Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:14])[C:6]=2[CH:15]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:8]=3[S:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: O=S1c2ccccc2-c2ccc(Br)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc(Br)ccc1-2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 69.8 g of glacial acetic acid and 27.9 g of 3-bromodibenzothiophene-5-oxide prepared in Example 1-1 in a nitrogen atmosphere, and cooled to 10° C. 239.8 g of concentrated sulfuric acid was added dropwise, and the resulting mixture was cooled to −2° C. Then 72.0 g of 70 wt % nitric acid was added dropwise at −2 to 8° C., and the resulting mixture was stirred at or below 5° C. for 2 hours. The reaction mass was poured into 1200 g of ice water to terminate the reaction, and stirred further. The reactant was filtered, washed with water, and dried. The resulting dry cake was washed with ethanol to obtain 31.9 g of 3-bromo-7-nitrodibenzothiophene-5-oxide. The product was subjected to elemental analysis, the results of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[CH3:20].O>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11]#[N:12])=[CH:6]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-cyanoindole (2.0 g) in N,N-dimethylformamide (50 mL) were added cesium carbonate (7.4 g) and 4-fluorobenzoic acid ethyl ester (3.0 g), and this mixture was stirred at 80° C. for 48 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (1.8 g).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1>CCO>[NH:2]([C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[N:8]=[CH:9][N:10]=1)[NH2:3]
Reactant: Clc1ncnc2c1CCCCCC2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncnc2c1CCCCCC2
Temperature: 60 °C
Yield: 60 %

Procedure:
Hydrazine monohydrate (0.21 mL; 4.34 mmol; 1.2 equiv) was added to a suspension of 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (0.71 g; 3.62 mmol; 1.0 equiv) in 8 mL of EtOH. The reaction was heated at 60° C. overnight. The solid was filtered, washed with H2O and dried to give 4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine as an off-white solid (0.42 g; 60% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:66][O:67][C:68](=[O:72])[CH2:69][CH2:70][SH:71].C(N(C(C)C)C(C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:7][C:2]=1[S:71][CH2:70][CH2:69][C:68]([O:67][CH3:66])=[O:72]
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Yield: 34.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) (0.05749 g, 0.06278 mmol), 5-bromo-4-(2,6-difluorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 128; 1.0 g, 2.511 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.07265 g, 0.1256 mmol), methyl-3-mercaptopropanoate (0.2920 ml, 2.637 mmol), N-ethyl-N-isopropylpropan-2-amine (0.8748 ml, 5.022 mmol) and dioxane (50 mL) were heated under argon at 80° C. overnight and then concentrated. The residue was purified by column chromatography to provide the desired product (0.375 g, 33.79% yield) as a yellow solid. 1H NMR (CDCl3) δ 10.97 (s, 1H), 8.37 (s, 1H), 7.26 (m, 1H), 7.03 (t, 2H), 6.26 (s, 1H), 6.03 (s, 1H), 3.67 (s, 3H), 3.12 (t, 2H), 2.62 (t, 2H), 2.06 (s, 3H).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:15]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:17])[CH2:3][CH2:4][C:5](=[O:14])[OH:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boc-L-Glu(OBzl)OSu (Bachem, 434 mg (1 mmol) is reacted with L-Ala-OtBu.HCl, 182 mg (1 mmol) in 10 mL DMF containing triethylamine (202 mg). After stirring for 16 hours at room temperature, the reaction mixture is rotary evaporated to dryness and the residue is redissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is redissolved in methanol, 50 mL, and transferred to a Parr flask. 10% Pd/C catalyst (Aldrich), 50 mg, is added and the flask is charged with 40 psi hydrogen gas on a Parr shaker. The mixture is shaken for 2 hours at room temperature or until no further consumption of hydrogen is noted. The Parr flask is evacuated and charged with argon gas. The mixture is filtered through Celite, and the filtrate is rotary evaporated to give crude Boc-L-Glu-Ala-OtBu.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(Cc1ccc(O)cc1-c1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (400 mg) in dimethoxyethane (4.00 mL) and water (1.20 mL) were added phenyl boronic acid (182 mg), sodium carbonate (396 mg), and 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (50.9 mg), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (5-hydroxybiphenyl-2-yl)acetate (344 mg).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:12]3=[N:13][S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][N:11]3[CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1>C1COCC1.[C].[Pd]>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:12]3=[N:13][S:14](=[O:17])(=[O:18])[CH2:15][CH2:16][N:11]3[CH2:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)cc3)C2=N1
Reaction time: 8 h
Yield: 104.8 %

