Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH:26]1([O:17][C:15]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH:16]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrC1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To N,N-dimethylformamide 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-hydroxybenzoate 0.30 g were added potassium carbonate 0.16 g and cyclohexyl bromide 0.42 mL at room temperature, and it was stirred at 80° C. for 8 hours. After the reaction mixture was cooled to room temperature,11.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=8:1] to give methyl 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoate 40 mg of colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CO>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccccc3)ccc2CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2ccc(-c3ccccc3)cc2c1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
In methanol (35 ml) was dissolved 7-phenyl-3,4-dihydro-naphthalene-2-carboxylic acid (1.50 g), and to the mixture was added concentrated sulfuric acid (0.1 ml), and then the mixture was refluxed for 9 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), and to the mixture was added activated manganese dioxide (9 g). The mixture was refluxed for 48 hours and then cooled to room temperature. The manganese dioxide was filtered off, and the filtrate was concentrated. The residue was dissolved in methanol (15 ml), and to the mixture was added 1N sodium hydroxide (10 ml). The mixture was refluxed for 4 hours and then cooled to room temperature. The mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-phenylnaphthalene-2-carboxylic acid (783 mg) as colorless crystals.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][C:8]([C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=O.[C:15]([CH2:17][C:18](=[S:20])[NH2:19])#[N:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[S:20]1[CH:7]=[C:8]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[N:19]=[C:18]1[CH2:17][C:15]#[N:16]
Reactant: N#CCC(N)=S
Reactant: O=C(CCl)c1cscn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1nc(-c2cscn2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A N,N-dimethylformamide (49 mL) suspension of 2-chloro-1-(1,3-thiazol-4-yl)ethanone (4.9 g), 2-cyanoethanethioamide (3.3 g) and potassium carbonate (4.6 g) was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. An organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1). Isopropyl ether was added to the residue, and the solid was collected by filtration to obtain the title compound (2.8 g) as a faint orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of NaOH (0.483 g, 12.06 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 45 minutes. To the mixture was added 1 N HCl (23 mL) and the mixture was stirred overnight. The solids were collected by filtration, washed with water (1×5 mL) and dried by vacuum filtration to give 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H-NMR: (400 MHz, DMSO-d6) δ ppm 13.97 (bs, 1H), 10.62 (bs, 1H), 8.26 (dd, 1H, J=1.6, 1.6, 3.2 Hz), 8.16 (ddd, 1H, J=8.1, 1.1, 1.1 Hz), 7.90 (ddd, 1H, J=8.1, 1.4, 1.4 Hz), 7.68 (dd, 1H, J=7.8, 7.8 Hz), 7.25-7.1 (m, 4H); MS (ESI) m/z 294.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 55 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (55 mg, 55.0%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:7]1.C([OH:38])(CC)(C)C.[OH-].[K+]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]([NH2:15])=[O:38])[CH2:7]1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC(Oc2cccc(O)c2)C1
Reactant: CCC(C)(C)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2cccc(O)c2)C1
Temperature: 80 °C

Procedure:
A suspension of 5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile (0.16 g, 0.38 mmol, 1 equiv), t-amyl alcohol (1.8 ml, 12 ml/g) and KOH (0.41 g, 7.26 mmol, 20 equiv) was heated to 80° C. for 2 d whereupon HPLC showed completion of reaction. The reaction was cooled to ambient then partitioned between water and TBME, the aqueous layer was acidified to pH 8 with aq HCl, layers separated and the organic layer concentrated to afford 5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide as a colourless oil, 0.11 g (68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11]COC.Cl[C:16]1[CH:17]=[C:18]([B:22]2C3C=CC(F)=CC=3CO2)[CH:19]=[CH:20][CH:21]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:22]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:16][CH:17]=3)[O:11][CH2:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COCOCCc1cc(F)ccc1Br
Reactant: Fc1ccc2c(c1)COB2c1cccc(Cl)c1
Product: Fc1ccc2c(c1)CCOB2c1ccccc1

