Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.N1C=CN=C1.[OH:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>C(OCC)C>[Si:30]([O:11][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)C=CC1=C(C)CC(O)CC1(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To 30 ml of an anhydrous dimethylformamide (hereinafter "DMF") solution containing 588 mg of imidazole and 1.2 g of 4-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)but-3-en-2-one was added dropwise 15 ml of an anhydrous DMF solution containing 1.3 g of t-butyldimethylchlorosilane at room temperature in a nitrogen atmosphere. After the dropwise addition, the mixture was stirred under the same conditions for 15 hours. Diethyl ether was added to the reaction mixture, and the mixture was washed several times with water cooled with ice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 78%) of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]-but-3-en-2-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:30])[C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[O:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:30][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[C:13]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(OC(C)=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetylchloride (0.7 g, 8.9 mmol) is slowly added to a cooled (0° C.) mixture of 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (3.0 g, 8.0 mmol) and pyridine (0.7 g, 8.9 mmol) in 30 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room temperature and subsequently poured on ice and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate and the solvent is evaporated, the residue is purified by chromatography on silica gel to give 2-acetoxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.13 (s, 3H, CH3CO2), 2.52 (t, 1H, C≡CH), 2.80 (t, 2H, CH2CH2), 3.57 (t, 2H, CH2CH2), 3.87 (s, 3H, OCH3), 4.79 (d, 2H, OCH2C≡C), 6.03 (s, 1H, CHOH), 6.65–7.34 (m, 8H, CH arom., NH).
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:27](=[O:28])[NH:26][C:21]1[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Et3N (1.7 mL) was added to an ice-cold solution of (S)proline methyl ester hydrochloride (1.31 g) and 3,5-dichlorophenylisocyanate (1,97 g) in CH2Cl2 (40 mL). The mixture was stirred for 3 hours. It was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/3) afforded (S)-N-[N-(3,5-dichlorophenyl)carbamoyl]proline methyl ester (2.27 g). mp. 110-112° C.; MS (m/z) 339 (M++Na).
Reaction SMILES: Cl.[CH:2]12[CH:7]([C:8]([NH2:10])=[O:9])[CH:6]1[CH2:5][NH:4][CH2:3]2.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:4]1[CH2:5][CH:6]2[CH:2]([CH:7]2[C:8]([NH2:10])=[O:9])[CH2:3]1
Reactant: NC(=O)C1C2CNCC21
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)CCN1CC2C(C1)C2C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
The 3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (169 mg, 1.04 mmol) prepared in Example 5 and a molecular sieve were dried in vacuum and dissolved in 5 mL of methylene chloride. Then, triethylamine (151 μL, 1.08 mmol) was added dropwise at 0° C. After adding 3,3-dimethylbutyraldehyde (135 μL, 1.08 mmol), the mixture was stirred at room temperature for 1 hour. After adding sodium triacetoxyborohydride (687 mg, 3.24 mmol) and then adding 10 mL of methylene chloride, the mixture was stirred for 2 hours and 30 minutes. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=10:1). After the reaction was completed, the reaction mixture was diluted with methylene chloride and extracted several times with saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=10:1) to obtain 173 mg (79.2%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CSCc1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 8.29 mmol) in DCM (20.0 mL) at −40° C. was added a solution of m-CPBA (77%, 1.86 g, 8.29 mmol) in DCM (20.0 mL) dropwise. The solution was stirred from −40° C. to room temperature overnight. The solution was then quenched with polymer bound diethylene triamine. After filtration and concentration, the residue was purified by flash chromatography on SiO2 to give ethyl 2-(4-fluorobenzylsulfinyl)acetate (2.0 g, 98% yield). MS(ESI+): m/z 267.09 (M+H)+.
