Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].CN(C=O)C.[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>O>[Br:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH2:1][CH3:2]
Reactant: CCI
Reactant: COC(=O)c1cc(O)c(Br)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1.0-liter egg plant-type flaks, ethyl iodide (6.91 mL, 86 mmol) was added to a DMF (150 mL) solution of the previously-obtained methyl 4-bromo-3-hydroxy-5-methoxybenzoate and potassium carbonate (11.9 g, 86 mmol), and stirred overnight at room temperature. Water was added to the reaction solution, the formed precipitate was taken out through filtration and dried under reduced pressure to obtain the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([C:22](Cl)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:22]([C:17]3[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2CN(C(=O)c3ccccc3-c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (Intermediate 1, 300 mg, 1.42 mmol), biphenyl-2-carbonyl chloride (429 mg, 1.98 mmol) and tri-ethyl amine (0.6 mL, 3.95 mmol) were dissolved into DCM (5 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield 8-(Biphenyl-2-carbonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (380 mg, 68.6%). MS (ESI) mass calcd. for C24H28N2O3, 392.49; m/z found, 293.2 [M+H]+ (mass without Boc group). 1H NMR (CDCl3): 7.57-7.30 (m, 9H), 4.60-4.35 (m, 0.5H), 4.17-3.98 (m, 0.5H), 3.90-3.71 (m, 1H), 3.60-3.25 (m, 3H), 3.22-2.66 (m, 2H), 2.54-2.38 (m, 0.5H), 2.37-2.22 (m, 0.5H), 2.10-1.92 (m, 0.5H), 1.85-1.56 (m, 1.5H), 1.55-1.27 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)c2ccccc2Oc2ccccc21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: N[C@@H](COC1(c2ccc(F)cc2)c2ccccc2Oc2ccccc21)C(=O)O

Procedure:
from 9-(4-fluorophenyl)-9H-xanthen-9-ol (Example 1 m) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[O:13]1[C:17]2([CH2:22][CH2:21][C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with diisopropylamine (16 mL) and tetrahydrofuran (311 mL). The solution was cooled to −78° C. under N2 and n-BuLi (2.5 M in hexanes, 44.8 mL) was added. The reaction was stirred for 30 minutes at −78° C. and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as a tetrahydrofuran solution (ca. 10 mL). The solution was stirred at −78° C. for 1 hour and ethyl chloroformate (9 mL) was added neat. After stirring at −78° C. for 10 minutes, the reaction was warmed to room temperature over 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with diethyl ether. The layers were separated, the aqueous layer was extracted with diethyl ether and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-65% hexanes/ethyl acetate).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.Cl.N1C=CC=CC=1.[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>ClC=C(Cl)Cl>[C:23]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: CC(C)C(N)=O
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC(=O)CC(=O)NC(=O)C(C)C
Yield: 83.6 %

Procedure:
Isobutyramide (8.7 g, 0.1 mole), pyridine (0.40 g, 0.005 mole), pyridine hydrochloride (1.73 g, 0.015 mole), diketene (8.4 g, 0.1 mole) and trichloroethylene (100 ml) were placed in a 250 ml, 3-neck flask equipped with a magnetic stirrer, a thermometer, a condenser, a drying tube and a heating mantle. The mixture was slowly heated to 80°, and the temperature range of 75°-81° was maintained for 1 hour. The slightly cooled reaction mixture was poured into a 500 ml, r.b. flask and the solvent was stripped off to give an orange oil. Crude N-acetoacetylisobutyramide thus obtained was dissolved in toluene (100 ml) and placed in a 250 ml, 3-neck flask equipped similarly as in Example 1. After addition of acetic acid (3 g, 0.05 mole), ammonia gas was bubbled in as the reaction mixture was heated at reflux for 1 hour and was further refluxed for 1 hour after the ammonia was turned off. Chloroform (~50 ml) was added to the cooled reaction mixture and the insoluble solid was filtered and washed with chloroform (~ 50 ml). The solvent of the filtrate was stripped off and 15.51 g (81.9%, by weight, of oxypyrimidine) of yellow crystals having m.p. 148°-160° were obtained. The yield was 83.6%.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Cl)[CH2:15][CH3:16]>O1CCCC1.CCOCC>[OH:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CCC[Mg]Cl
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled stirred solution of methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (11.0 g, 59 mmol) in dry tetrahydrofuran (120 ml) under nitrogen was added a 2M solution of n-propylmagnesium chloride in ether (36 ml). The resulting mixture was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature with sting over 20 h, and quenched by dropwise addition of saturated aqueous ammonium chloride. The supernatant solution was decanted from the white solids and concentrated to dryness to give the title compound (11.5 g) as an oil.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH:24]1([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:47])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:47])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1sc(N2CCN(CC3CCCCC3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)O
Yield: 86 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(cyclohexylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 86% yield: 1H NMR (300 MHz, DMSO-d6) δ 4.06-3.82 (m, 2H), 3.52-3.42 (m, 2H), 298 (d, J=6.9 Hz, 2H), 2.52 (s, 3H), 1.73-1.52 (m, 6H), 1.27-1.08 (m, 3H), 0.90-0.72 (m, 2H); MS (ES+) m/z 324.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:18][Cl:19])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=O)[NH:9]2)=[CH:4][C:3]=1[O:20][CH3:21].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([CH2:18][Cl:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([O:20][CH3:21])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(CCl)c2cc(OC)c(Cl)cc2[nH]c1=O
Product: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CCl
Reaction time: 0.5 h

