Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CN(C=O)C.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:3]=[C:2]([CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:1]=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Phenylpyruvic acid (25.0 g, 152.0 mmol) was coevaporated twice with dry pyridine and then redissolved in dry pyridine (250 mL). To this solution was added acetic anhydride (170 mL, 1.8 moles) and the solution was stirred at ambient temperature for 15 h. The reaction progress was monitored by TLC. When the reaction was complete, the solution was evaporated to a viscous syrup. The syrup was dissolved in dichloromethane (700 mL) and then washed three times with 0.1 M aqueous HCl solution (3×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an amber-colored syrup. This product was purified by flash chromatography on silica gel (250 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 24 g of a dry solid. This material was dissolved in THF (150 mL) and the solution was cooled in an ice-water bath. To the solution was added dropwise oxalyl chloride (51 mL, 580 mmol). After 10 min DMF (7.5 mL) was added to the reaction mixture and the reaction was stirred for 4 h at 0° C. Toluene (100 mL) was added and the reaction mixture was evaporated to give a thick oil. This material was coevaporated twice with toluene and the crude product was dried under vacuum for 5 h. The dried product was dissolved in a 1:1 mixture of THF-dichloromethane (200 mL) and the solution was cooled to −78° C. (dry ice-isopropanol bath) under argon. Then, lithium tri-tert-butoxyaluminohydride (152 mL of a 1.0 M solution in THF, 152 mmol) was added at a rate such that the internal temperature of the reaction was below 60° C. After addition was complete, the reaction was stirred below −60° C. for 10 h. The reaction was quenched by the slow addition of 2 M aqueous HCl solution (100 mL) and the mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with dichloromethane (500 mL) and then washed twice with 0.1 M aqueous HCl solution (2×100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give an amber-colored syrup. This material was purified by flash chromatography on silica gel (250 g) starting with 95:5 heptane-ethyl acetate, then with 9:1 heptane-ethyl acetate as mobile phase. Appropriate fractions were pooled and evaporated to afford 13.5 g (80%) of the desired compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:57]1([CH2:62]/[CH:63]=[CH:64]/[CH2:65]O)[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:65]/[CH:64]=[CH:63]/[CH2:62][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2
Reactant: OC/C=C/CN1CCCC1
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OC/C=C/CN1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Diethyl azodicarboxylate (65 μl, 0.4 mmol) was added in portions to a suspension of 4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg, 0.2 mmol), triphenylphosphine (107 mg, 0.4 mmol), (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (40 mg, 0.28 mmol) in DMF (0.4 ml) and dichloromethane (1.5 ml) cooled at 0° C. The reaction mixture was left to warm up to ambient temperature and was stirred overnight. The mixture was poured onto a column of silica and was eluted with methylene chloride followed by methylene chloride/methanol (98/2), followed by methylene chloride/3N ammonia in methanol (95/5 and 90/10) to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline (51 mg, 55%).
Reaction SMILES: [NH2:1]/[C:2](=[N:33]\[OH:34])/[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.[C:35](OCC)(=[O:37])C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[CH2:13]([C:8]1[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[C:6]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]3[NH:1][C:35](=[O:37])[O:34][N:33]=3)[CH:4]=2)[N:9]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C(N)=N/O)cc23)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4noc(=O)[nH]4)cc23)cc1
Yield: 90 %

Procedure:
To a solution of tert-butyl [6-[(Z)-amino(hydroxyimino)methyl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.25 g, 0.54 mmol) in tetrahydrofuran (10 ml)-ethyl acetate (10 ml) was added N,N-carbonyldiimidazole (0.26 g, 1.6 mmol), and the mixture was heated under reflux for 3 hrs. The reaction mixture was partitioned between ethyl acetate and 0.1M aqueous citric acid solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from n-hexane-ethyl acetate to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinolin-3-yl]methylcarbamate (0.24 g, yield 90%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15]C(=O)C.[N:20](OC(C)(C)C)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[C:6](=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)[NH:15][N:20]=1)=[O:19]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1NC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95° C. The mixture was then stirred for 0.5 h at 95° C., poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242° C. 1H NMR (DMSO-d-6) 8.25 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 3.95 (s, 3H). MS (FAB) m/z: 245.1 (M++1).
