Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([OH:15])=O)[N:9]([CH3:16])[C:8](=[O:17])[CH2:7][CH2:6]2.[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([N:29]2[CH2:34][CH2:33][C@@H:32]([NH:35][CH3:36])[C@H:31]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[CH2:30]2)=[O:28])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]>>[C:18]([N:21]1[CH2:22][CH2:23][CH:24]([C:27]([N:29]2[CH2:34][CH2:33][C@@H:32]([N:35]([CH3:36])[C:13]([C:12]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][C:8](=[O:17])[N:9]4[CH3:16])=[CH:4][C:3]=3[O:2][CH3:1])=[O:15])[C@H:31]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[CH2:30]2)=[O:28])[CH2:25][CH2:26]1)(=[O:20])[CH3:19]
Reactant: COc1cc2c(cc1C(=O)O)N(C)C(=O)CC2
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: COc1cc2c(cc1C(=O)N(C)[C@@H]1CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]1c1ccc(Cl)c(Cl)c1)N(C)C(=O)CC2

Procedure:
Using the compound obtained in step 1 and the compound obtained in Example 78, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.CO>[F:18][C:17]([F:19])([F:20])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 50 °C
Yield: 89.2 %

Procedure:
A mixture of 3.56 g (12 mmol) of 4-(3-trifluoromethyl-phenoxy)-benzoic acid methyl ester, and 15 mL (60 mmol) of 4 N sodium hydroxide (NaOH) solution in 45 mL of tetrahydrofuran (THF) and 15 mL of methanol (MeOH) was heated at 50° C. for 25 h, when analysis by thin layer chromatography revealed complete conversion of starting material to product. The reaction mixture was concentrated and acidified with 2N HCl solution while keeping the flask in an ice bath, when a white precipitate formed. The solid was filtered and dried to give 3.02 g (89%) of desired 4-(3-trifluoromethyl-phenoxy)-benzoic acid as a white solid as indicated by 1H NMR and 19F-NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH:9]=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH:9]=[N:11][NH:12][C:13](=[S:14])[NH2:15]
Reactant: NNC(N)=S
Reactant: O=C/C=C/c1ccccn1
Product: NC(=S)NN=CC=Cc1ccccn1
Yield: 43 %

Procedure:
The compound is prepared according to the method described in example 1A from (E)-3-pyridin-2-yl-propenal (0.2 mmoles) and from thiosemicarbazide (0.2 mmoles). Yield 43%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[NH:9][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH:15]2
Reactant: CC(=O)c1ccccn1
Reactant: Cc1ccc(NN)c([N+](=O)[O-])c1
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Yield: 16.1 %

Procedure:
(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (10 g, 49 mmol) and 2-acetylpyridine (5.5 ml, 49 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (2 g, Yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].N1CCCCC1>N1C=CC=CC=1>[C:15]([C:17](=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1)[C:18]([NH2:20])=[O:19])#[N:16]
Reactant: N#CCC(N)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(N)=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
100 g of 3,4,5-trimethoxy-benzaldehyde and 44 g of α-cyano-acetamide were dissolved in 300 cc of dry pyridine at 50°. To this solution 10 cc of piperidine were added and the mixture was heated at 50° with stirring for 2 hours. The reaction mixture was cooled at room temperature, filtered off and the precipitate was washed on the filter with 50 cc of cold isopropanol. The product was dried at 80° to yield 123.6 g (92.5%) of α-cyano-3,4,5-trimethoxy-cinnamamide; m.p. 192°-194°. This product was used for the hydrogenation step without further purification. A pure sample, recrystallized from isopropanol, melted at 193°-195°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2].[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4]([CH:18]=[O:20])=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Formylation. 3-Ethyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (94 g, 0.405 mol) was stirred with glacial acetic acid (670 mL), and hexamethylenetetramine (102.6 g, 0.73 mol) was added in one portion. The mixture was heated at 95° C. for 3 h, hot water (670 mL) added, and the heating was continued for an additional 1.5 h at 100° C. The mixture was cooled to 20° C., toluene (200 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (3×150 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was evaporated and the residue distilled to give 3-ethyl-2-formyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (77.9 g), bp 127°-132° C./0.5 mm, GLC purity 98%, 1H-NMR (CDCl3) δ12.87 (1H, s), 10.20 (1 H, s), 6.72 (1H, s), 2.89 (2H, q), 1.65 (4H, m), 1.44 (6H, s), 1.30 (3H, t), 1.29 (6H, s). 13C-NMR (CDCl3) δ194.3 (1C, d), 163.6 (1C, s), 156.7 (1C, s), 144.6 (1C, s), 130.8 (1C, s), 118.5 (1C, d), 115.2 (1C, s), 37.7 (1C, t), 35.5 (1C, s), 34.7 (1C, t), 34.0 (1C, s), 31.1 (2C, q), 27.7 (2C, q), 24.8 (1C, t), 16.9 (1C, q). IR (KBr) 1609 cm-1MS (m/e) 260.3 (M+, 22.6), 245.2 (100.0), 203.3 (18.2), 246.2 (17.0).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][C@H:27]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[NH:34]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.Cl>C(Cl)Cl.O1CCOCC1>[NH2:34][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:28][C@@H:27]([C:29]([N:30]([CH3:32])[CH3:31])=[O:33])[CH2:26]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@H](C(=O)N(C)C)C[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reaction time: 3 h

