Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23])#[N:17]>O>[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([N:23]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:24]=[CH:25][C:26]=1[Cl:27])#[N:17]
Reactant: N#CCCc1cc(N)ccc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: N#CCCc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred slurry of 5.0 g of 3,4,5,6-tetrahydrophthalic anhydride in 5 ml. of glacial acetic acid under N2 is added 7.5 g of 3-(2-cyanoethyl)-4-chloroaniline and the mixture heated to reflux for 2 hours. The reaction mixture is cooled to room temperature, water is added together with several mls. of conc. HCl and the mixture extracted with ether. The combined ether extracts are washed with saturated brine and then dried over MgSO4. Filtration and removal of the solvent yielded 8.9 g of a brown oil. The oil is dissolved in CH2Cl2, passed through a plug of alumina, the solvent removed, and then further purified by MPLC eluting with 25% EtOAc/hexanes to yield the product as a yellow solid, m.p. 87°-97° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][CH3:45].O>CN(C=O)C>[CH2:44]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]2[CH:17]=[N:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:6]3)=[N:20][CH:19]=2)[CH2:28][CH2:27]1)[CH3:45]
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCNCC5)cn4)c3)n2)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 mg (0.21 mmol) of 3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile are dissolved in 3 ml of DMF, 204 mg (0.63 mmol) of caesium carbonate and 16 μl (0.21 mmol) of bromoethane are added. The reaction mixture is stirred at room temperature for 15 h, a further 16 μl (0.21 mmol) of bromoethane are added, and the mixture is stirred at room temperature for a further 24 h. Water is added to the reaction mixture, which is then extracted with dichloromethane, dried and evaporated. The crude mixture is purified by means of preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Reactant: Clc1ccc(CBr)cc1
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(Cc2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 4-chlorobenzylbromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 to give 50.4 mg (21% overall yield) of the title compound: LC/MS (an10p8): Rt 2.6 min, m/z 482 [M−H]−. 1H NMR (DMSO-d6): δ 3.05 (dd, J=13.8, 9.7 Hz, 1H), 3.57 (dd, J=13.8, 4.9 Hz, 1H), 5.11 (dd, J=9.7, 4.9 Hz, 1H), 4.67 (s, 2H), 4.75 (s, 2H), 6.91 (d, J=8.7, 1H), 7.25-7.28 (m, 2H), 7.37-7.42 (m, 4H), 13.15 (br. s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:34]=[C:33]([C:35]([NH:37]O)=[NH:36])[CH:32]=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:37]=[C:35]([C:33]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:28])[CH:34]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccnc(N)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccnc(N)c5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane/hexane) as a yellow solid (167 mg, 66%). MS (EI) 505.2 [(M)+]; mp 245° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]4)[C:20]3=[O:28])[CH2:18]2)=[CH:15][CH:16]=1
Reactant: ClCCN1CCCCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C1N(CCN2CCCCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from with 1-(2-chloroethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H25ClN2O: 380, observed (M+H)+: 371.2 1HNMR (400 MHz, MeOD-d4) δppm 1.62 (br. s., 1 H) 1.89 (br. s., 3 H) 2.05 (br. s., 2 H) 2.21-2.30 (m, 2 H) 3.09 (br. s., 2 H) 3.30 (t, J=8.59 Hz, 1 H) 3.48-3.62 (m, 2 H) 3.76 (br. s., 1 H) 3.93 (br. s., 1 H) 4.22-4.32 (m, 1 H) 4.34-4.46 (m, 1 H) 6.15 (d, J=7.58 Hz, 1 H) 6.84 (t, J=7.58 Hz, 1 H) 7.15-7.21 (m, 1 H) 7.23-7.31 (m, 3 H) 7.33-7.40 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1
Reactant: OCc1cc(F)c(Oc2cccc(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(3-fluorophenoxyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: SCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCCc2ccccc2)cc1

Procedure:
A mixture of 174.6 grams (1.15 mole) of 3-phenylpropyl thiol, 158.8 grams (1.15 mole) of p-fluoroacetophenone and 158.8 grams (1.15 mole) of potassium carbonate in 500 ml. of dry dimethylformamide is stirred at its reflux temperature for approximately 24 hours. The reaction mixture is cooled, water added and extracted with methylene chloride. The extract is washed with water, a solution of 2 N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol to yield the desired p-(3-phenylpropylthio)acetophenone having a m.p. of 76°-8° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([SH:13])[N:8]=2)=[CH:4][CH:3]=1.[CH3:14]I>O.[OH-].[Na+].CCO>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Sc1nccc(-c2ccc(Br)s2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2ccc(Br)s2)n1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
4-(5-Bromothiophen-2-yl)-pyrimidine thiol (2.5 g, 9.15 mmol) was completely dissolved in 14.8 mL DI water and 2.4 mL 4 N NaOH. The mixture was diluted with EtOH (25 mL) and MeI (0.598 mL, 9.61 mmol) was added. The reaction was stirred 18 hours. The yellow solids were collected by filtration, washed with EtOH and dried to afford 4-(5-Bromothiophen-2-yl)-2-methylsulfanyl-pyrimidine (2.32 g, 88.6%) as a pale yellow solid. MS: m/z 287 (M+H+).
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]([CH3:20])=[N:6][N:7]([CH2:18][CH3:19])[C:8]=1[S:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:10]([S:9][C:8]2[N:7]([CH2:18][CH3:19])[N:6]=[C:5]([CH3:20])[C:4]=2[CH2:3][NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:17])[CH:13]=1
Reactant: CCn1nc(C)c(CCBr)c1Sc1cc(Cl)cc(Cl)c1
Reactant: Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(CNc2cccnc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 7.5 %

