Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Cl:20]N1C(=O)CCC1=O>ClCCl>[Cl:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2c(Cl)c(N)ncc2c1
Yield: 85.4 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (60.8 mg, 241 μmol) in dichloromethane (2.0 mL) was treated with N-chlorosuccinimide (35.2 mg, 264 μmol) at ambient temperature. After 24 h the mixture was absorbed directly onto silica gel in vacuo and purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the title compound as a pale orange solid (59.0 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.00 (t, J=8.3 Hz, 2H), 4.95 (s, 2H), 2.25 (s, 3H). 1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.18-7.12 (m, 2H), 6.40 (s, 2H), 2.24 (s, 3H). LCMS (Method E): RT=5.508 min, M+H+=287.0 & 289.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[Cl:18][C:19]([Cl:33])([Cl:32])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.O>CN(C=O)C>[Cl:18][C:19]([Cl:32])([Cl:33])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Reactant: O=C(O)Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Cesium carbonate (1.69 g, 5.20 mmol) was added to a mixture of 3-mercapto-phenylacetic acid (0.73 g, 4.33 mmol) and 2-bromomethyl-benzoic acid 2,2,2-trichloro-ethyl ester (1.50 g, 4.33 mmol) in DMF (25 mL). The mixture was stirred for 1 h at rt. Water was added and the mixture was washed with diethyl ether. The aqueous phase was made acidic (pH5-3) with 2M HCl and thereafter extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and concentrated to give the titled compound (1.88 g, 100%); 1H NMR (400 MHz, CDCl3): δ 3.50 (s, 2H), 4.46 (s, 2H), 4.88 (s, 2H), 7.01-7.08 (m, 1H), 7.10-7.16 (m, 4H), 7.22-7.35 (m, 2H), 8.00 (d, 1H); Mass spectrum: M−H+ 432.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:12][C:4]1[S:3][C:2]2[N:1]=[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][N:19]3[C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Product: Cc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, page 94-100, 1966), 18.5 g (0.1 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 15.7 g (0.1 mol) is heated in an oil bath at 170°-190° C. for 20 hours. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in hot pyridine, cooled and 0.4 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 312°-315° C. after recrystallization from methanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[CH:10]=[CH:11]2)[CH3:29]
Reactant: CCNCC
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCOS(C)(=O)=O)ccc32)cc1
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCN(CC)CC)ccc32)cc1

Procedure:
In analogy to example 5.5, Methanesulfonic acid 5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester and diethylamine were converted to yield Diethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine as yellow oil, MS: 355 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:38][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 2-methyl-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester, Example 24 (1.0 g, 3.48 mmol) in dry carbon tetrachloride (50 mL) was added 126 mg (0.52 mmol) of benzoyl peroxide and 712 mg (4.0 mmol) of recrystallized N-bromosuccinimide. A reflux condensor was attached and the mixture was heated to reflux and stirred overnight. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (250 mL) and washed with water, followed by saturated sodium bicarbonate, and then brine. The organic layer was dried (MgSO4) and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography using 10% ethyl acetate in hexanes gave 560 mg (44%) of the title compound as a white solid: 1HNMR (CDCl3): d 8.83 (d, J=2 Hz, 1H), 8.48 (dd, J=2 Hz, 9 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 4.96 (s, 2H), 3.85 (s, 2H), 1.0 (s, 9H); MS (ES-NEG): [M−H] 364/366; Anal. Calc. for C12H16BrNO5S: C, 39.35; H, 4.40; N, 3.82. Found: C, 39.88; H, 4.16; N, 3.85.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[O:8]1[CH2:11][CH2:10][C:9]1=[O:12]>C1COCC1.II>[OH:8][CH2:11][CH2:10][C:9]1([OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCO1
Reactant: BrCCCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
A solution of 1,4-dibromobutane (10 g, 46 mmol) in THF (100 mL) was treated with magnesium (2.81 g, 116 mmol) and I2 (100 mg). The mixture was stirred at room temperature for 3 hours a solution of oxetan-2-one (3.34 g, 46.3 mmol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours then quenched with saturated aqueous NH4Cl and extracted with isopropanol/CH2Cl2 (1:3) (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by distillation (95-100° C. at 0.6 Ton) to provide 1.1 g (18%) of the title compound. MS (DCI/NH3) m/z 148 (M+NH4)−.
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:48])([F:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:46][CH2:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:48])([F:31])[F:47])=[CH:34][CH:35]=3)[CH:44]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
Acid 15A (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. he residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:Petroleum ether) afforded 140 mg of a white solid. Yield=26.8% 1HNMR (DMSO, 400 MHz) δ 1.09 (2H, bs), 1.23 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=6.8 Hz), 4.41 (2H, bs), 7.26 (1H, dd), 7.42 (2H, t, J=8.8 Hz), 7.87 (4H, m), 7.98 (1H, bs), 8.30 (3H, bd), 8.64 (1H, dd, J=4.8 Hz) [M+1] 521.9 (C25H23F4N3O3S requires 521.53).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:11](=[O:18])[C:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH2:19])[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1

