Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:25])[CH2:24][O:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:41]=[CH:40][C:33]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:25])[CH2:22][O:23][CH2:24]3)[C:17]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:40][CH:41]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)COC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: C=CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: C=CCOC(=O)c1ccc(NC(=O)C(CC2(C)COC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
115 mg (285 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoic acid (racemate), 51 mg (285 μmol) of allyl 4-aminobenzoate, 40.6 mg (285 μmol) of Oxima and 45 μl (0.29 mmol) of DIC in 2 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 25 mg (16% of theory)
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].Cl[CH2:14][C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[NH:20][C:19]2[CH:29]=[CH:30][CH:31]=[N:32][C:18]1=2)=[O:16].C(=O)([O-])[O-]>CN(C)C=O>[CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:14][C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])[NH:20][C:19]3[CH:29]=[CH:30][CH:31]=[N:32][C:18]2=3)=[O:16])[CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)CC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3-[(diethylamino)-methyl]piperidine (4.6 g, 0.027 mol) in dry dimethylformamide (10 ml) is added dropwise over 2 hours to a suspension of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (5.2 g, 0.0181 mol) in anhydrous dimethylformamide (25 ml), then the resulting mixture is stirred for a further 6 hours at ambient temperature and left to stand overnight. The mixture is stirred into ice (200 g), made alkaline with postassium carbonate and extracted exhaustively with dichloromethane. The combined dichloromethane extracts are washed once with water (20 ml), dried over magnesium sulphate and concentrated by evaporation in vacuo. After recrystallization from ethyl acetate, colorless crystals (4.5 g) are obtained, mp. 199°-200° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[O:28]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37](O)=[C:36]([F:41])[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:37]1[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][C:36]=1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Temperature: 70 °C
Yield: 40.3 %