Procedure:
A mixture of 227 mg of 4-bromoethyl-5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole, 62 mg of 3-aminopyridine and 36 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 15 minutes. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol for the elution to give 17 mg of [5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridin-3-yl-amine as a brown gum. 1H NMR (DMSO-d6) 1.19 (t, 3H), 2.27 (s, 3H), 4.05–4.11 (m, 4H), 6.03 (t, 1H), 6.87 (d, 1H), 6.99 (m, 1H), 7.04 (d, 2H), 7.44 (t, 1H), 7.72 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].[CH2:19](I)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:17][C:14]1[CH:13]=[N:12][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:18][CH2:19][CH3:20])[CH:6]=2)=[N:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cn2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(Oc2ncc(Cl)cn2)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
2-Nitro-5-(5-chloro-2-pyrimidyloxy)phenol (0.65 g), ethyl iodide (2 ml), potassium carbonate (0.35 g) and methyl ethyl ketone (20 ml) were heated together under reflux with stirring for 15 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The chloroform extracts were dried and evaporated under reduced pressure to give a pale yellow solid which was recrystallized from ethanol to give the title compound as pale yellow needles (0.54 g), m.p. 114°-115° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.ClC1C=CC=C[N+]=1C.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:20]([O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(OCc1ccccc1)c1ccccc1
Yield: 83 %

Procedure:
To a CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium p-toluenesulfonate (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), benzoic acid (244 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2, and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl benzoate was isolated in 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][O:15]C(=O)C)[CH2:9]1)=[O:7].[OH-].[Li+]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOC(C)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 3.5 h

Procedure:
Combine (+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine (670 mg, 1.35 mmol) and aqueous lithium hydroxide solution (4.2 mL, 1M) in methanol (15 mL). After 3.5 hours, concentrate in vacuo to give a residue. Dissolve the residue in dichloromethane and extract with 1M hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. The residue was dried under high vacuum for 18 hours to give (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine: Rf=0.11 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][NH2:2].CO.CO.Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[CH3:1][NH:2][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: ClCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: CNCc1cccc2ccccc12
Temperature: 0 °C
Yield: 91.9 %

Procedure:
1.14 g (11.3 mmol), of triethylamine was mixed with a 40% methylamine-methanol solution and 5 ml of the methanol containing 2.00 g (11.3 mmol), of 1-chloromethylnaphthalene was dropped while stirring in an ice bath. After dropping, the reaction mixture was taken out of the ice bath and stirred at room temperature for 60 hours. The solvent was distilled off under reduced pressure and extracted with ether-2N hydrochloric acid. The organic extract was washed with saturated saline and dried with sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.78 g (yield: 91.9%), of the target compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:34][CH3:35])[C:32]=1[CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22](C)[C:23](=O)C(F)(F)F)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:35][O:34][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:32]=1[CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][CH3:23])=[O:7]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(C)C(=O)C(F)(F)F)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1cc(-c2noc(C)n2)ccc1CNC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A suspension of compound 1i (0.11 g, 0.22 mmol) and potassium carbonate (92.5 mg, 0.67 mmol) in a mixture of methanol (2.5 mL) and water (0.4 mL) was stirred at rt for 3 h. The reaction mixture was filtered and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed with water and brine, dried MgSO4, and concentrated to give compound 1j (30 mg, 34%). ESI-MS m/e 397.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4ccc(O)cc4O3)cc2o1
Temperature: 86 °C

Procedure:
(S)-2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (3.53 g, 16.2 mmole), 7-(3-bromopropoxy)coumarin (4.17 g, 14.7 mmole), and diisopropylethylamine (5.00 ml, 28.7 mmole) were combined in 300 ml of DMF and heated at 86° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 300 g of silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the free base redissolved in warm methanol. Five ml of 4N isopropanolic HCl was added, the mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 2.24 g of the title compound precipitated as an white solid, monohydrochloride, m.p. 245°-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][CH2:15]I.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:31])[CH:26]([CH2:15][CH2:14][C:3]1[CH:4]=[C:5]([O:10][CH:11]([CH3:13])[CH3:12])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cc(Br)c(CCI)cc1OC(C)C
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1cc(OC(C)C)c(OC)cc1Br)C(=O)OC