Procedure:
This compound was synthesized from 22a and 7a in a similar manner to compound 9f: colorless oil; 1H NMR (300 MHz, CDCl3) δ (ppm) 3.02 (t, J=6.1 Hz, 2H), 4.34 (t, J=6.1 Hz, 2H), 6.9-7.1 (m, 2H), 7.4-7.6 (m, 3H), 7.8-7.9 (m, 3H); ESI-MS m/z 227 (M+H)+; HPLC purity 95.3%; Anal (C14H12BFO 0.1H2O)C, H.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.C(B(CC)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd]Cl.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ncc(-c2cccnc2)nc1C(=O)O
Yield: 83.4 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (8 g, 34.48 mmol), diethyl-(3-pyridyl)borane (6.084 g, 41.38 mmol), dichloropalladium; triphenylphosphane (1.210 g, 1.724 mmol) and disodium carbonate (51.70 mL of 2 M, 103.4 mmol) in DME (100 mL) were heated overnight at 80° C. The reaction mixture was cooled and EtOAc was added. The resultant precipitate was collected, treated with water and the resultant suspension heated and filtered hot. The solution was then allowed to cool and acidified with AcOH to approx pH 5. The precipitate was collected, washed with MeOH and dried to yield the product as a yellow powder (6.22 g, 83% Yield). 1H NMR (400.0 MHz, DMSO) d 7.49 (dd, J=4.8, 7.4 Hz, 1H), 7.60 (s, 2H), 8.44 (d, J=7.6 Hz, 1H), 8.57 (d, J=3.7 Hz, 1H), 8.97 (s, 1H) and 9.27 (s, 1H) ppm; MS (ES+) 217
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)Cl.[CH2:16]([O:23][C:24](=[O:30])[CH:25]=[CH:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:26]([CH:27]([CH3:29])[CH3:28])[CH:25]([C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:30])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:15]
Reactant: CC(C)C=CC(=O)OCc1ccccc1
Reactant: COC(=O)C(Cl)=NNc1ccc(F)cc1
Solvent: C1COCCO1
Product: COC(=O)C1=NN(c2ccc(F)cc2)C(C(=O)OCc2ccccc2)C1C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of [(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methyl ester (20.93 g, 90.8 mmol) and 4-methyl-pent-2-enoic acid benzyl ester (18.54 g, 90.8 mmol) in dioxane (400 mL) at 25° C. was added Ag2CO3 (63.0 g, 227 mmol; commercially available from Sigma Aldrich). The reaction was protected from light and stirred at 25° C. for 48 hr. Subsequently, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product mixture was subjected to silica gel chromatography (5-20% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester in approximately 90% purity (29.3 g, 73%):: H-NMR (CDCI3) δ 7.30-7.24 (m, 3 H), 7.15-7.12 (m, 2 H), 7.01-6.96 (m, 2 H), 6.93-6.88 (m, 2 H), 5.14 (d, 1 H), 4.58 (d, 1 H), 3.83 (s, 3 H), 3.51-3.49 (m, 1 H), 2.40-2.36 (m, 1 H), 1.00 (d, 3 H), 0.69 (d, 3 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:17])([CH3:16])[CH3:15]>CS(C)=O>[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:31][CH:32]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N2CCOCC2)cc1)C(C)(C)C
Temperature: 120 °C

Procedure:
Morpholine (1.41 mL, 16.2 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (0.5 g, 1.62 mmol) in DMSO (8 mL), and the mixture heated at 120° C. for 15 hours. The solvent was removed in vacuo and the residual solid taken up in ethyl acetate (30 ml), and washed with 10% citric acid (aq.) (1×40 ml). The aqueous layer re-extracted with ethyl acetate (1×30 mL) and the combined organic phases were washed with brine (1×40 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a pale brown oil which was used without further purification (0.63 g, 100% crude).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1.O.[NH2:18][NH2:19]>CO.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:18][NH2:19])=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1
Reactant: NN
Reactant: CC1(C)COB(c2ccc(C(=O)O)cc2)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Product: CC1(C)COB(c2ccc(C(=O)NN)cc2)O1
Yield: 72 %