Procedure:
2',3'-Dichloro-4'-methoxy-2-cyclopentyl-acetophenone (51.6 g., 0.18 mole) is dissolved in dioxane (460 ml.) and paraformaldehyde (21.6 g., 0.72 mole) and concentrated sulfuric acid (9.65 g.) are added. The mixture is heated at 80°-85°C. for 20 hours. The dioxane is evaporated at reduced pressure. Water is added to the residual gum which then is extracted into ether. The ether extract is washed with water and dried over magnesium sulfate. The ether is evaporated and upon triturating the residue with hexane (5 ml.) there is obtained a solid that is crystallized from ligroin to obtain (33.3 g.), m.p. 59°-63°C. Crystallization from butyl chloride affords a sample (m.p. 66°-67.5°C.) for analysis.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C=O)C>C(Cl)Cl>[C:5]1([CH:11]([CH2:15][CH3:16])[C:12]([Cl:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C(=O)Cl)c1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Thionyl chloride (0.12 mol) in 60 mL of CH2Cl2 was added to a stirred solution of 2-phenylbutyric acid (16.4 g, 0.10 mol). A catalytic amount of DMF was added and the reaction was allowed to continue overnight at room temperature. The volatiles were removed under vacuum and the residual liquid was vacuum distilled to yield 12.4 g (68%) of 2-phenylbutyryl chloride. IR (neat) 1798 cm-1 (C=O).
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[O:14])(=O)C1C=CC=CC=1>C(OCC)(=O)C.[H][H].[Pd]>[OH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[O:14]
Reactant: COc1ccc(C(=O)N2CCCC2=O)cc1OC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1O
Temperature: 25 °C

Procedure:
150 mg of 1-(3-benzoyloxy-4-methoxybenzoyl)pyrrolin-2-one are dissolved in 100 ml of ethyl acetate and hydrogenated with hydrogen over 150 mg of 5% palladium/carbon at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated. The residue is stirred at room temperature in diethyl ether. After filtration, there is obtained 1-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone of melting point 122°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)cccc1F
Yield: 76.9 %

Procedure:
A mixture of 2,6-difluorobenzoic acid (10 g, 63.3 mmol) and DMF (3 drops) in dichloromethane (150 ml) was treated with thionyl chloride (23 ml, 316.5 mmol). The mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue azeotroped (toluene 3×50 ml) to give 2,6-difluorobenzoyl chloride as an oil (8.59 g, 77%). N Boc-L4-aminophenylalanine methyl ester (100.92 g, 40.6 mmol) and NMM (5.3 ml, 48.7 mmol) were added to a solution of the above acid chloride in DMF (50 nm). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to give a pale brown oily solid. Trituration with ether gave the title compound as a white solid (6.93 g). δH(d6 DMSO) 7.67-7.53 (3H, m), 7.27-7.20 (5H, m), 4.19-4.11 (1H, m), 3.62 (3H, s), 3.00-2.73 (2H, m), 1.33 (9H, s); m/z (ESI, 70V) 457 (M++Na).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][C:61]=1[C:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:68]>C1(C)C=CC=CC=1>[Cl:66][C:63]1[CH:64]=[CH:65][C:60]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:61]([C:67]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:68])[CH:62]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Br
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N1CCNCC1
Temperature: 110 °C