Procedure:
A mixture of 10% palladium-carbon (50% wet, 12 mg) and 9-biphenyl-4-yl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (115 mg) in THF (50 ml) was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (122 mg) as a white solid. The obtained solid was crystallized from acetonitrile, diisopropyl ether and hexane to give a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]1[CH:16]([C:17]([CH2:19]P(=O)(OC)OC)=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](=O)[C:41]([O:43]C)=[O:42])=[CH:31]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]1[CH:16]([C:17]([CH2:19][CH:40]([CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[C:41]([OH:43])=[O:42])=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6]
Reactant: COC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: COP(=O)(CC(=O)C1Cc2ccccc2CN1C(=O)c1cc(C)cc(C)c1)OC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(C(=O)N2Cc3ccccc3CC2C(=O)CC(Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
A Wittig-Horner reaction according to example 78 between dimethyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarbonylmethylphosphonate [from methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate (prepared according to example 88) as described in example 78] and methyl 3-indolepyruvate followed by catalytic hydrogenation of the double bond in the presence of Wilkinson's catalyst according to example 78 and hydrolysis of the methyl ester moiety according to example 12 gives 3-[N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl]-2-(3-indolyl)methyl-propionic acid as a mixture of isomers; FAB-MS m/e 495 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cnn(Cc2ccccc2)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnn(Cc2ccccc2)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution (50 mL) of 1-benzyl-4-methyl-1H-pyrazol-5-amine (5 g) and tetrahydro-4H-pyran-4-one (3.2 g) in acetic acid was added sodium cyanoborohydride (6.8 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium 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 (1.9 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:29][O:30][CH2:31][CH2:32][N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: COCCBr
Product: COCCN1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and bromoethyl methyl ether in the same manner as in Example 32.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].N1C=CN=C1.[Si:39](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>C(Cl)Cl>[Si:39]([O:8][CH:7]1[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1=[CH2:1])([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Ethyl (2-methylene-3,4-dihydroxy-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate (0.466 g) was dissolved in 5 ml of methylene chloride, and 0.204 g of imidazole and 0.30 g of tert-butyldiphenylsilyl chloride were added, followed by stirring the mixture at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.664 g of ethyl (3,5-bis-(tert-butyldiphenylsilyloxy)-4-hydroxy-2-methylene-cyclohexylidene)acetate having the following property.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Br

Procedure:
A solution of 2-bromo-3-methyl-benzoic acid (21.5 g, 100 mmol) in 500 mL of methanol and 8 mL of concentrated sulfuric acid is refluxed overnight. Methanol is removed under reduced pressure, the residue is taken up in ether, washed with sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[C:24]1(/[CH:30]=[CH:31]/B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([CH:31]=[CH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3C=Cc3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), trans-2-phenylvinylboronic acid (148 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (53 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])[C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[CH3:20]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1
Reaction time: 3 h

Procedure:
A solution of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g) in dry ethanol (250 ml) was saturated with gaseous hydrogen chloride. The reaction mixture was allowed to ware during the inlet of the hydrogen chloride. After standing for 3 hours, the solvent was removed by evaporation in vacuo. The residue was dissolved in a mixture of diethyl ether and dilute sodium hydrogen carbonate. The organic layer was separated, washed with water and dried. The diethyl ether was distilled off, and the residue was recrystallized from dry ethanol, yielding the ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate with a melting point of 154°C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH3:12])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[CH:3]=1
Reactant: CCCCCC[Mg]Br
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(CCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (5.1 g, 12 mmol) in dry THF (80 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (3 ml of a 0.1M solution in THF, 3 mol %). A solution of hexylmagnesium bromide (13 ml of a 2.0M solution in diethyl ether, 0.026 mol) was added dropwise over 30 min. The reaction was stirred for 2 h, during which time the internal temperature rose to 15° C. The reaction was cooled to 0° C. and further lithium tetrachlorocuprate (1 ml of a 0.1M solution in THF, 1 mol %) was added. The reaction was then stirred for 24 h at 25° C., before quenching and workup as above. Yield (61%). M.p 47-49° C. 1H and 13C NMR spectra as expected. M+=504 (t). Anal. Calcd. For C26H32Br2: C, 61.9; H, 6.4; N, 0.0. Found C, 61.8; H, 6.1; N, <0.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH3:16])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:15])([CH3:14])[CH3:13])[CH:7]=1.[Mg]>CO>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:15])([CH3:13])[CH3:14])[CH:7]=1
Reactant: COC(=O)C(C)=Cc1cccc(C(C)(C)N)c1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C(C)Cc1cccc(C(C)(C)N)c1

Procedure:
The mixture of 3-[3-(1-amino-1-methyl-ethyl)-phenyl]-2-methylacrylic acid methyl ester (2.0 g, 8.6 mmol), magnesium (0.63 g, 25.8 mmol) in methanol was heated to reflux for 3 h until the starting material was consumed. The mixture was brought to room temperature, filtered and the filtrate was concentrated. The residue obtained was washed with saturated NH4Cl, brine, dried over magnesium sulfate and concentrated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[C:7](=O)[CH2:8][CH3:9].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:13][C:7]=1[CH2:8][CH3:9]
Reactant: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1oc(-c2ccc(C)cc2)nc1CCCCCl
Yield: 90.1 %

Procedure:
To 150 ml of toluene, 6.5 g of 8-chloro-4-(p-toluoylamino)-3-octanone was dissolved, and 4.1 ml of phosphorus oxychloride was added and heated to reflux for 1.5 hours. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The extract was washed with an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=8:1) to provide 5.5 g of the objective compound as yellowish crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([OH:31])=O)[N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([NH2:37])=[O:31])[N:28]=3)=[CH:32][CH:33]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(=O)O)cs3)cc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(N)=O)cs3)cc2)c1-c1ccc(F)cc1
Yield: 87.7 %

Procedure:
A mixture of 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylic acid (0.24 g), a 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.12 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxamide as colorless crystals (0.21 g, yield 88%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48]([O-])=[O:49].[Na+]>CN(C)C=O>[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48](=[O:49])[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[CH2:13]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: c1ccc2c(c1)NCC21CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CC3(CCOCC3)c3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 770 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 4d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 15 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 45 mg of 3-methyl-6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following: