichloroacetyl chloride (14.7 g.) was dissolved in methylene chloride (50 ml.). To the solution was added 2-hydroxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (5.65 g.) (syn isomer) with stirring under ice-cooling. The solution was stirred for 30 minutes at room temperature after ether (10 ml.) was added. To the reaction mixture was added petroleum ether under ice-cooling. The precipitates were collected by filtration and thorougly washed with petroleum ether to give 2-dichloroacetoxyimino-2-(3-nitro-4-hydroxyphenyl)-acetic acid (syn isomer) (6.1 g.), which was used as a starting material for the following acylating reaction without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6](O)[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:7]=1
Reactant: CCOC1=C(O)N=C(CBr)S1=C=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC1=C(S(=O)(=O)c2ccc(C)cc2)N=C(CBr)S1=C=O
Yield: 70.1 %

Procedure:
2-Bromomethyl-5-ethoxy-carbonyl-4-hydroxy-thiazole (8 g, 0.03 mol) was dissolved in 80 ml of chloroform. The solution was then cooled down to 0° C. p-Toluenesulfonyl chloride (5.7 g, 0.03 mol) was added, followed by slow addition of triethylamine (3.64 g, 0.036 mol) at 0° C. The reaction was monitored by TLC and LCMS. After the reaction was done, solvent was evaporated and the crude product was then purified by column chromatography to give 8.5 g of title product (yield 67%; LC: Retention Time=2.05 min; MS: M+1=421).