Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH2:41][CH3:42])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CCCn1cc(C(=O)CCCCCBr)c2ccccc21
Agent: Cl
Product: CCCn1cc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c2ccccc21

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 6-bromo-1-(1-propyl-1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 0.83 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-propyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:10]=1)=[O:29]
Reactant: CCOC(=O)CCCCCCc1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCCCCCC(=O)O)cc1

Procedure:
By the reaction of ethyl 6-[4-(2-aminoethyl)-phenyl]-hexane-carboxylate hydrochloride (m.p. 182°-185° C.) with 5-chloro-2-methoxybenzoyl chloride to give 6-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-hexane-carboxylic acid; m.p. 36° C., after recrystallisation from toluene.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[Cl:18][C:17]1[C:12]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1Cl
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)C(F)(F)COc1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2,2,3,3-Tetrafluoropropan-1-ol (60.0 g, 0.45 mol) was added to a slurry of NaH (60% dispersion in oil, 15.20 g, 0.63 mol) in anhydrous THF (450 mL) at 0° C. and the reaction mixture allowed to warm up to room temperature, then stirred for 1 hour. 2,3-dichloropyridine (45.0 g, 0.30 mol) was added and the reaction heated to a gentle reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between EtOAc (300 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a yellow oil (71 g, 96%):
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(CC(N)=O)C1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-bromo-acetamide (57 mg, 0.414 mmol) and DIPEA (215 mL, 1.24 mmol) in IMS (2 mL) was stirred in a sealed vial at 70° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo and the resulting residue was triturated with MeOH affording 133 (59 mg, 34%). LCMS: RT 1.80 min [M+H]+ 420.1. 1H NMR (DMSO, 400 MHz): δ 8.25 (1H, s), 8.14 (1H, s), 8.01-7.90 (1H, m), 7.74-7.66 (1H, m), 7.63-7.55 (1H, m), 7.28-7.03 (4H, m), 5.95 (1H, bs), 4.75 (1H, br), 3.04-2.86 (4H, m), 2.74 (1H, bd, J=11.16 Hz), 2.24 (1H, bt, J=11.70 Hz), 1.80-1.55 (5H, m), 1.35-1.19 (1H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Yield: 94.6 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 mmol) in CH2Cl2 at room temperature for 18 h to give {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a pale yellow oil (2.4 g, 95%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A mixture of 3.73 g of 2,3-dichloropyrazine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 8 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 3.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 2.69 g of diethyl (3-chloro-2-pyrazinyl)malonate.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>C(COC)OC>[CH2:27]([O:28][C:29]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1)(=[O:3])=[O:4])=[O:30])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Yield: 40.8 %

Procedure:
A mixture of methyl 4-(aminosulfonyl)benzoate (5.10 g) and potassium carbonate (655 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30 mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding 1N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a pale yellow oil, which was solidified upon standing. The solid was triturated in diisopropyl ether (30 mL) to give methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a white powder (3.38 g).
Reaction SMILES: II.[CH2:3](Br)[CH3:4].[CH2:6]([O:13][C@@H:14]([CH3:20])[CH:15]=[N:16][NH:17][CH:18]=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OC)(C)(C)C>[CH2:6]([O:13][C@H:14]([C@@H:15]([NH:16][NH:17][CH:18]=[O:19])[CH2:3][CH3:4])[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](C=NNC=O)OCc1ccccc1
Reactant: CCBr
Agent: II
Solvent: COC(C)(C)C
Product: CC[C@H](NNC=O)[C@H](C)OCc1ccccc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
A mixture of methyl tertiary butyl ether (150 ml), Mg turnings (18 g) and I2 (0.03 g) was heated to 40-45° C. under nitrogen atmosphere and ethyl bromide (81.8 g) was added slowly to the reaction mixture for about 1 hour. The reaction mixture was further heated to 50-55° C. and methyl tertiary butyl ether (60 ml) was added to it. The reaction mixture was stirred for 2 hours at 50-55° C. and cooled 0-10° C. N,O-Bistrimethyl silyl acetamide (60.9 g) was added to a mixture of methyl tertiary butyl ether (150 ml) and (S)—N′-(2-(benzyloxy)propylidene)formohydrazide compound of formula-16 (30 g) over a period of 45 minutes at 25-30° C. and stirred for 1 hour at 25-30° C. This reaction mixture was added to the above reaction mixture at 0-10° C. under nitrogen atmosphere. Temperature of the reaction mixture was raised to 25-30 C and stirred for 8 hours at 25-30° C. After completion of reaction, the reaction mixture was quenched with 8% acetic acid in chilled water. The reaction mixture was stirred for 30 minutes at 25-30° C. and both organic and aqueous layers were separated. The organic layer was washed with 10% sodium chloride solution and followed by water. Distilled off the solvent completely to get the title compound. The obtained compound was taken into next step without isolating the compound. Yield: 48 g
Reaction SMILES: [CH2:1]([N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])[CH2:2][CH2:3][CH:4]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[O:14]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:6]1[CH2:1][CH2:2][CH2:3][CH:4]=[O:16]
Reactant: C=CCCCN1CCCCCCC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCN1CCCCCCC1=O
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Osmium tetroxide (17 mg, 0.07 mmole) was added to 1-pent-4-enyl-azocan-2-one (5.52 g, 28.3 mmole) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) under ambient water bath cooling. The mixture was stirred for 5 minutes and solid sodium periodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes. The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride, and extracted with methylene chloride. The organic phase was dried (magnesium sulfate) and concentrated. Purification by silica gel chromatography, eluting with chloroform, gave 4-(2-oxo-azocan-1-yl)-butyraldehyde (4.72 g).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47](O)=[O:48])[N:45]=1)=[O:39]>C(Cl)Cl>[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:20])[CH3:21])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]23)=[O:48])[N:45]=1)=[O:39]
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: -5 °C