Procedure:
Tert-butyl 4-((3R,4S)-4-(benzyloxy)-3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (620 mg, 1.32 mmol) was dissolved in dry DMSO (10 mL) and 4-bromo-2-fluorophenol (303 mg, 1.59 mmol) and K2CO3 (219 mg, 1.59 mmol) were added and the reaction heated to 70° C. under nitrogen overnight. The reaction was partitioned between water and EtOAc, extracted, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (50 to 75% EtOAc in hexane) to afford tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (300 mg, 0.532 mmol, 40.2% yield) as a crude material, which was taken forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10]N.O=[C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]2[C:3]=1[NH:10][C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:15][C:14]2=1
Reactant: N#Cc1ccc(NN)c(Cl)c1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Product: CC(C)C(=O)NC1CCc2[nH]c3c(Cl)cc(C#N)cc3c2C1
Yield: 50 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-chloro-4-cyanophenylhydrazine (Preparation 13) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a pink powder in 50% yield. MS (ES): m/z 316 (M+H), 314 (M−H); HPLC (Method A): Rt=1.96, (90%).
Reaction SMILES: [CH3:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]([CH3:19])([CH2:20][NH2:21])[CH2:16][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:22])[CH2:23][NH2:24])[CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)Cc1cccc(-c2cccc(CC(C)(C)C#N)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(CN)Cc1cccc(-c2cccc(CC(C)(C)CN)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 2-liter flask, equipped as described in Example 1(b), was put 10.90 g of 3,3'-bis(2-methyl-2-cyanopropyl)biphenyl and 500 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 118 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 25 minutes. The mixture was refluxed for 18 hrs, and then allowed to stand at room temperature for 1 day. After the mixture had been cooled in an ice-water bath, a solution of 7 ml of water in 35 ml of methanol was added dropwise with stirring. This was followed by the dropwise addition of a solution of 33 ml of water in 66 ml of methanol. The ice-water bath was removed, and the mixture was stirred for 1 hour. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. The cloudy viscous residue weighed 10.8 g after it was evacuated for several hours with the oil pump at room temperature. Distillation of this material through a small Vigreux still gave 5.94 g of 3,3'-bis(2,2-dimethyl-3-aminopropyl)biphenyl as a clear, colorless, viscous liquid boiling at 159° to 168°/0.2-0.5 mm.
Reaction SMILES: [OH:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[NH2:29]C(C)(CC(C)C)C(O)=O>CN(C=O)C.O1CCOCC1.Cl>[NH2:29][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:9]2[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][C:6]3[C:5]4=[N:4][N:3]=[C:2]([OH:1])[N:14]4[CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:16][CH:17]=1
Reactant: CC(C)CC(C)(N)C(=O)O
Reactant: O=Cc1ccc(-c2nc3ccn4c(O)nnc4c3cc2-c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NCc1ccc(-c2nc3ccn4c(O)nnc4c3cc2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A suspension of 4-(3-hydroxy-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)-benzaldehyde (3-6, 2.4 g, 6.6 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 1.9 g, 13.1 mmol) in DMF (25 mL) was heated at 150° C. for 20 min. The reaction mixture was cooled, diluted with dioxane (50 mL) and 2N HCl (50 mL) and heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (0-60% acetonitrile/water) to give, upon evaporation of the solvent, the title compound as a yellow solid. HRMS m/z (M+1) Calcd: 368.1506. Found 368.1504.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+].C=O.O>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 mL of anhydrous tetrahydrofuran, add potassium tert-butoxide (161 mg, 1.4 mmol) and paraformaldehyde (66 mg, 2.2 mmol) in one portion, the result mixture is stirred at room temperature overnight under nitrogen atmosphere. The reaction mixture is added 15 mL of water, extract with toluene, the organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum, the residue is purified by column chromatography to get (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:27])[CH2:26]C[O:24][CH2:23]1)#[CH:21]>>[OH:27][C:22]([CH3:26])([CH2:23][OH:24])[C:20]#[C:21][C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCOC1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CO
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol (US2010/144757 A1) to give the titled compound as a brown solid (30 mg, 14%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>>[C:1]1([C:7]2[NH:12][C:11]3[C:13]([CH:8]=2)=[CH:14][CH:15]=[CH:16][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccccc1I
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid (92% yield). 1H NMR (300 MHz, DMSO) δ 11.54 (s, 1H), 7.86-7.84 (d, J=7.15, 2H), 7.53-7.50 (d, J=7.72, 1H), 7.45-7.40 (t, J=7.72, 3H), 7.30-7.25 (t, J=7.34, 1H), 7.01-6.96 (t, J=6.97, 1H), 6.87 (s, 1H). 13C NMR (75 MHz, DMSO) δ 138.48, 138.01, 133.09, 132.43, 132.30, 129.76, 129.25, 128.24, 125.84, 122.44, 120.93, 120.24, 112.18, 99.55. Anal. Calcd. for C14H11N: C, 87.01; H, 5.74; N, 7.25. Found C, 86.87; H, 5.72; N, 6.99. m.p.: 183-184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(F)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 395(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:30]=[O:31])=[C:25](B(O)O)[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:30]=[O:31])=[C:23]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(5-bromopicolinamido)propanoate (3.4 g, 10.3 mmol), (5-chloro-2-formylphenyl)boronic acid (2.1 g, 11.3 mmol), Pd(dppf)Cl2 (840 mg, 1.0 mmol), and K2CO3 (3.1 g, 22.6 mmol) were dissolved in 1,4-dioxane (35 mL) and water (9 mL) and heated to 90° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc and water and the layers were separated. The combined organics were washed dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[OH:10])[C:5]([F:8])=[CH:6][CH:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COc1c(Br)ccc(F)c1C(O)c1ccc2ccccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(Br)ccc(F)c1C(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
To a solution of 1.72 g of (3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanol in 34.4 ml methylene chloride was added 5.16 g of activated manganese dioxide, followed by stirring at room temperature for 17 hours. Then, the manganese dioxide was filtered off through Celite. The solvent was removed by distillation, to give 1.63 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2].[OH-].[K+].[I:23]I>CN(C=O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:23])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(I)n[nH]c2c1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1H-indazole (Preparation 15, 1.46 g, 5.4 mmol) in DMF (20 mL) was added KOH (1.14 g, 20.3 mmol) and the mixture was stirred for 5 minutes. A solution of iodine (2.75 g, 10.8 mmol) in DMF (5 mL) was slowly added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (2×100 mL) and saturated sodium metabisulfite aqueous solution (100 mL), dried over MgSO4 and concentrated in vacuo to furnish the title compound (1.94 g) in a 91% yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:12]([N:11]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:10])[CH3:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(C)c1ccc(C=O)cc1
Yield: 89 %