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N+:12]([O-])=O)[CH:3]=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][N:2]1[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=2[N:12]=[CH:3]1
Reactant: Cc1ccc(N(C)C=O)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)ncn2C
Temperature: 80 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
N-Methyl-N-(4-methyl-2-nitrophenyl)formamide, 20 g (103 mmols), was added to 400 ml of ethanol and a solution of sodium hydrosulfite, 54g (310 mmols) in 300ml of water was added dropwise to the mixture at 80° C. After stirring at 80° C. for 7 hours, the mixture was stirred at room temperature for further 16 hours. The solvent was distilled off under reduced pressure and 200 ml of 1N sodium hydroxide aqueous solution was added to the residue followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were washed with ether to give 10.0 g (67,3%) of 1,5-dimethylbenzimidazole.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:27][CH2:26][O:25][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2011/154734A1, which is incorporated herein by reference, 340 mg, 1.28 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (0.26 mL, 1.92 mmol) and Ph3P (671 mg, 2.56 mmol) in dry THF (10 mL) was added diethylazodicarboxylate (0.41 mL, 2.56 mmol) and the mixture stirred for 10 min. Water (4 drops) was added and the mixture concentrated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (450 mg, 89%). LCMS (Method 3): Rt 3.73 min, m/z 394 [MH+].
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][NH2:48])=[CH:46][C:41]=2[O:40][CH2:39]1>>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][NH:48][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccc2c(c1)OCO2
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCO5)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and C-benzo[1,3]dioxol-5-yl-methylamine, m.p. 167-168° C. MS [(+)ESI, m/z]: 586 [M+H]+ Anal. Calcd for C36H31N3O5: C, 73.83; H, 5.34; N, 7.17. Found: C, 73.41; H, 5.43; N, 7.12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[N:27]1([CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15]3[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)=[CH:3][CH:4]=5)[N:13]4[N:14]=3)=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and triethylamine (19 μl, 0.133 mmol) in dichloromethane (1 ml) was added benzoyl chloride (17 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered through a plug of silica, washed with methanol and the filtrates combined and concentrated in vacuo. The product was purified by preparatory LCMS to provide the desired product. RT: 2.77 min, MI: 519, Method: 2; 1H NMR (DMSO, 300 MHz): 8.62 (s, 1H), 8.07 (2H, d), 7.97 (2H, d), 7.92 (d, 2H) 7.54-7.41 (m, 5H), 7.01 (1H, d), 6.85 (d, 2H), 4.31 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 3.12 (s, 1H), 2.99 (s, 1H), 2.02 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)CN(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Yield: 103.1 %

Procedure:
To a solution of 4.2 g of methyl 2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acetate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.42 g of 10% Pd on carbon (wet--50% H2O) and the mixture shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals. m.p. 100°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([CH2:32][CH3:33])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:30]([CH2:32][CH3:33])[CH3:31])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)Br
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(-c2nc(-c3ccc(F)cc3)ncc2OC)c1
Yield: 70.1 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine, 5.5 g of potassium carbonate, and 5.5 g of 2-bromobutane were added to 200 ml of acetone, and the resulting mixture was heated under reflux for 2 days. The solvent was distilled away under reduced pressure. The residue was washed with water, and then purified by column chromatography on silica gel, thereby obtaining 1.0 g of 2-(4-fluorophenyl )-4-[3-sec-butoxyphenyl)-5-methoxypyrimidine (Compound 50).
Reaction SMILES: [Mg].[C-:2]1([CH:7]=O)[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:9]1[CH:13]=CC=[CH:10]1.[Fe+2:14].C(Br)C=C.C[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C-:2]1([CH:7]=[CH:13][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:20]1[CH:21]=[CH:22][CH:23]=[CH:24]1.[Fe+2:14]
Reactant: CCCCCC
Reactant: O=C[c-]1cccc1
Agent: [Fe+2]
Agent: [Mg]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC=C[c-]1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
72 mg (3.0 mmole) of magnesium metal was placed in a 50 ml round bottom flask. 214 mg (1.0 mmole) of ferrocenaldehyde and 181.5 mg (1.5 mmole) of allyl bromide were dissolved in 15 ml of THF. The resulting mixture was poured into the round bottom flask containing the magnesium metal, while stirring at room temperature for two hours. After two-hour stirring, the cover of the flask was opened, and the liquid portion of the reaction mixture was introduced into a silica gel column, which had been wetted with n-hexane. All the liquid migrated into the silica gel, and the column was placed still for 24 hours. Next, the column was eluted with n-hexane. After evaporating the solvent from the eluate collected, 200 mg (0.84 mmole) of a purified title product was obtained with a yield of 84%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([O:16][CH2:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15].C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:15])[O:16][CH2:17][CH:18]1[CH2:21][NH:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of tert-butyl 3-((((2-amino-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.12 g, 0.30 mmol) in dichloromethane (5 mL) was added TFA (1.5 mL) at 0° C. The reaction was then warmed to room temperature and stirred for 2 h. The solvents were then removed under reduced pressure. A saturated solution of sodium bicarbonate was added. The product was extracted with ethyl acetate, washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was washed with ether to obtain azetidin-3-ylmethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (49.6 mg, 55% yield). ESI+ MS: m/z 304 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.78 (bs, 1H), 7.53 (bs, 1H), 7.34 (d, J=4.5 Hz, 1H), 7.22-7.16 (m, 2H), 7.04 (dd, J=5.5; 4.0 Hz, 1H), 6.76-6.70 (m, 1H), 5.18 (bs, 2H), 4.23 (d, J=6.0 Hz, 2H), 3.92 (t, J=8.5 Hz, 2H), 3.70-3.64 (m, 2H), 3.08-3.00 (m, 1H).