Procedure:
tert-butyl ((1S,2R,4S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(dimethylcarbamoyl)cyclopentyl)carbamate (0.062 g, 0.103 mmol) was taken up in DCM (2 ml) and treated with 4M HCl in dioxane (3 ml) and stirred for 3 hours. The solvent was removed to give crude (1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentane-1-carboxamide, quantative yield. MS (ES+) C24H27Cl2N5O3 requires: 504, found: 505 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH3:24]>>[CH3:13][C:9]1([CH3:12])[CH2:8][O:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[C:2][C:21]3[CH:20]=[CH:19][C:18]([S:23][CH3:24])=[CH:17][CH:22]=3)=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: CSc1ccccc1Br
Product: CSc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and bromothioanisole. MS (ESI) 324.2 (M•)+.
Reaction SMILES: [F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc(-c2cccc(F)c2)c1F
Yield: 86.7 %

Procedure:
To a solution of methyl 2,6-difluoro-3-(3-fluorophenyl)benzoate (1.7 g, 6.4 mmol, 1.0 eq) in mixture of MeOH (20 mL) and THF (20 mL) was added a solution of aqueous NaOH (1M aqueous solution, 20 mL, 20 mmol, 3.1 eq) at room temperature. The reaction mixture was heated to reflux for 30 mins, then cooled and the resulting mixture concentrated in vacuo to remove the organic solvent. The residue was diluted with water and adjusted to pH 5-6, by addition of 1M HCl. The precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (1.4 g, 87%).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24]O>>[CH:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSC3CCCCC3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)C3CCCCC3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-(4-cyclohexylmercapto-butoxy)-carbostyril and hydrogen peroxide.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)O)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), isobutylene oxide (1.9 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (5 mL) was stirred in a sealed tube at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>CN1C(=O)CCC1>[OH:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([CH3:19])[CH:21]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: OCCOc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCO)cc3)ncn2)c1
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 6-chloro-4-[4'-(2-hydroxyethoxy)anilino]pyrimidine (1.0 g), 3-methylaniline (5 ml) and NMP (20 ml) was stirred and heated to 140° C. for 72 hours. The mixture was cooled and partitioned between ethyl acetate and water. The precipitate was removed by filtration, the ethyl acetate fraction chromatographed on silica and the combined products extracted with boiling ethyl acetate. The product was recrystallised from a mixture of ethyl acetate and hexane to give 4-[4'-(2-hydroxyethoxy)anilino]6-(3'-methylanilino)pyrimidine in 20% yield, m.p. 196°-199° C.;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[C:1]([C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:28])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CO)c(OCCCCC#N)cc1OCCCCC#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C(C)=O)c(OCCCCC#N)cc1OCCCCC#N
Reaction time: 8 h