Procedure:
1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.0 g, 45.1 mmol), potassium carbonate (32.0 g, 321 mmol, anhydrous, freshly ground) and malonic acid dimethyl ester (50.0 g, 378 mmol) are stirred in absolute DMF (200 ml) for 12 hours at 80° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:12]=2)[CH:6]=[CH:5][C:4]=1[OH:26]>[Pd]>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH:12]=2)[CH:6]=[CH:5][C:4]=1[OH:26]
Reactant: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(O)c(CO)c2)c1
Agent: [Pd]
Product: CC(C)(O)CCCCCc1cccc(CCc2ccc(O)c(CO)c2)c1

Procedure:
In a manner similar to Example 9(a), by reacting 97 mg (0.27 mmol) of 2-hydroxymethyl-4-{2-[3-(6-hydroxy-6-methylheptyl)phenyl]vinyl}phenol with 27 mg of 10% palladium/carbon, yellowish crystals (m=70 mg; Y=73%) are obtained. m.p.=73-5° C.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][NH:11][C:12]([NH2:14])=[S:13]>O>[CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(N)=S
Reactant: O=Cc1ccccc1O
Solvent: O
Product: NC(=S)NN=Cc1ccccc1O
Temperature: 75 °C
Yield: 98 %

Procedure:
Salicylaldehyde was added dropwise over 5 min. to a solution of thiosemicarbazide (5.47 g, 60 mmol) in 75 mL water maintained at 75° C. A white solid began to precipitate immediately. The resulting mixture was heated to reflux for 2 hours, then cooled to room temperature and filtered to give salicylaldehyde thiosemicarbazone (11.5 g, 98%) as a white crystalline solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:29])[NH:6][C:7]1[C:8]([CH3:28])=[C:9]([CH2:26][CH3:27])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[CH2:26]([C:9]1[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]([CH3:25])=[C:7]([NH:6][C:5]([NH:32][CH2:33][CH2:34][OH:35])=[O:29])[C:8]=1[CH3:28])[CH3:27]
Reactant: NCCO
Reactant: CCc1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
Using 2,2,2-trichloroethyl(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 139 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 57%. Melting point: 147-148° C. (hexane-ethyl acetate).
Reaction SMILES: [CH:1]([C:9]1[C:10]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[CH:11][CH:12]=[C:13]2[C:18]=1[CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:34].[CH3:35]O>>[ClH:34].[CH:1]([C:9]1[C:10]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:31])([F:30])[F:32])[CH:22]=2)=[CH:11][CH:12]=[C:13]2[C:18]=1[CH2:17][N:16]([CH3:35])[CH2:15][CH2:14]2)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2C=Cc2ccccc2)CNCC3)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Product: COc1ccc(C(=O)Nc2ccc3c(c2C=Cc2ccccc2)CN(C)CC3)cc1C(F)(F)F

Procedure:
The title compound (0.033 g) was prepared from N-(8-styryl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.068 g) according to the method of Example 3. The free base was converted into the hydrochloride salt by treatment of a methanol solution with excess ethereal HCl.
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]([C:14]([OH:16])=[O:15])=[CH2:13])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]O>[Pd]>[CH2:1]([N:8]1[CH:11]([CH:12]([C:14]([O:16][CH3:21])=[O:15])[CH3:13])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)C1C(C(C)O)C(=O)N1Cc1ccccc1
Reactant: CO
Agent: [Pd]
Product: COC(=O)C(C)C1C(C(C)O)C(=O)N1Cc1ccccc1
Yield: 78 %

Procedure:
To a solution of 38 mg (0.14 mmol) of 1-benzyl-4-(1-carboxyethenyl)-3-(1-hydroxyethyl)-2-azetidinone dissolved in 1 ml of methanol, 5 mg of 5% palladium charcoal was added and the mixture was stirred under hydrogen atmosphere for a night. The reaction solution was filtered with selite, the filtrate was added with an ethereal solution of diazomethane and the resultant was concentrated. The concentrate was purified with 2 g of silica-gel column (benzene:ethyl acetate 1:1) to give 30 mg of 1-benzyl-4-(1-methoxycarbonylethyl)-3-(1-hydroxyethyl)-2-azetidinone (yield: 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>ClCCl.CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])[CH:8]=2)[CH:3]=[N:2]1
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 1H-indazol-6-ol (0.88 g, 6.6 mmol) in dichloromethane (10 ml) at room temperature was added triethylamine (0.98 ml, 7.0 mmol) and DMAP (0.05 g) followed by trimethylacetyl chloride (0.82 ml, 6.6 mmol). After stirring for 1 h, the mixture was diluted with saturated aqueous solution of ammonium chloride (20 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 10% to 20% ethyl acetate in hexane) to give an oil (1.1 g, 76%): 1H NMR (CDCl3) δ 8.15 (d, J=0.8 Hz, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6 Hz, 1H), 1.59 (s, 9H); MS(ES) m/z 219 (M+).