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:13][C:14]1[C:15](=[O:29])[NH:16][C:17](=[O:28])[N:18]([CH:27]=1)[C@@H:19]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:20]1.C(O[CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)C.C(N(CC)CC)C>ClCCl>[F:13][C:14]1[C:15](=[O:29])[N:16]([CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[C:17](=[O:28])[N:18]([CH:27]=1)[C@@H:19]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:20]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(=O)OC1CCCO1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 16.5 g quantity of N,O-bis(trimethylsilyl) acetamide was added to a suspension of 5.00 g of 2'-deoxy-5-fluorouridine in 50 ml of dry dichloromethane at room temperature with stirring, and the mixture was stirred for four hours. Then a solution of 4.00 g of 2-acetoxytetrahydrofuran and 1.17 ml of stannic chloride in 10 ml of dry dichloromethane was added and the mixture was stirred for 1.5 hours. Then 8.0 ml of triethylamine was added to neutralize the mixture and the mixture was washed with water. The dichloromethane layer was concentrated and the residue was dissolved in 100 ml of methanol. A 3 ml quantity of acetic acid was added thereto and the mixture was left to stand at 40° C. for 3 hours. The solvent was distilled off and the residue was applied to a silica gel column to conduct gradient elution using chloroform and methanol (up to 4%)-chloroform mixtures, giving 5.25 g of 2'-deoxy-5-fluoro-3-(2-tetrahydrofuranyl)uridine as an oil in a yield of 81.7%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(C)(=O)=O)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A27 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (50 μl), methanesulfonyl chloride (10 mg, 0.087 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 2.13 (m,4H), 2.85 (s, 3H), 3.08 (s, 3H), 3.31 (m, 2H), 3.57 (m, 2H), 4.13 (m, 1H), 5.69 (m, 1H), 7.87 (d,2H), 7.98 (d,2H), 8.42 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C14H21N5O7S2 471.09, found 472.3 (MH+).
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]4[N:30]=[N:31][NH:32][N:33]=4)=[CH:23][CH:22]=3)=[O:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:50][NH2:51]>C1COCC1>[CH3:50][NH:51][C:9](=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]3[N:30]=[N:31][NH:32][N:33]=3)=[CH:23][CH:22]=2)=[O:18])[CH:11]=1
Reactant: CN
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl) benzyl]-ureido}benzoic acid pentafluorophenyl ester was added a solution of methylamine in THF (2M, 5 mL). The mixture was shaken at 25° C. overnight, filtered and washed with THF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:3]=1.[C:28](C1NC=CN=1)(C1NC=CN=1)=[S:29]>CN(C=O)C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:3][C:2]4[NH:1][C:28]([SH:29])=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2cc3[nH]c(S)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 45 °C

Procedure:
To a solution of 4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 181) in DMF (1 mL) was added thiocarbonyl diimidazole (0.55 mmol). Following the addition, the mixture was warmed at 45° C. for 1 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Cl:22]CCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:22])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoic acid (15.7 g, 55.82 mmol, 1.00 equiv), dichloromethane (200 mL), oxalic dichloride (10.56 g, 83.20 mmol, 1.49 equiv) and dimethylforamide (cat.). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 16.7 g (crude) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride as a white solid. Rf: 0.30 (in ethyl acetate:petroleum ether=1:5).