Procedure:
A suspension of ethyl 7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate (116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is heated to reflux for 6 hours. The phosphoryl chloride is distilled off. The residue is taken up in water and agitation is carried out for 30 min. The precipitate is filtered out and washed with water until neutrality. The precipitate is taken up in dichloromethane and with a saturated solution of sodium chloride. After filtering through a bed of celite the filtrate is decanted. The organic phase is washed again with a saturated solution of sodium chloride, followed by drying over magnesium sulphate, filtering and evaporating under reduced pressure. 15.88 g of a brown oil is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cncc2cc(Cl)ccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cncc2c([N+](=O)[O-])c(Cl)ccc12
Reaction time: 1 h

Procedure:
A mixture of 17.7 g. (0.1 mole) of 7-chloro-4-methylisoquinoline and 100 ml. of concentrated sulfuric acid is treated with 10 g. (0.1 mole) of potassium nitrate dissolved in 150 ml. of concentrated sulfuric acid. The mixture is stirred for one hour, quenched on ice, made alkaline with ammonium hydroxide and filtered to yield 7-chloro-4-methyl-8-nitroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:30])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:30])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:27][CH2:26][C:25]([CH3:28])([CH3:29])[CH2:24][CH2:23]3)[N:17]=2)[CH:14]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(F)(F)F)c(F)cc3Cl)[nH]c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)CC1
Yield: 89 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-124, 1.0 g), KOH (1.0 g), water (5 mL) and THF (40.0 mL) to afford 0.700 g of the desired product.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[O-]P([O-])([O-])=O.[Na+].[Na+].[Na+].[CH3:36][NH:37][C:38](=[O:41])[CH2:39]Cl>CN1C(=O)CCC1>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:39][C:38]([NH:37][CH3:36])=[O:41])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CNC(=O)CCl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CNC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1
Yield: 28.5 %

Procedure:
A solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride from Example 65 (70 mg, 0.2 mmol) in NMP (2 mL) was treated with sodium phosphate tribasic (85 mg, 0.6 mmol) then N-methyl-2-chloro acetamide (24 mg, 0.22 mmol) in NMP (0.2 mL) and the mixture stirred at RT for 18 h. The mixture was loaded onto an Isolute® SCX-2 cartridge eluting with MeOH then 2M NH3 in MeOH. Appropriate fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 212 (24 mg, 29%). 1H NMR δ (ppm)(CDCl3): 8.50 (1 H, d, J=8.29 Hz), 7.89 (1 H, s), 7.68 (1 H, s), 7.22 (1 H, s), 7.10 (1 H, dd, J=8.33, 1.81 Hz), 6.99-6.96 (1H, m), 6.03-5.94 (1 H, m), 4.53-4.49 (2 H, m), 4.48-4.44 (2 H, m), 3.96 (2 H, t, J=7.77 Hz), 3.81 (1 H, t, J=7.74 Hz), 3.54 (2 H, t, J=7.43 Hz), 3.35 (2 H, s), 2.86 (3 H, d, J=4.93 Hz), 1.60 (6 H, d, J=6.63 Hz). LCMS: RT=2.53 min, M+H+=422
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](N)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Br:12])[N:3]=1.N([O-])=O.[Na+].[ClH:17]>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:17])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Br:12])[N:3]=1
Reactant: Cl
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1c(Cl)cc(Br)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,6-Dibromo-4-amino-5-nitro-pyridine (3 g) was taken up in concentrated hydrochloric acid (20 mL) and cooled to 0° C. Sodium nitrite (3.5 g) was added and the reaction mixture was allowed to stir at 0° C. for 1 h. The ice bath was removed and the reaction allowed to warm to room temperature over 3 h, and was then quenched by the addition of ethyl acetate (50 mL) and water (100 mL). The organic layer was separated, dried over MgSO4 and filtered and evaporated in vacuo to a pale yellow oil, which was purified by column chromatography using 35:1 pentane:EtOAc as eluant to give the title compound (2.2 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:35]1[NH:40][CH2:39][CH2:38][N:37]2[CH:41]=[CH:42][CH:43]=[C:36]12>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:39][CH2:38][N:37]5[CH:41]=[CH:42][CH:43]=[C:36]5[CH2:35]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: c1cc2n(c1)CCNC2
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCn3cccc3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine following General Procedure B.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].C1C(=O)N([Cl:24])C(=O)C1.O>CN(C=O)C>[C:1]([O:4][C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[C:9]([Cl:24])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(CC(=O)O)ccc1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)c(Cl)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [4-(acetyloxy)-3-methoxyphenyl]acetic acid (650 mg, 2.90 mmol) in DMF (10 mL) was added a solution of NCS (428 mg, 3.192 mmol) in DMF (5 mL) dropwise at 0° C. The mixture was stirred at ambient temperature for 6 hrs, and then poured into water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were washed with 1 N HCl, brine, dried over Na2SO4 and then concentrated to obtain [4-(acetyloxy)-2-chloro-5-methoxyphenyl]acetic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Br-]>CN(C=O)C>[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 28) (0.6 g, 1.52 mmol) in anhydrous DMF (20 mL), sodium azide (0.65 g, 10 mmol) was added and the mixture was stirred at room temperature for 1 hour. The TLC of the RM showed the complete disappearance of the starting bromide. The reaction mixture was poured into ice water (300 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with water (100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 30% EtOAc in hexanes as eluent to isolate 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (0.506 g, 94%) as a low melting solid. m/z 355 (MH+), 1H NMR (300 MHz) δ 0.57 (d, 3H), 1.07 (d, 3H), 2.50-2.74 (m, 1H), 2.98 (s, 3H), 3.71 (d, 1H), 5.05 (d, 1H), 5.78 (d, 1H), 7.12-7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].Cl>>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=[C:2]([Cl:1])[N:3]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: NCc1cccc(I)c1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (61, 372 mg, 0.89 mmol) and 3-iodobenzylamine.HCl (1.34 mmol, 360 mg). The mixture was purified by column chromatography (eluens 2% MeOH in CH2Cl2). Yield 383 mg (0.72 mmol, 81%), mp 84–86° C.; Rf 0.59 (10% MeOH in CH2Cl2). The product was recrystallised from CH3COCH3; 1H NMR (DMSO-d6) δ 8.89 (bs, 1H, NH), 8.35 (s, 1H, H-8), 7.73 (s, 1H, CCHCI), 7.60 (d, 1H, J=5.83 Hz, CCHCHCH), 7.33 (d, 1H, J=6.12 Hz, CCHCH), 7.12 (t, 1H, J=7.55 Hz, CCHCH), 5.82 (d, 1H, J=5.15 Hz, H-1′), 5.54 (d, 1H, J=5.84 Hz, OH-2′), 5.30 (d, 1H, J=5.49 Hz, OH-3′), 4.61–4.51 (m, 3H, NHCH2, H-2′), 4.09–4.00 (m, 2H, H-3′,4′), 3.56–3.52 (m, 2H, H-5′), 3.28 (s, 3H, OCH3); MS m/z 532 (M+H)−; Anal. (C18H19ClIN5O4.0.3 CH3COCH3) C, H, N.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: c1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccc2ccccc2c1)n1ccc2ccccc21
Yield: 92 %

Procedure:
The title compound was prepared from naphthalene-2-sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 92%; mp 103-105° C.; 1H NMR (CDCl3) δ 8.33-8.34 (m, 1H), 7.85-7.89 (dd, J=8 Hz, 1H), 7.69-7.76 (m, 1H), 7.52-7.64 (m, 3H), 7.29-7.46 (m, 4H), 6.97-7.24 (m, 2H), 6.46-6.48 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 135.6, 135.5, 135.3, 132.3, 131.2, 130.1, 129.8, 128.9, 128.3, 128.2, 126.8, 125.1, 123.8, 121.9, 121.8, 113.9, 109.7; MS (AP+) m/z 308.04 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B(O)O
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccnn2C)cc1
Temperature: 80 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (2.0 g, 16 mmol), 1-bromo-4-methylbenzene (1.96 mL, 15.9 mmol), sodium carbonate (5.05 g, 47.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (557 mg, 0.794 mmol) were combined in a mixture of water (20 mL) and 1,2-dimethoxyethane (100 mL), and heated at 80° C. for 18 hours. After the reaction mixture had cooled, it was filtered through Celite, and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 1.15 g, 6.68 mmol, 42%. LCMS m/z 173.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.89 (s, 3H), 6.29 (d, J=2.0 Hz, 1H), 7.30 (br AB quartet, JAB=8 Hz, ΔvAB=18 Hz, 4H), 7.51 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][CH2:31][CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][CH2:31][F:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCCF
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-fluoro-ethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl- 3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+48° (c=0.25% in benzene).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CCN(C(C)C)C(C)C.CN([C:24]([O:28][N:29]1N=NC2C=CC=N[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]([O:28][CH3:24])[CH3:30])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol) and DIEA (7.7 ml, 44 mmol) in DMF (30 mL) was added HATU (6.1 g, 16 mmol) at 23° C. under nitrogen. Darkened suspension stirred for 1 h, then added n,o-dimethylhydroxylamine hydrochloride (2.1 g, 22 mmol). Solution stirred overnight at 23° C. Reaction then partitioned between 2.5% NaHCO3 (250 mL) and diethyl ether (100 mL). Aqueous further extracted with ether (2×50 mL). Combined ethereal extracts dried over MgSO4, then concentrated an amber oil under reduced pressure. 4-bromo-2-chloro-N-methoxy-N-methylbenzamide isolated as a light amber oil.