Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].C(O[CH:6]1[S:23][CH2:22][C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]1[O:8][C:9](=[O:11])[CH3:10])(=O)C>C(O)(=O)C.ClC(Cl)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:22][S:23][C@H:6]1[Br:1])(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC1SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Br
Reaction time: 2.5 h
Yield: 39 %

Procedure:
3.50 ml of a 30% solution of hydrobromic acid in glacial acetic acid are added at 10° C. to a solution of 2.10 g (6.3.10-3 mol) of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 10 cm3 of dichloroethane. After 2 to 3 h, the reaction medium is hydrolyzed, washed with a solution of sodium bicarbonate and dried over sodium sulfate (Na2SO4) and the solvent is evaporated off to dryness under reduced pressure. 0.87 g (yield: 39%) of the expected product is obtained after precipitation in ether.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH:22]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[N:10]1)([CH3:24])[CH3:23]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Yield: 76.8 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-1-isopropyl-7-trifluoromethyl-1H-indazole (0.043 g, 0.13 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.032 g) as an off-white solid, mp 156–157° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:12])[O:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[O:5]1.Br.CCOCC.CCCCCC>C(Cl)Cl>[Br:1][C:7]1[C:8](=[O:10])[O:9][C:4]([CH3:12])([CH3:3])[O:5][C:6]=1[CH3:11]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: BrBr
Agent: Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(Br)C(=O)OC(C)(C)O1
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
Bromine (0.105 mol, 5.38 ml) was added dropwise to a 20° C. solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TKD, 0.1 mol, 14.2 g) in 100 ml CH2Cl2 over five minutes. The reaction solution was rapidly decolorized and hydrogen bromide evolved. After 15 minutes, the solvent was removed in vacuo to provide 22 g (99%, >95% pure by NMR) of a pale yellow oil which solidified upon refrigeration. Flash chromatography (10% ether/hexane on silica) afforded 16.5 g (75%) of the title compound as colorless plates.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1)=[C:2]=[S:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1>O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][C:15]=1[NH:20][C:2]([NH:1][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1)=[S:3]
Reactant: COc1ccc(N)c(N)c1
Reactant: CN1CCC(N=C=S)CC1
Solvent: C1CCOC1
Product: COc1ccc(N)c(NC(=S)NC2CCN(C)CC2)c1
Yield: 100 %

Procedure:
A mixture of 37.5 parts of 4-isothiocyanato-1-methylpiperidine, 21.8 parts of 4-methoxy-1,2-benzenediamine and 270 parts of tetrahydrofuran was stirred and refluxed for 2 hours. The whole was evaporated, yielding 44 parts (100%) of N-(2-amino-5-methoxyphenyl)-N'-(1-methyl-4-piperidinyl)thiourea as a residue (interm. 26).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([CH3:36])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:35])[C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:35])[C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:37])=[O:5]
Reactant: CN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
2-Methyl-2-({4-[2-(methyl{5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (210 mg) obtained in Example 163-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (150 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].OC1C=CC=C2C=1N=CC=C2.NN>C(O)CC(C)C>[Cl:11][C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH2:5][NH:6]2)=[CH:2][CH:10]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: NN
Agent: Oc1cccc2cccnc12
Solvent: CC(C)CCO
Product: Clc1ccc2c(c1)NCC2

Procedure:
This material was conveniently prepared on multigram scale from the cyclization of 2,4-dichlorophenethylamine in the presence of Na2 CO3 (s) (1.2 mol eq), Cu2Cl2 (0.01 mol eq) and 8-hydroxyquinoline (0.012 mol eq) in isoamyl alcohol (1 vol) at 130° C. for 5 hours. After addition of hydrazine (0.0055 vol) and 1 hour reflux, the mixture was filtered, solvent was removed in vacuo (45° C. @ ~10 mm Hg) and 6-chloro-indoline was obtained pure by vacuum distillation (95°-100° C. @ 2 mm Hg)(65-95%).
Reaction SMILES: S(=O)(=O)(O)O.[S:6]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])(=[O:8])[NH2:7].[CH3:23]O>>[CH3:23][O:21][C:20]([C:12]1[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=[C:10]([S:6](=[O:8])(=[O:9])[NH2:7])[CH:11]=1)=[O:22]
Reactant: CO
Reactant: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Yield: 81.2 %

