Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-hydroxy-4-methylbenzoate (19.7 g, 0.119 mole) in pyridine (15 ml) was treated with acetic anhydride (15 ml, 16.23 g, 0.158 mol). The reaction was stirred at ambient temperature overnight and then the solvent evaporated. The residue was dissolved in CH2Cl2 and the solution washed with 2N aqueous HCl, water, saturated aqueous NaHCO3 solution, dried (MgSO4) and evaporated to give methyl 2-acetoxy-4-methylbenzoate which was used without further purification (24.58 g, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([Cl:16])=[CH:9][C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.O1C[CH2:20][CH2:19][CH2:18]1.[H-].[Na+].C(Br)C=C>O>[CH2:20]([O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([Cl:16])=[CH:9][C:10]=1[Cl:15])[CH:19]=[CH2:18]
Reactant: OCc1cc(-c2ncccn2)c(Cl)cc1Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOCc1cc(-c2ncccn2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 5.10 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol and 100 of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.53 gm sodium hydride added. The system was stirred for 20 additional minutes and 2.1 ml of allyl bromide was then added. The system was allowed to come to room temperature over 1/2-hour and stirred there for an additional 2 hours. Afterwards the system was heated at reflux for 17 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was then washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 5.47 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol allylether as an orange liquid and listed as Compound No. 2, Table I.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH2:12][CH3:13])(=[O:10])[C:5]([O:7]CC)=O.C(O)C.[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26]>CO>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26][C:5](=[O:7])[C:4]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ncc([N+](=O)[O-])n1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ncc([N+](=O)[O-])n1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 180 parts of a 30 percent strength by weight sodium methylate solution in methanol, 146 parts of diethyl oxalate and 150 parts by volume of ethanol is added in the course of 30 minutes, at 60° C., to a suspension of 141 parts of 1,2-dimethyl-5-nitroimidazole in 250 parts by volume of ethanol. After stirring for one hour at 60° C., the mixture is cooled and the sodium enolate of ethyl 1-methyl-5-nitroimidazol-2-yl-pyruvate is filtered off. The salt is then introduced into 1,300 parts by volume of 3 percent strength by weight hydrochloric acid, whilst stirring. The mixture is stirred for a further half-hour and the product is then filtered off. 190 parts (79% of theory) of ethyl 1-methyl-5-nitroimidazol-2-yl-pyruvate of melting point 141° C. (after recrystallization from ethanol) are obtained.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[CH:14]([O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[S:25])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C1C=CC=CC=1>[F:29][C:28]([F:30])([F:31])[CH2:27][N:26]=[C:24]1[N:23]([CH2:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH:14]([CH3:16])[CH3:15])=[CH:19][CH:20]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:25]1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Reactant: CC(C)Oc1ccc(CNC(=S)NCC(F)(F)F)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(C)C)cc3)C2=O)cc1
Yield: 36.3 %

Procedure:
1.00 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.40 g of 1-(4-isopropyloxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of benzene, and the solution was heated under reflux for 4 hours. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; eluent: hexane/ethyl acetate (10/1)1 to give 0.75 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34].O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Yield: 64.5 %

Procedure:
Raltegravir (10 gm) was dissolved in dimethylformamide (100 ml) at room temperature and cooled to 10 to 15 deg C. To the reaction mass was added slowly a mixture of potassium hydroxide (1.5 gm) and water (2 ml) at 10 to 15 deg C. and the temperature was raised to 25 to 30 deg C., filtered. The solid obtained was washed with dimethylformamide and dried at 110 to 120 deg C. for 48 hours to obtain 7 gm of raltegravir potassium crystalline form H1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:3]5[CH:4]=[N:5][O:6][C:2]=5[CH3:1])=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1oncc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oncc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A mixture of 5-methyl-isoxazole-4-carboxylic acid (7.3 mg, 0.05 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with triphenylphosphine (17 mg, 0.06 mmol). This mixture was cooled to 0° C. and then was reacted with N-chlorosuccinimide (10 mg, 0.07 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 5-methyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.6 mg, 24.4%) as an off-white solid: EI-HRMS m/e calcd for C29H27N6O4F (M+) 542.2078, found 542.2083.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([F:4])[F:3].[CH3:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]([C:2]([F:3])([F:1])[F:4])=[N:6][N:7]=1)=[O:12]
Reactant: CNCCC=O
Reactant: O=C=Nc1nnc(C(F)(F)F)s1
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C(F)(F)F)s1