Reaction SMILES: C(O[C:6]1[C:19](C)=[C:18](C)[C:17]2[O:16][C:15]3[C:10](=[C:11](C)[C:12](OCC4OC4)=[C:13](C)[C:14]=3C)[CH:9](C3C=CC=CC=3)[C:8]=2[C:7]=1C)C1OC1.C(O[C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51](OCC3OC3)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)C1OC1.OC1C=CC(C2C=CC(O)=CC=2)=CC=1.C([O-])(=O)C.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>CN(C)C(=O)C.CO>[CH:11]1[C:10]2[CH2:9][C:8]3[C:17](=[CH:18][CH:19]=[CH:6][CH:7]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH:50]1[C:49]2[C:44]3[C:45](=[CH:46][CH:47]=[CH:42][CH:43]=3)[C:48]=2[CH:53]=[CH:52][CH:51]=1
Reactant: Cc1c(C)c2c(c(C)c1OCC1CO1)C(c1ccccc1)c1c(C)c(OCC3CO3)c(C)c(C)c1O2
Reactant: c1cc(-c2ccc(OCC3CO3)cc2)ccc1OCC1CO1
Agent: CC(=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)-c1ccccc1-2
Product: c1ccc2c(c1)Cc1ccccc1O2
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1.555 g (manufactured by DAINIPPON INK & CHEMICALS Co., Ltd., “EXA7335”, 3.2 mmol) of 2,7-diglycidyloxy-1,3,4,5,6,8-hexamethyl-9-phenylxanthene, 0.238 g (0.8 mmol) of 4,4′-diglycidyloxybiphenyl, 0.67 g (3.6 mmol) of 4,4′-dihydroxybiphenyl and 0.0106 g (0.02 mmol) of ethyltriphenylphosphonium acetate in a 70% methanol solution were reacted for 4 hours by stirring while heating to 160° C. in 2.463 g of N,N-dimethylacetamide under a nitrogen atmosphere. After cooling, a pale yellow transparent semi-solid reaction solution was diluted with 11.495 g of N,N-dimethylacetamide and then added dropwise in ice. The resulting white massive precipitate was suction-filtered, washed with ice water and then boiled in 200 ml of water for 30 minutes while vigorously stirring. After cooling, the precipitate obtained by decantation was ground and the powered precipitate was washed with water and methanol, and then vacuum dried at 60° C. to obtain a xanthene-biphenylene copolymer type linear epoxy resin. The amount of the resulting xanthene-biphenylene copolymer type linear epoxy resin was 2.33 g and the yield was 95%.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([O:15][CH3:16])[CH3:14])[C:4](=[O:17])[CH:3]=1.[CH2:18]=[C:19]1[O:23][C:21](=O)[CH2:20]1.[C:24]1(C=CC(O)=CC=1)O>C1C=CC=CC=1>[CH3:24][N:7]1[C:2]2[NH:1][C:19]([CH3:18])=[CH:20][C:21](=[O:23])[C:3]=2[C:4](=[O:17])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([O:15][CH3:16])[CH3:14])[C:6]1=[O:8]
Reactant: CO[C@H](C)CCCCn1c(=O)cc(N)[nH]c1=O
Reactant: Oc1ccc(O)cc1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CO[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 523.8 %

Procedure:
A mixture of (R)-6-amino-3-(5-methoxyhexyl)uracil (152 mg, 0.595 mmol), diketene (0.07 ml, 0.89 mmol), hydroquinone (7 mg, 0.06 mmol) and benzene (5 ml) was heated at reflux for 3 hours. Another portion of diketene (0.2 ml) was added and heating at reflux was continued for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene to provide (R)-1,7-dimethyl-3-(5-methoxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (101 mg, 53% yield) as an oil which crystallized on standing. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, 3H), 1.30-1.79 (m, 6H), 2.48 (s, 3H), 3.29 (m, 1H), 3.30 (s, 3H), 3.75 (s, 3H), 4.02 (t, 2H), 6.50 (s, 1H), 12.21 (s, 1H).