Procedure:
58.5 g (250 mmol) of 4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoic acid are dissolved in 250 ml of methanol, and 12.5 g (250 mmol) of hydrazine hydrate and 1.5 g (12.5 mmol) of 4-dimethylaminopyridine are added. The solution is refluxed for 12 hours. Removal of 200 ml of methanol by distillation gives 44.6 g (180 mmol, 72%) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 12 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl N-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol) and 4-chlorobenzaldehyde (0.90 g, 6.37 mmol) in DCE (10 mL) was stirred for 30 minutes, followed by the addition of NaBH(OAc)3 (1.98 g, 9.36 mmol) in a single portion. After being stirred for 12 hours, the mixture was acidified to pH 2 with 0.2N HCl, and extracted with DCM (3 times, each discarded). The acidic aqueous layer was basified to pH 10 with 2.0 M NaOH, and extracted with DCM. The DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester as an oil (1.0 g). LCMS (APCI+) m/z 285, 287 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: OCCCn1cncn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)-[1,2,4]-triazole (119 mg, 0.93 mmol), (EP0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 g. 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 3 hours at ambient temperature. The mixture was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/32/8). The purified product was triturated with a mixture of pentane and ether, collected by filtration and dried under vacuum to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation. The solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)quinazoline hydrochloride (121 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=S>O1CCOCC1>[N:17]1([C:15]2[NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[S:11](=[O:14])(=[O:13])[N:12]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Nc1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
4-Amino-3-sulfamoylbenzoic acid (6 g) and thiocarbonyldiimidazole (23.2 g) in dioxane (60 mL) was refluxed for 2 h. The solvent was removed by distillation under reduced pressure. The residue was dispersed in water (200 mL) and supplemented with a 10% aqueous solution of NaOH (40 mL). After stirring for 30 min. at room temperature, the solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 2 with 12N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (yield: 4.5 g); m.p. >300° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][Br:14])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Br)c(CBr)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
4-Bromo-3-methyl-benzoic acid ethyl ester (18.24 g, 75.4 mmol), N-bromosuccinimide (14.1 g, 79.2 mmol), and benzoyl peroxide (0.9 g, 3.77 mmol) were combined in CCl4, and the reaction was heated to 80° C. and stirred with a halogen desk lamp shining on it for 6 hours. The mixture was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was separated and washed with H2O and brine, and then dried and concentrated. The residue was triturated with hexane (3×50 mL) and dried to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26][N:27]=[C:28]=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:28]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:29])=[CH:30][CH:31]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)NCc2ccc(Cl)cc2)cc1-c1ccnn1C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (20.5 mg, 0.075 mmol) in CH2Cl2 (2 mL) was added 4-chlorobenzyl isocyanate (0.17 μL, 0.128 mmol) and stirred overnight. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 126 as a slightly yellow oil (29.8 mg, 90%). LCMS m/z (%)=442 (M+H35Cl, 100), 444 (M+H37Cl, 40) 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (bs, 1H), 7.43 (d, J=1.81 Hz, 1H), 7.41-7.36 (m, 4H), 7.34-7.28 (m, 3H), 7.03 (d, J=8.94 Hz, 1H), 6.63 (d, J=6.00 Hz, 1H), 6.20 (d, J=1.83 Hz, 1H), 4.26 (d, J=5.96 Hz, 2H), 3.94 (t, J=6.36 Hz, 2H), 3.63 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.06 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.CO.O.N>>[CH3:1][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: N
Solvent: O
Solvent: CO
Product: C=Cc1ccc(OC)cc1

Procedure:
p-Methoxystyrene was polymerized in the same manner as in Example 10, and 25 ml (0.26 mole/1) of p-tert-butoxystyrene was thereafter added to the reaction mixture and further polymerized therewith at an elevated temperature of 25° C. Subsequently, methanol (330 mmoles/1) containing a small amount of ammonia water was added to the reaction system to terminate the polymerization and obtain a mixture containing a polymer. The mixture was washed first with a hydrochloric acid aqueous solution (8 vol. %) and then with water, followed by evaporation for the removal of the solvent, etc. to collect the polymer.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: N#Cc1cccc(O)c1
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C#N)c1
Yield: 24.9 %

Procedure:
If the procedure described in Preparation LXXVIII is followed starting from 0.5 g (1.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10-3 mol) of 3-hydroxybenzonitrile and 170 mg (2.1.10-3 mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 ml of acetonitrile, 138 mg (yield: 25%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: [C@H:1]1([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[O-:23][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:23]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:2][CH2:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@H](N2C(=O)c3ccccc3C2=O)c2ccccc21
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a solution of (R)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione (3.9 g) in acetone (60 mL) at 0° C. was added MgSO4.7H2O (11.5 g) and water (20 mL). Then KMnO4 (11.5 g) was added portionwise over the period of 2 h and stirring continued at room temperature overnight. The brown solid was filtered off and the filtrate treated with saturated sodium metabisulfite, filtered, and extracted with CH2Cl2. The combined organic layer was washed with distilled water and saturated brine, dried over MgSO4, and concentrated in vacuo. The resultant was chromatographed on silica gel (EtOAc/hexane, 25/75) to afford 0.14 g of the title compound.