Procedure:
Meanwhile, 121 mg of pivaloyloxymethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 141 mg of N,N-diethylaniline were dissolved in 5 ml of methylene chloride and stirred at -5° C. The resulting mixture was added dropwise to the mixture containing 2-(2-chloroacetamidothiazol-4-yl]-2-methoxyiminoacetic acid prepared as described above. The reaction mixture was stirred for 15 minutes and then concentrated by evaporation under reduced pressure. To the residue were added 20 ml of ethyl acetate and 5 ml of water, and the ethyl acetate layer was separated, washed, in turn, with 5 ml of a saturated aqueous solution of sodium bicarbonate, 5 ml of a 5% w/v aqueous solution of hydrogen chloride and 5 ml of a saturated aqueous solution of sodium chloride, and finally dried over anhydrous magnesium sulphate. The drying agent was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 2:1 by volume mixture of ethyl acetate and hexane, to afford 55 mg of pivaloyloxymethyl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:16][C:15]#[CH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C#CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (1.56 g) in DCM (25 mL) benzyltrimethylammonium chloride (0.18 g) was added. To this solution aqueous 50% NaOH (30 g) and propargyl bromide (1.05 mL of 80% solution in toluene) were added and the mixture was vigorously stirred at room temperature for 3 h. Phases were diluted and separated; the organic phase was washed with water (2×15 mL), dried and evaporated under reduced pressure. The residue was purified by chromatography (silica gel, 0-5% methanol in DCM) to give the title compound as a pale-orange oil (1.53 g); ESMS m/z 222.4 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH2:27][C@@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:29][C@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (Z-(R)-Phg-OH) (2.0 g, 7.0 mmol) and tert-butyl O-(tert-butyl)-L-serinate (2.0 g, 7.9 mmol) and 2.6-lutidine were dissolved in DCM (30 ml). After stirring 5 minutes at 0° C. TBTU (2.5 g, 7.8 mmol) was added and stirring was continued 30 minutes at 0° C. and 4 hours at room temperature. The reaction mixture was washed with water (2×100 ml), dried and purified with flash chromatography (DCM) to give the title compound (3.3 g, 97%). NMR (300 MHz, CD3OD): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (bs, 1H), 4.85 (s, 2H), 5.1 (s, 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10 H).
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[CH:7]=[C:6]([CH2:17]OS(C)(=O)=O)[N:5]=1>C(Cl)Cl>[Cl:3][C:4]1[N:5]=[C:6]([CH2:17][I:1])[CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 40 °C
Yield: 91.7 %

Procedure:
Sodium iodide (1.006 ml, 24.61 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidine (1.584 g, 4.92 mmol) in DCM at RT. The resulting solution was refluxed at 40° C. for 18 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to afford the desired product (1.596 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[NH:29][C:30]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:31]
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 2-Chloro-4-trifluoromethylphenyl isocyanate (0.106 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 48 as a colorless solid (0.109 g, 56%). LCMS m/z (%)=455 M+H+ (37Cl, 35), 453 M+H+ (35Cl, 100), 1H NMR (400 MHz, acetone-d6) δ: 8.78 (bs, 1H), 8.48 (d, J=8.97 Hz, 1H), 7.99 (bs, 1H), 7.615 (s, 1H), 7.52-7.46 (m, 1H), 7.375 (d, J=1.41 Hz, 1H), 7.337 (d, J=2.64 Hz, 1H), 6.973 (d, J=8.92 Hz, 1H), 6.027 (d, J=1.63 Hz, 1H), 4.151 (m, 1H), 3.676 (s, 3H), 1.244 (d, J=6.61 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:36])=[O:35])[C:24]([Cl:43])=[CH:23][N:22]=1>>[Cl:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:35])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCC(O)C1
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCC(O)C4)n3)c(OC)c2CC1
Yield: 7 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and 1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzenesulfonyl]-pyrrolidin-3-ol were combined to yield 1-(2-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-benzenesulfonyl)-pyrrolidin-3-ol (12.27 mg, 7% yield) as a beige foam. 1H-NMR (CDCl3) δ 9.36 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.46 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.35 (s, 1H), 3.72 (s, 3H), 3.45 (m, 2H), 3.38 (m, 5H), 3.28 (m, 2H), 2.80-2.75 (m, 4H), 2.68-2.45 (m, 2H), 2.13-1.85 (M, 4 h), 1.25 (M, 6 h). LC/MS (ESI+)=617 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 67.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-isobutyl-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-L-arabinopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [N:1]1[C:2]([CH:13]=O)=[CH:3][N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH:26]=[CH:13][C:2]3[N:1]=[C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][N:4]4[CH:3]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: O=Cc1cn2c(n1)-c1ccccc1C2
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(C=Cc3cn4c(n3)-c3ccccc3C4)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5H-Imidazo[2,1-a]isoindole-2-carbaldehyde (150 mg, 0.81 mmol) in dry THF (5.3 mL) was added to (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium chloride (374 mg, 0.81 mmol) under argon and 1,8-diazabicyclo [5.4.0]undec-7-ene (120 micro L, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours after which it was evaporated onto silica gel (2 g). Silica gel chromatography (gradient elution; A:B 100:0 to 0:100, where A is ethyl acetate and B is 10% MeOH in ethyl acetate) afforded the title compound as a mixture of the cis and trans isomers (139 mg, 52%). LC-MS: m/z=329.3 (MH+), tR=0.96 minutes.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:35])[C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28]>C(O)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:30](=[O:29])[C:25]4[C:26](=[CH:32][CH:33]=[CH:34][C:24]=4[N:23]([CH3:22])[CH3:35])[C:27]3=[O:28])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)c1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Solvent: CC(=O)O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(C)C)c3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.18 mmol) and 3-dimethylaminophthalic anhydride (608 mg, 3.18 mmol) in acetic acid (10 mL). The product was obtained as a yellow solid (780 mg, 50% yield): mp, 192.0-194.0 ° C.; 1H NMR (CDCl3) δ 1.61-1.64 & 1.82-2.00 (2 m's, 8H, C5H8), 2.79 (s, 3H, CH3), 3.08 (s, 6H, CH3), 3.81 (s, 3H, CH3), 3.82 (dd, J=5.5, 14.5 Hz, 1H, CHH), 4.52 (dd, J=9.8, 14.5 Hz, 1H, CHH), 4.75-4.81 (m, 1H, OCH), 5.87 (dd, J=5.0, 9.7 Hz, 1H, NCH), 6.80 (d, J=8.3 Hz, 1H, Ar), 7.03-7.26 (m, 3H, Ar), 7.47 (dd, J=7.3, 8.4 Hz, 1H, Ar); 13C NMR (CDCl3) δ 24.05, 32.75, 41.47, 43.37, 48.84, 55.36, 56.02, 80.55, 111.88, 113.74, 114.46, 114.71, 120.41, 122.04, 129.88, 134.39, 134.77, 147.91, 150.22, 150.39, 167.05, 168.13; Anal Calcd for C25H30N2O6S: C, 61.71; H, 6.21; N, 5.76. Found: C, 61.58; H, 6.06; N, 5.53.