Procedure:
429 g of methanol were introduced into a balloon flask provided with a condenser and then, under cooling, 54 g of 93% sulfuric acid and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux and then cooled. The crystals were dried off, washed with methanol and then treated with 500 cm3 of water and 5 g of sodium carbonate. The precipitate was dried off, washed with water and dried. 95 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 225°-226° C.; yield: 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 150 °C
Yield: 41.1 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.377 g, 1.92 mmol) and 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (0.520 g, 2.11 mmol) in DMA (20 mL) was added NaHSO3 (0.240 g, 2.3 mmol) followed by p-TsOH (0.037 g, 0.192 mmol) and the reaction heated at 150° C. for 6 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 (150 mL), washed with brine (2×150 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.333 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1H), 7.88-7.91 (m, 2H), 6.78-6.82 (m, 3H), 6.42 (d, J=2.2 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.62-3.80 (m, 6H), 3.36-3.48 (m, 2H), 1.98-2.12 (m, 5H). ESI MS m/z 421 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].[OH-].[K+]>C1COCC1.O>[CH2:15]([O:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:14]=[CH2:13]
Reactant: Oc1cccc2cnsc12
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1cccc2cnsc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.0 g of 7-hydroxy-1,2-benzisothiazole are dissolved in 20 ml of THF, and 460 mg of sodium hydride (60%) are added to the mixture at 0° C. When the evolution of gas has ended, 1 ml of allyl bromide is added dropwise, the reaction mixture is stirred for one day at room temperature. Again, 1 ml of allyl bromide and 40 mg of sodium hydride are added, and the mixture is stirred for 2 days under reflux. The reaction mixture is poured into water, rendered basic using 1 N potassium hydroxide solution and extracted using ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate, filtered and concentrated. Silica gel chromatography with ethyl acetate/hexane (1:5) as mobile phase gives 2.0 g of 7-allyloxy-1,2-benzisothiazole; nD20 =1.6039 .
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][NH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]1>C(O)CCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]([CH3:9])[CH:11]2[CH2:12][C:13]([CH3:19])([CH3:20])[NH:14][C:15]([CH3:18])([CH3:17])[CH2:16]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Solvent: CCCCO
Product: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 3,6-dichloropyridazine (4 g, 26.8 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mL round bottom flask was added butan-1-ol (67 mL) to give a colorless solution. The mixture was heated to 120° C. for 72 h. Butan-1-ol was removed using a rotary evaporator. The residue was partitioned between water and DCM, and the water layer was further extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The black crude material was stirred in small amount of EtOAc overnight, and the resulting off-white solid was collected to provide 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min (condition B), MS (M+1)=283.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.40 (d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s, 3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:30][N:25]1[C:26]([C:27](=[O:28])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:16]=[C:10]3[CH:11]=2)=[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:23]=[N:24]1
Reactant: Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.2 %

Procedure:
A mixture of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (945 mg, 4.49 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.07 g, 5.39 mmol), propylphosphonic anhydride (50% in ethyl acetate, 6.62 ml, 11.2 mmol) and diisopropylethylamine (3.93 ml, 22.5 mmol) in tetrahydrofurane (50 ml) is stirred for 2.5 days at 25° C. The crude material is loaded on silicagel and purified by flash chromatography on a 50 g silica column using heptane/ethyl acetate 20-100% and then ethyl acetate/methanol 10-30% as eluent. The fractions containing product are evaporated to dryness and the residue (4.23 g light yellow solid) is dissolved in tetrahydrofurane (20 ml); sodium bicarbonate solution (30 ml) is added and the mixture is stirred for 30 minutes at 25° C. The solid is collected by filtration, washed with water and dried affording ethyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (1.336 g, 76.1%) as an off-white solid. mp.: 242-3° C. MS: m/z=391.2 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20]O)[CH:16]=[CH:17][CH:18]=1.[Br:22]Br>C(Cl)Cl>[Br:22][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:14]=1
Reactant: OCCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: BrBr
Solvent: ClCCl
Product: BrCCc1cccc(OCc2ccc3ccccc3n2)c1
Reaction time: 16 h
Yield: 189.2 %