Procedure:
A mixture of 5 trifluoromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (9.5 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Uracil is bis-trimethylsilylated according to the procedure of Niedballa and Vorbruggen. Uracil is dissolved in benzene, and added to 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 33.1b (Xi=β--OAc) (Niedbala and Vorbruggen) in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)uracil 33.1b (Xi=β-uracil-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(β-D-glucopyranosyl)uracil 33.1a (Xi=β-uracil-1-yl) is obtained. This is converted into the morpholino subunit 32.2b (Xi=β-uracil-1-yl) by the general procedure.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([F:9])=[CH:7][N:6]=[CH:5][C:4]=1[F:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[C:19]2[N:20]([C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH:21]=[CH:22][CH:23]=1>CN(C=O)C.O>[F:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:9])[C:3]=1[CH2:2][O:17][C:18]1[C:19]2[N:20]([C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Reactant: Fc1cncc(F)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cncc3F)cccn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At RT, 1.86 g of 4-(chloromethyl)-3,5-difluoropyridine (Example 115A, 9.1 mmol, 2.0 equivalent) and 4.44 g of caesium carbonate (13.6 mmol, 3 equivalent) were added to 1.0 g of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 3A, 4.54 mmol, 1.0 equivalent) in 100 ml of DMF, and the mixture was stirred at 60° C. for 1 h. The mixture was then diluted with 500 ml of water and extracted twice with in each case 300 ml of ethyl acetate. The combined organic phases were washed with 400 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. The residue obtained was purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 7:1 to 1:1). This gave 900 mg (54% of theory) and 200 mg (13% of theory; purity about 85%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccnc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl chloride hydrochloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide as a white powder, m.p. 188.6-189.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (dd, J=2.2, 0.7 Hz, 1H), 8.70-8.65 (m, 2H), 8.22 (s, 1H), 8.11 (dt, J=8.3, 2.0 Hz, 1H), 8.04 (dd, J=8.2, 0.9 Hz, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.50-7.39 (m, 2H), 7.23-7.18 (m, 1H), 6.58 (broad s, 2H), 4.64 (t, J=7.0 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.60 (m, 2H); MS (EI) m/e 360.1696 (360.1699 calcd for C20H20N6O).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([O:17][CH:24]2[CH2:25][C:26](=[O:27])[NH:22][C:23]2=[O:28])=[O:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc21
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1CC(OC(=O)[C@@H]2CCCN2C(=O)CC2CCc3ccccc32)C(=O)N1
Yield: 64.8 %

Procedure:
Into a 4 ml of tetrahydrofuran were dissolved 0.82 g of 1-(2-indanylacetyl)-L-proline and 0.35 g of N-hydroxysuccinimide. To the solution was dropwise added a solution of 0.74 g of DCC in 2 ml of tetrahydrofuran at room temperature with stirring. After stirring for a further 17 hours at the same temperature, insoluble components were removed by filtration. From the filtrate the solvent was evaporated under reduced pressure. The oily residue thus obtained was washed with n-hexane, dissolved in 5 ml of benzene, and treated with activated carbon. Benzene was evaporated under reduced pressure to produce 0.72 g of 1-(2-indanylacetyl)-L-prolyloxysuccinimide as coloress amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C>CO>[OH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(C)O)cc1

Procedure:
To a solution of 1-(4-acetylphenyl)-ethanone (1.0 g, 6.2 mmol) in dry methanol (30 mL) at 0° C. was slowly added NaBH4 (0.07 g, 1.9 mmol). The reaction mixture was allowed to stir at 0° C. for 4 h, at which time silica gel TLC in hexanes and ethyl acetate (1:1 v/v, rf=0.5 desired product) showed a mixture of starting material, desired product, and the double-reduction side product. The reaction mixture was treated slowly with 1 N HCl solution (1 mL) at 0° C. until bubbling was no longer observed. Methanol was removed in vacuo to provide an orange residue, which was then partitioned between ethyl acetate (100 mL) and 1 N HCl (100 mL). The organic layer was washed with the 1 N HCl followed by a saturated NaCl solution (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford an orange oil. The crude product was purified by flash chromatography through a silica gel column with hexanes and ethyl acetate (65:35 v/v) to provide the desired compound (0.55 g, 54%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (d, 2H), 7.50 (d, 2H), 5.00 (dt, 1H), 2.61 (s, 3H), 1.52 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>CN(C)C=O>[C:7]([NH:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16]([NH:15][CH2:14][CH2:13][Cl:12])=[O:17])=[CH:11][CH:10]=1)(=[O:9])[CH3:8]
Reactant: O=C=NCCCl
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1800 g of p-aminoacetanilide in 7000 ml of dimethylformamide is stirred at room temperature. The solution is then cooled to 10°-15° in an ice-water bath. To the stirred cooled solution is added 1440 g of 2-chloroethyl isocyanate in a thin stream over a 50-minute period, keeping the reaction mixture temperature between 20° and 25°. The reaction mixture is stirred at room temperature for 90 minutes; 8000 ml of ice-water is added over a 20-minute period. After stirring for an additional 2 hours, the solid is filtered off and washed with 4000 ml of water. The crude product is slurried with 7000 ml of 95% alcohol. The solid is filtered off and air-dried overnight at room temperature to give 1-(p-acetamidophenyl)-3-(2-chloroethyl)-urea, m.p. 207°-9° dec.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2Cl)cn1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and pyrrolidine to give the title compound in 17% yield; NMR Spectrum: 1.66-1.68 (m, 4H), 2.45 (s, 3H), 2.51-2.56 (m, 4H), 2.90 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.71 (d, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1H), 8.68 (br s, 1H; Mass Spectrum: 466 (MH+).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O>CCOCC.C(Cl)Cl>[Br:2][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH3:5]
Reactant: Cc1nc(-c2ccccc2)oc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)oc1CBr
Reaction time: 4 h

Procedure:
80 mL (0.67 mmol) of PBr3 is added slowly to a solution of 104 mg (0.57 mmol) of (4-methyl-2-phenyl-oxazol-5-yl)-methanol in 0.5 mL of Et2O and 1.5 mL of CH2Cl2 at 0° C. The coolin bath is removed, and the reaction mixture is stirred for 4 h. The reaction mixture is then partitioned between saturated aqueous NaHCO3 solution and Et2O. The organic phase is separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to produce 5-bromomethyl-4-methyl-2-phenyl-oxazole as a solid; 1H NMR (250 MHz, CDCl3) δ7.90-7.99 (m, 2H), 7.32-7.40 (m, 3H), 4.50 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37]([O:19][CH2:18][CH:17]([C:16]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Reactant: OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(OCC(c3c4ccccc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, 2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 29.1) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-n-butylphosphine and N,N,N′,N′-tetramethylazodicarboxamide in THF at ambient temperature to give the title compound as off-white solid. MS: m/e=545.3 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:16][CH2:17]C[CH2-].ICC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH2:16][CH3:17])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [CH2-]CCC
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (80 mL of 1.49M in hexanes, 120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78° C. and then for 2.5 hours at -10° C., the solution was then recooled back down to -78° C. and iodoethane (77.2 mmol, 6.18 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid: mp 101°-102° C.; IR (KBr, cm-1) 3174, 2968, 1725, 1594, 1519, 1442, 1278, 1249, 1156; 1H NMR (300 MHZ, DMSO-d6) δ 8.98 (s, 1 H), 8.17 (m, 1H), 7.61 (m, 1H), 7.15 (m, 1H), 2.52 (q, J=7.5 Hz, 2H), 1.39 (s, 9H), 1.08 (t, J=7.5 Hz, 3H); MS (FD) m/e 222 (M+); UV (EtOH) 270 nm (ε=4398), 223 nm (ε=6745). Anal. Calcd for C12H18N2O2 : C, 64.84; H, 8.16; N, 12.60. Found: C, 64.91; H, 8.34; N, 12.42.