Procedure:
A mixture of 688 mg of 5,5'-[(4-acetyl-6-hydroxymethyl-1,3-phenylene)bis(oxy)]bis[pentanenitrile] in 15 ml of dimethylformamide was added to a suspension of 0.184 g of a 50 % oil dispersion of sodium hydride and 0.62 ml of methyl iodide in 45 ml of dimethylformamide at 0° C. The reaction was allowed to come to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid to which sodium chloride had been added. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-70% ethyl acetate in hexane gradient to provide 110 mg of the desired title product. NMR, MS.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:9]([N:21]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:23]=[N:22]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCOC(=O)C=C
Reactant: CCCCCCCCCCCCN=[N+]=[N-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Propargyl acrylate (13 g, 0.118 mmoles), dodecyl azide (22.3 g, 0.118 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.75 g, 2 mmoles) are dissolved in DMF (200 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (33.5 g; yield 95%; mp 50-52° C.). 1H NMR (CDCl3, δ ppm) 7.78 (broad, 1H), 6.42 (d, 1H), 6.16 (dd, 1H), 5.82 (d, 1H), 5.30 (s, 2H), 4.32 (t, 2H), 1.92 (t, 2H), 1.28 (m, 20H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 165.7, 142.4, 131.1, 127.9, 123.5, 57.6, 57.5, 50.2, 31.7, 30.1, 29.4, 29.3, 29.2, 29.1, 28.8, 26.3, 22.4, 13.9.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2O.P(Cl)(Cl)([Cl:18])=O>>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[Cl:18]
Reactant: Oc1ccnc2c(OC(F)F)cccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)Oc1cccc2c(Cl)ccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from step b) was heated to reflux in phosphorus oxychloride (80 ml) for 1 hour. The reagent was evaporated under reduced pressure to give an oil which was carefully poured into a mixture of ice/880 ammonia solution (400 ml) and stirred for 30 minutes. The solid was filtered off and dried in vacuo to give the sub-title compound (6.80 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1>CO.C(OCC)C>[CH3:24][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:22])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Solvent: CCOCC
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)c(C)c1
Yield: 70.3 %

Procedure:
Using 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (1.00 g), 5-dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is obtained in the same manner as in Example 978 except that methanol/diethyl ether is used instead of ethyl acetate as recrystallization solvent, as white powder, m.p. 183°-185° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5](F)=[C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)[CH:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([C:24]#[N:25])[CH:3]=1)[NH:28][N:27]=[C:8]2[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C#N)c2F)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Yield: 58.3 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[(5-bromo-3-cyano-2-fluorophenyl)carbonyl]-1-piperidinecarboxylate (1.35 g, 3.3 mmols) and hydrazine hydrate (0.21 ml, 6.9 mmols) in ethanol (30 mL) was heated at reflux overnight. After cooling, the solvent was evaporated and the residue was purified by flash chromatography eluting with pentane/ethyl acetate 4:1 v/v to give the title compound (0.78 g) as a yellow solid (59%).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:17][C:16]3=[O:35])[CH:10]=[N:9][CH:8]=1)(C)(C)C.[ClH:37]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[O:35]=[C:16]1[C:15]2[C:32](=[CH:33][CH:34]=[C:13]([C:11]3[CH:10]=[N:9][CH:8]=[C:7]([CH:12]=3)[C:6]([OH:36])=[O:5])[CH:14]=2)[O:31][C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-{1′-tert-butoxycarbonyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid tert-butyl ester (14.0 g, 28.3 mmol) was dissolved in CHCl3 (70 mL) and 4N HCl in dioxane (210 mL) was added thereto, and stirred at room temperature for 20 h. The resulted precipitate was filtered and washed with CHCl3 and Et2O to afford 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride as a colorless solid.
Reaction SMILES: CCN(CC)CC.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:16][CH:17]=2)[O:29]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(NC(=O)C3CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
Et3N (239 μL, 1.71 mmol) and cyclopropanecarbonyl chloride (114 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 4 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with 10% aqueous citric acid, sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1) to afford desired product (291 mg, 88.9%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.82-7.70 (m, 2H), 7.59-7.47 (m, 2H), 7.43 (br s, 1H), 1.54-1.44 (m, 1H), 1.33 (s, 12H), 1.09 (dt, J=7.4, 4.2 Hz, 2H), 0.85 (td, J=7.4, 4.2 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:49](O)[CH2:50][C:51]#[CH:52]>>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([O:48][CH2:52][CH2:51][C:50]#[CH:49])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CCCO
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC(C)(C)C)cc4C)CC3)C(=O)N2C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Yield: 71 %

Procedure:
8-[2-(4-tert-Butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (37.9 mg, 71%) was obtained by the same method as in Reaction 366-9 using 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester and 3-butyn-1-ol as starting materials.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:28][N:29]([CH3:35])[S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:33][S:30]([N:29]([CH3:35])[CH3:28])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: C=CS(=O)(=O)N(C)C
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(=O)(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure of Example 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with N,N-dimethylethenesulfonamide to give 197 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, d, J=0.67 Hz), 7.61 (1H, s), 7.05 (1H, dd, J=8.32, 1.83 Hz), 6.95 (1H, d, J=1.78 Hz), 6.00-5.90 (1H, m), 4.48-4.39 (4H, m), 3.80-3.72 (2H, m), 3.72-3.64 (1H, m), 3.27-3.19 (2H, m), 3.02-2.89 (4H, m), 2.87 (6H, s), 1.56 (6H, d, J=6.63 Hz). LCMS: RT=6.35 min, M+H+=486