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C)=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC([O-])=O.[Na+]>>[CH2:3]([N:10]1[C:18]([Br:1])=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: CCCCCCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCCc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of 4-amino-5-cyanoimidazole (1.09 g, 11 mmol) and hexaneamide (4.39 g, 38 mmol) was heated at 210° C. for 15 h under N2 atmosphere. After cooling, the residue was dissolved in a mixture of DMF (200 ml) and water (50 ml). Benzyl chloride (3 ml) and K2CO3 (3 g) was added to the mixture, and heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by CH2Cl2. The resulting organic layer was evaporated under vacuum. 9-benzyl-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1-50:1). Bromine (2 ml) was added to the mixture of 9-benzyl-2-hexyladenine and NaOAc (5 g) in ACOH (40 ml) within an ice bath, and the mixture was heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, 9-benzyl-8-bromo-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1). A mixture of 9-benzyl-8-bromo-2-pentyladenine and conc.HCl (20 ml) was refluxed for 6 h. After cooling, aqueous NH3 was added to neutralize and crystallize the product (pH=8), and the desired compound was collected by filtration (0.25 g, Yield: 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][CH2:20][CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[OH:24]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h
Yield: 85 %

Procedure:
In 2 ml of acetic acid were dissolved 0.2 g of 2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-4,5-dihydro-1,2,4-triazine-3(2H)-one and 0.2 ml of hydrogenperoxide (30%). The reaction was allowed to proceed for 3 hours at temperatures ranging from 100 to 110° C. To the reaction mixture was added 20 ml of water to cause precipitation of the titled compound as crystalline product. The product was collected by filtration. The yield was 85%. m.p.175-176° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.[H-].[Na+].[CH3:41]N(C)C=O.CI>C(OCC)(=O)C>[CH3:41][O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCO)CC2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCOC)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A mixture of 4′-({4-[4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), sodium hydride (0.019 g) and N,N-dimethylformamide (10 mL) was stirred at 0° C. for 10 min, methyl iodide (0.029 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.078 g, 38%).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:20](=[O:24])([OH:23])([OH:22])O.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([OH:19])([P:20]([OH:24])(=[O:22])[OH:23])[P:20]([OH:23])(=[O:24])[OH:22])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)O
Reactant: CN(CCCCCc1ccccc1)CCC(=O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CN(CCCCCc1ccccc1)CCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
12.75 g (0.0446 mol) of 3-[N-(5-phenylpentyl)-N-methylamino]-propionic acid hydrochloride are heated under reflux at 100° with 6.1 ml of 85% phosphoric acid and 30 ml of chlorobenzene, while stirring. 11.7 ml of phosphorus trichloride are then added dropwise at 100°, evolution of the gas taking place. The reaction mixture precipitates a thick mass in the course of 30 minutes. The mixture is heated at 100° for a further 3 hours and the supernatant chlorobenzene is then decanted off. The viscous mass which remains is heated at the boil under reflux with 45 ml of 9N hydrochloric acid for 3 hours, while stirring. It is filtered hot, with addition of charcoal, and the filtrate is concentrated under reduced pressure. Addition of acetone gives the crude 3-[N-(5-phenylpentyl)-N-methyl-amino]-1-hydroxypropane-1,1-diphosphonic acid, which is recrystallized from water: melting point 124°-127° (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:14][CH2:13][CH2:12][N:10]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CC(C#N)c1cccc(Br)c1
Product: CC(C1=NCCN1)c1cccc(Br)c1

Procedure:
rac-2-[1-(3-Bromo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-bromo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): light yellow solid; MS (ISP): 252.9; 254.9 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)C.[K+].[CH2:7]1[C@@H:11]([OH:12])[CH2:10][NH:9][CH2:8]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31][C:32](F)=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:12][C@@H:11]4[CH2:7][CH2:8][N:9]([C:2](=[O:5])[CH3:1])[CH2:10]4)=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CC[C@@H](Oc2ccc3c(C4CCN(C(=O)OC(C)(C)C)CC4)ncnc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of KOt-Bu (55.1 mg, 0.47 mmol) in THF (1 mL) was added (R)-hydroxypyrrolidine (37.7 mg, 0.43 mmol), followed by 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (110.3 mg, 0.33 mmol), which was prepared as described in Example 12b, in THF (1 mL). The mixture was stirred for 1 h at room temperature, quenched with (CH3CO)2O. The mixture was then partitioned between EtOAc and water. The organic extracts were washed with brine and evaporated and the residue was used for the next step reaction without further purification. LC/MS for C24H33N4O4 (MH+) 440.2, found 440.5.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17]O.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH2:17][CH2:16][Cl:15])=[O:9])=[CH:13][CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: OCCCl