Procedure:
8.6 g of 2-[3-(quinol-2-ylmethoxy)phenyl]ethanol are dissolved in 200 ml of methylene chloride. There are added 9.8 g of tdphenylphosphine and then, at 10° C., 1.9 g of bromine dissolved in 50 ml of methylene chloride. Stirring is carded out at room temperature for 16 hours. The mixture is concentrated to dryness and the residue is taken up in ether. The mixture is washed with a 10% sodium carbonate solution and dried over sodium sulphate. Concentration to dryness is carded out. The residue is chromatographed on 450 g of silica using methylene chloride as eluant. There are obtained 7.7 g of 1-bromo-2-[3-(quinol-2-yl-methoxy) phenyl]ethane. Yield: 72%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4]([CH:5]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:16])[CH3:2]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccccc1Cl)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 26, ethyl-2-oxo-4-(2-chlorophenyl)butyrate and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-ethoxycarbonyl-3-(2-chlorophenyl)-propyl]-L-alanyl-L-proline. The mass spectrum shows a peak at 411, (M+1), and a strong peak at 392, (M-18).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[F:22])(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:37][C:38]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[O:41]>N1C=CC=CC=1.CN(C=O)C>[C:40]([C:39]1[C:38]2[N:37]=[C:1]([C:4]3[CH:9]=[CH:8][C:7]([CH:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=3[F:22])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)(=[O:41])[NH2:42]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 50D (1.48 g) in pyridine (5 mL) and DMF (5 mL) was added CDI (0.856 g). The solution was stirred at 45° C. for 2 hours, treated with 2,3-diaminobenzamide dihydrochloride (1.08 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (30 mL), and this solution was heated at 80° C. for 3 hours and concentrated. The concentrate was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 0-15% methanol in 2:1 ethyl acetate/hexane.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=O.O.[C:17](=[S:20])([S-:19])[NH2:18].[NH4+]>C(O)C>[SH:20][C:17]1[S:19][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)[N:18]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2csc(S)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a mixture of ethyl 4-(bromoacetyl)benzoate (2 g), water (15 ml) and ethanol (14 ml) was added ammonium dithiocarbamate (813 mg) under stirring at room temperature. The stirring was continued for 1 hour at the same temperature and the resulting crystal was collected by filtration. The crystal was added to a mixture of water (15 ml) and ethanol (15 ml), and the mixture was refluxed for 1.5 hours under stirring. The stirring was continued for 30 minutes at 10° C. to give crystal, which were collected by filtration and dried, to give ethyl 4-(2-mercaptothiazol-4-yl)benzoate (1.15 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:14]>>[NH2:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2ccc(I)cc12
Agent: [OH-]
Product: Nc1ncnc2ccc(I)cc12

Procedure:
500 mg of 4-chloro-6-iodo-quinazoline are treated with 30 ml of aqueous ammonium hydroxide solution and heated to reflux for 2 hours. After cooling the precipitated title compound is filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])=[S:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]([O:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])=[S:4]
Reactant: COC(=S)OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=S)OC(C(=O)O)c1ccccc1
Reaction time: 0.08 h

Procedure:
3.92 g. (10 mM) of the benzhydryl ester from Example 2 are stirred together with 30 ml. of trifluoroacetic acid and a few drops of anisole at 0° for 10 minutes. After distilling the solvent off in vacuum, the residue is treated with petroleum ether until it becomes solid. The solid is then stirred for five minutes in 50 ml. of sodium bicarbonate and filtered. After acidification with 2 N hydrochloric acid and extraction twice, each time with 20 ml. of ether and then drying from the organic phase, 1.2 g. of α-[(methoxycarbonothioyl)oxy]benzeneacetic acid are obtained from the filtrate in the form of white crystals after crystallization from cyclohexane/benzol, m.p. 86°-87°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:14][NH:15][CH3:16].Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:14][N:15]([CH3:16])[CH2:12][C:10]1[O:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)o1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.7 %

Procedure:
To a solution of 23 (54 mg, 0.31 mmol) was added a solution of dimethylamine (2.9 M, 0.65 mL, 1.89 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.16 mL, 0.63 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (20 mg, 0.31 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 48 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.2) to afford the title compound 43 (23 mg, 37% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.91 (m, 1H), 8.46 (m, 1H), 7.94 (m, 1H), 7.28 (m, 1H), 6.68 (d, J=3.3 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 2.31 (s, 6H); LRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203. found 203; m/z calcd for C10H8NO [M−N(CH3)2]+ 158. found 158; HRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203.1184. found 203.1205; HPLC>99% (tR=6.00 min, 60 (A):40 (B): 0.07 (C); tR=5.10 min, 60 (A):40 (B): 0.1 (C)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C:10]([I:11])=[CH:9]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 14.34 mmol, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.04 g, 20.08 mmol, 1.4 eq), and PPh3 (7.5 g, 28.68 mmol, 2.0 eq) in dry THF (30 mL), DIAD (5.80 g, 28.68 mmol, 2.0 eq) was added dropwise at 0° C. The mixture was stirred at RT for 5 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE: EtOAc=1:1) to afford (S)-2-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 77% in yield).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH:42]([NH2:45])[CH2:43][CH3:44])[CH3:41]>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:45][CH:42]([CH2:43][CH3:44])[CH2:40][CH3:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CCC(N)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC(CC)CC)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and 1-ethylpropylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.