Procedure:
Piperazine (3.6 g, 42.5 mmol), Pd(II)acetate (0.007 g, 0.043 mmol), sodium t-butoxide (0.22 g, 2.4 mmol) and BINAP (0.042 g, 0.068 mmol) were stirred at room temperature in 10 mL dry toluene for 15 min. (2-Bromo-5-chloro-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol) in 10 mL dry toluene was then added into the reaction mixture. The reaction mixture was refluxed at 110° C. for 20 hrs, filtered through a celite bed, washed with toluene, concentrated, taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (eluted with CHCl3-MeOH) afforded the title compound as product.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:9]=1)=[C:2]=[S:3].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCO>[C:24]([NH:32][NH:33][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:9]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N=C=S)ccc1C)c(=O)n2C
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NNC(=O)c3ccccc3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 19 (50 mg, 0.16 mmol) in EtOH (1.0 mL), benzohydrazide (26 mg, 0.19 mmol) was added and stirred at rt for 2 h. The solvent was removed under vacuum to yield crude 2-benzoyl-N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)hydrazinecarbothioamide, which was used without purification. MS m/z 458.2 (M+1).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][C:25]1=[O:40].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:40])[CH2:26]4)=[N:35][CH:34]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(N2CCN(C)C(=O)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(=O)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) and methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 0.98 mmol) in toluene (5.00 mL) at 25° C. The resulting solution was stirred at 60° C. for 24 h. The reaction mixture was added to methanol (100 mL), then treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (204 mg, 45%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([S:21]Cl)=[O:20]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:19](=[O:20])[S:21][N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 90 °C

Procedure:
To a solution of 4-benzyloxybenzamide (0.25 g, 1.10 mmol) in toluene (15 ml) was added chlorocarbonylsulfenyl chloride (0.18 ml, 2.20 mmol) and the resulting reaction mixture was refluxed at 90° C. overnight. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was then dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.310 g, 98%) that was used as such for the next step.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: CO[SiH](OC)OC
Product: CO[Si](CCCOCC1CO1)(OC)OC

Procedure:
In the example, allyl glycidyl ether was reacted with trimethoxysilane to form 3-glycidyloxypropyltrimethoxysilane. The reaction was carried out continuously by feeding the raw materials (allyl glycidyl ether: 9.6 kg/h and trimethoxysilane: 8 kg/h) together with the Pt Karstedt catalyst in the presence of acetic acid (0.05% by weight, based on the total mass of reactants) into a tube reactor. The concentration of the catalyst based on metallic platinum was 2 ppm. The Pt Karstedt catalyst was dissolved in 3-glycidyloxypropyltrimethoxysilane. The reaction temperature was about 160° C. The reaction was carried out using an excess of allyl glycidyl ether (molar ratio of allyl glycidyl ether:trimethoxysilane=1.28:1). The reaction mixture formed was composed of:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.85 mL, 5.1 mmol) was added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (1 g, 3 mmol) (Aldrich, Cat 469106) and triethylamine (1 mL, 10 mmol) in methylene chloride (30 mL) at −78° C. The reaction was stirred for 1 h. at −78° C. Saturated NaHCO3 was added and the reaction was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) to obtain (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid methyl ester (1.2 g, 80%) as light yellow oil. Analytical LCMS (M+H-Boc)+: m/z=327.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)nc1
Yield: 88 %

Procedure:
To a solution of 2-amino-5-pyridinecarboxylic acid 113 (150 g, 1.09 mol) in ethanol (2 L) was added thionyl chloride (259 g, 2.18 mol) at 0° C. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure. Saturated aq Na2CO3 was added to adjust the pH to 9 and the resulting solid was collected by filtration, rinsed with H2O, and dried to give 114 (160 g, 88% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.CO>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(/C=C/c2c[nH]cn2)cc1

Procedure:
Prepared by refluxing the 4-[2-(4-nitro-phenyl)-(E)-ethenyl]-1-triphenylmethyl-1-H-imidazole (melting point: 280-285° C.) obtained in Example 9.9 (a) in 1N hydrochloric acid (4 hours) and column chromatography on silica gel with CH2Cl2 /MeOH (10:1) as eluant.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CS(O[CH:25]1[CH2:28][N:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)(=O)=O>C(#N)C.O1CCCC1>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]2[CH2:28][CH:25]([N:10]3[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]3)[CH2:26]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Potassium carbonate (26 g) was added to a solution of tert-butyl piperazine-1-carboxylate (7.7 g) in acetonitrile (100 ML), to which a suspension of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (12.05 g) in tetrahydrofuran (30 mL) was added at room temperature, and the mixture was stirred for 4 hours at 100° C., and then concentrated. To the resulting residue was added water, and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1→1:2), and the product was washed with tert-butyl methyl ether and collected by filtration to give the title compound (10.68 g) having the following physical data.