Agent: Cl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCCl

Procedure:
107.3 g (0.5 mole) of p-chlorophenoxy-2-methylpropionic acid are dissolved in 241.5 g (3 moles) of 2-chloroethanol. The solution is saturated with HCl gas. The excess of solvent is distilled under 11 Torr. The ester is distilled under 0.02 Torr, at a temperature of 97°-98°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC#N>[CH2:20]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of 4-(trifluoromethyl)phenol (50 g, 308 mmol) in CH3CN (600 ml) was added potassium carbonate (64 g, 463 mmol, 1.5 eq) and allyl bromide (48 g, 397 mmol, 1.3 eq) with stirring for overnight at 50° C. in an oil bath. The solids were filtered off and the filtrate was concentrated to a minimum volume, which was diluted by water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (2×200 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum to afford 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene as yellow oil (35 g, 56%); 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 5.98-6.11 (m, 1H), 5.30-5.46 (m, 2H), 4.57-4.58 (m, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[O:8][C:7]([C:9]([Cl:11])=[O:10])=[N:6][N:5]=1)[CH3:2].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[C:15]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:14]=1>>[ClH:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[C:15]([N:27]2[CH2:32][CH2:31][N:30]([C:9]([C:7]3[O:8][C:4]([S:3][CH2:1][CH3:2])=[N:5][N:6]=3)=[O:10])[CH2:29][CH2:28]2)[N:14]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCSc1nnc(C(=O)Cl)o1
Product: CCSc1nnc(C(=O)N2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)o1
Product: Cl

Procedure:
The title compound was prepared from 5-ethylthio-1,3,4-oxadiazole-2-carbonyl chloride (0.79 g., 4.1 mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.19 g., 4.1 mmole) following the procedure described in Example 1. The product had a M.P. of 246°-248.5° C.
Reaction SMILES: [Br-:1].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][NH:26][CH3:27]>C(O)C>[BrH:2].[Br-:1].[CH3:25][N:26]([CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:27]
Reactant: CNC
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCO
Product: Br
Product: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
According to the teachings in EP 0235795, a suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM4) in ethanol was reacted with 13.5 equivalents of an aqueous dimethylamine solution (50%) to provide dimethylaminopropyltriphenylphosphonium bromide HBr. After this reaction, the solvent was distilled off and the residue was recrystallized (yield: 59%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([F:18])=[C:12]([CH:14]=[CH:15][C:16]=1[F:17])[NH2:13].CCCCCC.O>CN(C)C=O>[Br:1][C:14]1[CH:15]=[C:16]([F:17])[C:10]([Cl:9])=[C:11]([F:18])[C:12]=1[NH2:13]
Reactant: Nc1ccc(F)c(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Nc1c(Br)cc(F)c(Cl)c1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
18.9 g of N-bromosuccinimide was gradually added to a stirred solution of 17.4 g of 3-chloro-2,4-difluoroaniline in 150 cm3 of dry dimethylformamide, cooled to a temperature in the region of −20° C., while this temperature was maintained. After stirring for 1 hour, the temperature was brought to the region of 20° C. and then the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C. The residue obtained was supplemented with 400 cm3 of hexane and 200 cm3 of water. The mixture was stirred and the aqueous phase decanted off. The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane. The extracts were combined, washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 19.2 g of 2-bromo-5-chloro-4,6-difluoroaniline was obtained in the form of a white solid, which melted at 62° C.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=12)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>[Pd].CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:14]3[C:9](=[O:8])[NH:10][N:11]=[CH:12][C:13]=3[CH:17]=[C:16]2[CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2c(C)cc3c(Cl)nnc(OCc4ccccc4)c32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(C)cc3cn[nH]c(=O)c32)cc1
Yield: 69 %

Procedure:
38.3 g (97 mmol) of 7-benzyloxy-4-chloro-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine (contaminated with about 5% of the isomeric 4-benzyloxy compound), 15 ml of triethylamine and 3.0 g of palladium (5%)/carbon catalyst are hydrogenated with hydrogen for 10 h in 3 1 of methanol. Purification: crystallization from methanol. Yield: 69%, m.p.: 212°-213° C.