Procedure:
To a solution of 4-fluorobenzaldehyde (1.5 g) and methylethylamine (1.56 mL) in dimethylsulfoxide (9 mL) was added potassium carbonate (2.17 g) and the mixture was stirred by using a microwave synthesizer (Biotage LTD.) at 120° C. for 2 hours. Thereto was added water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→80:20) to give 4-(N-ethyl-N-methylamino)benzaldehyde (1.89 g, yield: 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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]>[N:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Cl)cc4)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5cncnc5)cc4)CC3)C2)c2ccccc21

Procedure:
A mixture of (1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15.0 mg, 0.0000408 mol, prepared by a procedure analogous to that in step 1 of example 173), pyrimidin-5-ylboronic acid (5.6 mg, 0.000045 mol), tris(dibenzylidene acetone)dipalladium(0) (2 mg, 0.000002 mol), and tri-tert-butylphosphine (0.8 mg, 0.000004 mol), cesium carbonate (16 mg, 0.000049 mol) in 1,4-dioxane (1.0 mL, 0.013 mol) was microwave irradiated at 90° C. for 30 minutes. The crude product was purified with prep-HPLC. LC/MS: 412.2 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1>C(#N)C>[Br:1][C:26]1[CH:25]=[C:24]([O:27][CH3:28])[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][C:21]=1[CH2:20][N:12]([CH:9]1[CH2:11][CH2:10]1)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)ccc1OC
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(Br)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 137.2 %

Procedure:
N-Bromosuccinimide (978 mg) was added to a solution of tert-butyl cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]carbamate (6.36 g) in acetonitrile (50 ml) under ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate/=4/1 to 3/1) to give tert-butyl [2-bromo-4-methoxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate (3.35 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:14]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCC(CCCCN)c1cccc(-c2cccnc2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(F)cc1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.144 g (0.44 mmol) methyl 8-amino-4-[m-(3-pyridyl)-phenyl]-octanoate in 2 ml methylene chloride is added a catalytic amount (0.02 g) 4-dimethylaminopyridine followed by 0.08 ml (0.57 mmol) triethylamine and 0.098 g (0.5 mmol) p-fluorophenylsulfonyl chloride. The mixture is stirred at room temperature for 18 h, diluted with methylene chloride, washed with saturated sodium bicarbonate solution, water and brine, dried, filtered and evaporated to give a greenish oil which is purified by chromatography using 3:2 ethyl acetate/hexane as eluent to obtain methyl 8-(p-fluorophenylsulfonamido)-4-[m-(3-pyridyl)-phenyl]-octanoate as an oil; NMR (CDCl3): delta 3.63 (s,3H), 2.9 (q,2H), 8.95 (d,1H), 8.67 (dd,2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][CH2:17][CH2:16][C:11]21OCC[O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][CH2:17][CH2:16][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCCCC23OCCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCCCC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 6-((Benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane (2.4 g 9.1 mmol) in acetone (40 mL) was treated with 1.5N HCl (18 mL) and stirred at rt for 5 hours. The reaction mixture was neutralized with aqueous sodium carbonate and the volatile removed in vacuo. The residue was extracted with Et2O (3×50 mL) and the combined organic layer were washed with water (30 mL), brine (30 mL) and dried over sodium sulfate and concentrated to yield the desired product as pale yellow oil that was used in the next step without further purification. MS m/z 219.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br-].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Br-]
Product: Clc1ccc(/C=C/CCCBr)cc1

Procedure:
4-Chlorobenzaldehyde (1.0 g) and 4-bromobutyl-triphenylphosphonium bromide (4.08 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH:19]1([C:24](OC)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(O)(=O)C.O>[CH:19]1([C:24](=[O:25])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C1CCCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)C1CCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (11.55 g, 0.093 mol) in 150 ml of anhydrous THF at -78° C. was added dropwise a solution of n-butyl lithium in hexane (1.67N, 56.1 ml, 0.094 mol) under argon atmosphere, and the mixture was stirred for 30 minutes. To this reaction mixture was added a solution of methyl cyclopentanecarboxylate (5.0 g, 0.039 mol) in 10 ml of anhydrous THF. After being stirred for 30 minutes, the reaction mixture was allowed to warm to 0° C. and stirred for 1 hour. The reaction mixture was diluted with 5.4 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue. The mixture was extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-cyclopentyl-2-oxo-ethylphosphonate (7.65 g, 0.035 mol, yield 89.1%, b.p. 106°-108° C./0.2 mmHg), which was assigned the structure by the following data: