Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (250 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solution was stirred at room temperature for 30 minutes, after which time the mixture was concentrated under vacuum. Acidification with 2M aq. HCl followed by extraction using EtOAc and drying with Na2SO4 followed by filtration through a plug of silica, gave 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulfonamide. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS(negESI) m/z=311(M-H+). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to a solution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained as above (500 mg, 1.6 mmol) in CH2Cl2 (20 mL) followed by addition of K2CO3 (310 mg, 2.3 mmol) The reaction mixture was heated to reflux. After 2.5 h, the solution was concentrated under vacuum. After adjusting to pH=6, the product was extracted using EtOAc to give, after drying with Na2SO4 and concentration, 450 mg (72%) of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as an orange oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H+). To a solution of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225 mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry in EtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution concentrated to give yellow oil. The oil was dissolved in a mixture diethyl ether/EtOAc followed by addition of excess of HCl/ether. The resulting precipitate was filtered and washed with ether to give, after drying under vacuum at 40° C., 88 mg (38%) of 3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as a beige solid. Mp 84-85° C. MS (posESI m/z=361 (M+H+). 1H NMR (MeOH-d3) δ7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H), 3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C18H24N4SO2.2HCl) C,H,N,S.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([O:30][C:31]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride salt (0.17 mmol, 70 mg), ethylchloroformate (0.25 mmol, 25 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided compound A123 as a white solid (14 mg, 15%). Exact mass calculated for C20H23N5O5S 445.49, found 446.10 (MH+).
Reaction SMILES: Cl.CO[C:4](=[O:8])[CH2:5][NH:6][CH3:7].C1CCN2C(=NCCC2)CC1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]1[C:4](=[O:8])[CH2:5][N:6]([CH3:7])[C:28]1=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCC(=O)OC
Reactant: S=C=NCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CC(=O)N(Cc2ccccc2)C1=S
Yield: 99.9 %

Procedure:
To a solution of sarcosine methyl ester hydrochloride (0.56 g, 4.0 mmol) and DBU (0.60 mL, 4.0 mmol) in anhydrous ethanol added benzyl isothiocyanate (0.53 mL, 4.0 mmol). The resulting solution was heated at reflux 16 h, cooled, concentrated and chromatographed (silica gel, DCM) to give the title compound (0.88 g, quant.). 1H-NMR (CDCl3): δ 7.49–7.53 (2H, m), 7.28–7.35 (3H, m), 5.02 (2H, s), 4.03 (2H, s), 3.34 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][OH:14])=[N:10][CH:11]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCOCc1ccc(CCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Yield: 78.5 %

Procedure:
To a solution of 2-(5-methoxymethoxymethyl-2-pyridyl)ethanol (11.6 g) and 4-fluoronitrobenzene (8.5 g) in N,N-dimethylformamide (100 ml) was added by portions sodium hydride in oil (60%, 2.8 g) with ice-cooling. The reaction mixture was stirred with ice-cooling for additional 1 hour, poured into water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-methoxymethoxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (14.7 g, yield: 79%) as oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:21]=[N+:22]=[N-:23])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc2c(s1)C(N=[N+]=[N-])COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 110.5 %

Procedure:
To a stirred mixture of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in MeOH (20 mL) was added a solution of NaN3 (93.1 mg, 1.43 mmol) in water (2 mL) dropwise at room temperature. The mixture was heated to 60° C. overnight. The mixture was cooled to room temperature, and then 20 mL of water was added. The mixture was stirred for 0.5 h and then filtered to afford 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J=2.5 Hz, 1H), 7.56 (dd, J=8.7 Hz, J2=2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 5.35 (m, 1H), 4.75 (m, 1H), 4.33 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[H-].[Na+]>C1COCC1>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: Fc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Sc1ccc(F)cc1
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of 4-fluorothiophenol (1.0 g, 7.8 mmol) and 2-chloronitrobenzene (1.2 g, 7.8 mmol) in THF (10 mL) at 0° C. was added NaH (60% dispersion in oil, 390 mg, 9.4 mmol). The reaction was brought to room temperature and allowed to stir for 18 h. Ice was added and the layers separated. The aqueous layer was extracted three times with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL) and dried (Na2SO4) and evaporated affording 4-fluorophenyl 2-nitrophenyl sulfide (1.6 g, 82%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.24 (dd, 1H, J=1.5, 8 Hz), 7.58-7.63 (m, 2H), 7.38 (dt, 1H, J=1.5, 7.4 Hz), 7.15-7.25 (m, 3H), 6.82 (dd, 1H, J=1.1, 8.1 Hz) ppm.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:61]3[CH2:62][CH:57]4[CH2:58][CH:59]([CH2:63][CH:55]2[CH2:56]4)[CH2:60]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([O:52][CH2:53][C:54]3([C:64]#[N:65])[CH:55]4[CH2:63][CH:59]5[CH2:58][CH:57]([CH2:62][CH:61]3[CH2:60]5)[CH2:56]4)=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2Cl)C2CC3CC(C2)CC1C3

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 18%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.41 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 4.02 (t, J=7.7, 7.7 Hz, 4H), 2.17-2.07 (m, 6H), 1.98-1.78 (m, 6H), 1.70-1.61 (m, 4H); MS (ES−) m/z 480.1, 482.1 (M−1).
Reaction SMILES: [H-].[Na+].Cl.[NH:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5]1.[CH3:15]I>CCOC(C)=O.O>[CH3:15][N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5]1
Reactant: COC(=O)C=Cc1c[nH]cn1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cn(C)cn1
Reaction time: 24 h

Procedure:
NaH (0.85 g of a 60% dispersion in oil, 21.2 mmol) was placed in a flask, suspended in hexanes, and allowed to settle. The hexanes was decanted and DMF (50 mL) was added, followed by 35-2 (2 g, 10.6 mmol). After 10 minutes methyl iodide (0.79 mL, 12.7 mmol) was added. After stirring for 24 hr the solution was diluted with EtOAc and H2O and the layers were separated. The water layer was basified to pH 11 with saturated NaHCO3 and extracted with EtOAc and CH2Cl2. The organic layers were combined and evaporated. The residue was chromatographed (5% CH3OH/CHCl3 saturated with NH3) to give 35-3 as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.3 g, 0.51 mmol) and 1-methylpiperidin-4-one (0.086 g, 0.76 mmol) in dichloroethane (5 mL), acetic acid (0.18 g, 3.06 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 34.38%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])(=[O:12])[CH3:11].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.O1CCOCC1>[C:10]([O:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:7])(=[O:12])[CH3:11]
Reactant: C=CC(=O)COC(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a round bottom flask containing 4-bromobenzaldehyde (1.4 g, 7.80 mmol), 2-oxobut-3-enyl acetate (1 g, 7.80 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride (0.21 g, 0.78 mmol) was added dioxane (20 ml). The mixture was stirred at room temperature and triethylamine (0.65 ml, 0.60 mmol) was added. The reaction mixture was heated to 80 C for overnight. Afterward, the reaction was cooled down to room temperature, quenched with a solution of saturated ammonium chloride and concentrated. The residue was taken up in MTBE and washed with saturated ammonium chloride solution twice, then once with brine. The organic portion was dried over sodium sulfate, filtered and concentrated. The resulting crude material was purified by column chromatography to afford the title compound as a light orange solid after drying (1.63 g, 67% yield). MS (ESI) m/z 315.0 (M+1). Retention time 1.14 min. (Condition X).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>C(O)CCC>[N:28]1[CH:27]=[CH:26][C:25]([O:24][C:23]2[CH:31]=[CH:32][C:20]([NH:19][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([CH2:12][C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[N:4][N:3]=3)=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(Oc2ccncc2)cc1
Solvent: CCCCO
Product: c1ccc2c(Nc3ccc(Oc4ccncc4)cc3)nnc(Cc3ccncc3)c2c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A mixture of 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see Novartis patent WO98135958, 11.02.98) (0.540 g, 2.11 mmol) and 4-(4-aminophenoxy)pyridine (1.18 g, 6.33 mmol) in anhydrous 1-butanol (8.4 mL) was stirred under argon at 130° C. for 18 h. The reaction mixture was quenched with saturated aqueous potassium carbonate (˜50 mL) and then extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography in 7:11:2 v/v acetone-dichloromethane-methanol provided the title compound as an oil (0.340 g, 0.84 mmol, 40% yield). 1H-NMR (DMSO-d6) 9.26 (s, 1H), 8.58 (d, J=8.3, 1H), 8.41 to 8.44 (m, 4H), 8.10 (d, J=8.2, 11H), 7.90 to 8.03 (m, 4H), 7.30 (d, J=5.9, 2H), 7.17 (d, J=9.2, 2H), 6.91 (d, J=5.8, 2H), 4.56 (s, 2H); MS ES 406 (M+H)+, calc. 405; TLC (1:7:12 v/v methanol-acetone-dichloromethane) Rf=0.08.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])[CH3:16])=[CH:11][CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH:15]([C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)[CH3:16])=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (4.80 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.50 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 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 pale-yellow oil (1.50 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23](O)=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23]([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccc1F
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place starting from the compound of Example 114A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 44 mg (48% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:54]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OCc3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 73.3 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (137 mg, 0.519 mmol), benzylalcohol (0.0534 mL, 0.519 mmol) and 40% DEAD-toluene solution (0.237 mL), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 90/10) to obtain 4-benzyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (70 mg, yield 73%).
Reaction SMILES: CN(/[CH:4]=[C:5](/[C:10](=O)[CH3:11])\[C:6]([O:8][CH3:9])=[O:7])C.Cl.Cl.[CH2:15]([NH:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:10]([CH3:11])=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)/C(=C\N(C)C)C(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cn(Cc2ccccc2)nc1C
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 58.3 %

Procedure:
To a solution of (Z)-methyl 2-((dimethylamino)methylene)-3-oxobutanoate (15.8 g, 92.5 mmol) in ethanol (50 mL) was added 1-benzylhydrazine dihydrochloride (18 g, 92.3 mmol). The resulting solution was stirred for 3.5 h at 80° C., then concentrated under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate. The organic layer was washed with 1×40 mL of water and 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as the eluent to furnish 12.4 g (58%) of the title compound as a yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:10][CH:9]2[NH:11][CH:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N1C2CCC1CN(C)C2)(OCC)=O>>[CH2:12]([NH:14][C:15]([N:11]1[CH:9]2[CH2:8][CH2:7][CH:6]1[CH2:5][N:4]([CH3:3])[CH2:10]2)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: CN1CC2CCC(C1)N2
Agent: CCOC(=O)N1C2CCC1CN(C)C2
Agent: Cl
Product: CCNC(=O)N1C2CCC1CN(C)C2
Yield: 33.6 %

Procedure:
3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (3.0 g, 0.0151 mole), prepared as described in Example 5, was reacted with 1.21 ml (0.0151 mole) ethyl isocyanate in a procedure as described for 8-carbethoxy-3-methyl-3,8-diazabicyclo[3.2.1]octane in Example 6. The crude desired product, as the free base, was purified by chromatography on alumina with chloroform elution. An hydrochloride salt was made by treatment of a solution of the free base in diethyl ether with ethanolic hydrogen chloride and filtering to collect 1.0 g (28% yield) white solid exhibiting a dual melting point of 100°-140° C and 191°-202° C until dried 2 hours at 126° C in vacuo after which the desired product hydrochloride salt melted at 205°-215° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[OH:17].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[NH:27][N:26]=[N:25][C:23]=2[N:24]=1>>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[O:17][C:21]1[C:22]2[NH:27][N:26]=[N:25][C:23]=2[N:24]=[C:19]([Cl:18])[N:20]=1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1O
Reactant: Clc1nc(Cl)c2[nH]nnc2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 eq) is added to 2,6-dimethyl-4-(pyridin-4-yl)phenol (prepared according to literature procedures, see Combellas et al., Tetrahedron Letters, 1992, 33, 4923) (1.2 eq) in 1-methyl-2-pyrridone (2 ml/mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 min and a solution of 5,7-dichloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (see Helvetica Chimica Acta, 1951, 34, 835) (1 eq) in 1-methyl-2-pyrridone (1 ml/mmol) is added. The resulting mixture is heated to 100° C. for 16 h, cooled to room temperature, poured into ice water and extracted with CHCl3 (×3). The combined organic layers are washed with water and brine, dried (Na2SO4), concentrated to dryness and purified by silica gel chromatography.