Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:43]([N:50]1[CH2:55][CH2:54][C:53]2([C:63]3[C:58](=[CH:59][CH:60]=[CH:61][C:62]=3[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[NH:57][CH2:56]2)[CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl[C:74]1[C:75]2[CH:82]([CH:83]([CH3:85])[CH3:84])[CH2:81][CH2:80][C:76]=2[N:77]=[CH:78][N:79]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(C)C=CC=CC=1>[CH2:43]([N:50]1[CH2:55][CH2:54][C:53]2([C:63]3[C:58](=[CH:59][CH:60]=[CH:61][C:62]=3[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:69])([CH3:71])[CH3:70])[N:57]([C:74]3[C:75]4[CH:82]([CH:83]([CH3:85])[CH3:84])[CH2:81][CH2:80][C:76]=4[N:77]=[CH:78][N:79]=3)[CH2:56]2)[CH2:52][CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reactant: CC(C)C1CCc2ncnc(Cl)c21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Temperature: 100 °C
Yield: 69.3 %

Procedure:
A flask was charged with Pd2 dba3 (0.233 g, 0.254 mmol) and Xantphos (0.221 g, 0.381 mmol) and purged with nitrogen. The flask was then charged with tert-butyl (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.04 g, 2.54 mmol), 4-chloro-5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.500 g, 2.54 mmol), Cs2CO3 (1.24 g, 3.81 mmol) and toluene (12.7 mL). The reaction was purged with nitrogen and heated to 100° C. overnight. The reaction was cooled to room temperature and filtered through celite, then GFF, and concentrated under reduced pressure. The crude residue was purified by column chromatography (1-5% MeOH/DCM) to yield tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.0 g, 69%). LCMS (APCI+) m/z 568.3 [M+H]+; Rt=4.30 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[C@@H:42]([O:46][Si](C(C)(C)C)(C)C)[C@H:41]([NH:54]C(=O)OC(C)(C)C)[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[NH2:54][C@H:41]1[C@H:42]([OH:46])[C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1cc2ccc(N3CCCCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(2-oxopiperidin-1-yl)quinoline-2-carboxylic acid (0.015 g, 0.036 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.019 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined and concentrated under reduced pressure. To the resulting residue, 2 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.0072 g, 32%). LCMS calc. for C34H38N7O5 [M+H]: m/z=624.3. found: 624.3.
Reaction SMILES: N1C(F)=NC(F)=NC=1F.[C:10]([O:14][C:15]([N:17]([CH3:30])[C@@H:18]([CH3:29])[C:19]([NH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:25])=O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C@H:38]1[C:46]([O:48][CH2:49][CH3:50])=[O:47].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:49]([O:48][C:46]([C@@H:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:37]1[C:23](=[O:25])[C@@H:22]([NH:21][C:19](=[O:20])[C@@H:18]([N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH3:30])[CH3:29])[CH:26]([CH3:28])[CH3:27])=[O:47])[CH3:50]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 51.3 %

Procedure:
Cyanuric fluoride (3.25 g, 2.08 mL, 24.1 mmol) was added to a solution of (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.4 g, 17.9 mmol) and pyridine (1.95 mL, 24.1 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at 23° C. for 2.5 h. The resulting precipitate was filtered off and the mother liquor was concentrated. The residue was dissolved in EtOAc (250 mL), and the solution was washed with saturated NaHCO3, 0.5 M citric acid and brine. The organic layer was dried over Na2SO4, filtered, concentrated and dried under vacuum. The resulting yellow oil was taken up in CH2Cl2 (35 mL) and cooled in a dry ice-MeOH bath. To this solution was added a solution of (S)-ethyl indoline-2-carboxylate (2.3 g, 12.0 mmol) and 2,6-di-tert-butylpyridine (4.6 g, 5.31 mL, 24.1 mmol) in 25 mL of CH2Cl2. The resulting mixture was stirred at rt overnight. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.93 g), m/z=476 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O.C[O-].[Na+].Cl>CS(C)=O.CCCCCCC>[C:4]1([C:1](=[O:3])[CH2:2][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Acetophenone (10.1 g; 0.084 mol) and MCPC (25.2 g; 0.25 mol; 3 equiv) were dissolved in DMSO (46.1 g). Sodium methoxide (9.1 g; 0.168 mol; 2.0 equiv) was added slowly while maintaining the temperature below 30° C. The reaction mixture was then heated to 40° C. for 5 h. Heptane (100 mL) was added followed by sufficient 20% aqueous HCl such that the pH was less than 5. The mixture was stirred for 15 min and then allowed to settle. The lower aqueous layer was decanted and discarded. The upper organic layer was washed with 40 mL of water, and the solvent was stripped to afford 14 g of crude 8, which was 97.2% pure by GC (area %) to afford an 86% yield of 8.
Reaction SMILES: CB1OB(C)OB(C)O1.[C:10]([O-])([O-])=O.[K+].[K+].C(OC(C1N=C(Cl)C2C(C=1O)=CC(OC1C=CC=CC=1)=CC=2)=O)CCC.[CH2:42]([O:46][C:47]([C:49]1[N:50]=[C:51](Cl)[C:52]2[C:57]([C:58]=1[OH:59])=[CH:56][CH:55]=[C:54]([O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:53]=2)=[O:48])[CH2:43][CH2:44][CH3:45]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:42]([O:46][C:47]([C:49]1[N:50]=[C:51]([CH3:10])[C:52]2[C:57]([C:58]=1[OH:59])=[CH:56][CH:55]=[C:54]([O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:53]=2)=[O:48])[CH2:43][CH2:44][CH3:45]
Reactant: O=C([O-])[O-]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccccc3)ccc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccccc3)cc2c1O
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a mixture of anhydrous 1,4-dioxane (200 ml), Pd(PPh3)4 (3.47 g, 3 mmol), trimethylboroxine (4.22 ml, 30 mmol), and K2CO3 (12.44 g, 90 mmol) was added a regioisomeric mixture of 1-chloro-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester and 1-Chloro-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (11.15 g, 30 mmol). The mixture was refluxed under N2-protection with stirring for 3 h and was then stirred at ambient temperature for 48 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (100 ml) and the mixture was extracted with EtOAc (300 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=9:1 as the eluent gave the title compound as a yellowish solid (4.40 g, first fraction); MS-(+)-ion M+1=352.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[N:8][CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[N:8][CH:9]=1
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cn2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccc(N)cn2)cc(OC)c1OC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 5-nitro-2-(3,4,5-trimethoxyphenyl)-pyridine (1.50 g, 5.17 mmol) in methanol-ethyl acetate (1:4, 50 mL) was added 10% palladium on charcoal (158.6 mg), and the resulting mixture was stirred at 45° C. for 2 hours and 30 minutes under hydrogen. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the title compound as colorless needles (melting point: 153.5-155.5° C. )(1.25 g, yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:28])[N:13]([C:16](=[O:27])[C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=4[O:25]C)[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.FC1C=C(F)C=CC=1C1C=CC=CC=1C(NC(=O)C1C=CC(OC)=CC=1OC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:28])[N:13]([C:16]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[OH:25])=[O:27])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1ccc(C(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c(OC)c1
Agent: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O
Yield: 99 %

Procedure:
3-fluoro-5-(2,4-dimethoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—The title compound was prepared from N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-2,4-dimethoxybenzamide (1.29 g, 3.2 mmol), anhydrous THF (10 mL), and lithium bis(trimethylsilyl)amide (4.0 mL, 1M in THF) according to the procedure and in the same manner as described in Example 33, step d. The resulting residue was purified by flash column chromatography (Biotage® 40 Mi, 30-50% methyl tert-butylether in hexane) affording 1.2 g (99%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.76 Hz, 3 H) 3.79 (br m, 6 H) 3.92 (s, 1 H) 6.28 (s, 1 H) 6.62 (m, 1H) 7.06 (s, 1 H) 7.34 (br m, 1 H) 7.42 (br m, 3 H) 7.52 (br d, J=7.54 Hz, 1 H) 7.96 (m, 2 H); MS (ESI) m/z 378 ([M+H]+); HRMS: calcd for C23H20FNO3, 377.1427 (M), 378.15000 ([M+H]+); found (ESI_FT), 378.14878
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][N:18]([C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:19][CH2:20]1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccccc4)CC3)c2cc1OC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
In 5 ml of ethanol was dissolved 278 mg (1.0 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 0.109 ml (1.0 mmol) of phenyl isocyanate was added thereto. The mixture was heated under reflux for 10 minutes and then allowed to cool to room temperature. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 174.3 mg of the desired compound as colorless crystals. yield: 44%
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[NH:30][CH:29]=[CH:28]2>ClCCl>[CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)[C:28]2[C:27]3[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=[C:25]([F:24])[CH:26]=3)[NH:30][CH:29]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
100 mg (0.44 mmol) of the compound from Example 157A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 5 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 151 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].N1CCCCC1>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[CH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[OH:19])[C:7]1=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccccc2N1C1=NCCS1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccc2O)c2ccccc2N1C1=NCCS1
Yield: 64.1 %

Procedure:
To a warmed solution of 1-(2-thiazolin-2-yl)-indolin-2-one (prepared as described in Example 3A; 2.0 g; 9.2 mmole) and salicylaldehyde (1.6 g; 12.9 mmole) in dry benzene (100 ml) is added a small amount of piperidine (0.6 ml). The resultant mixture is heated at reflux temperature for 2 hours. The reaction mixture is extracted with dilute HCl solution (5 ml of concentrated HCl in 120 ml of water) twice. The acidic layers are combined and treated with saturated NaHCO3 solution until pH paper indicates it is slightly basic. The precipitate is collected by filtration and washed well with water. This crude material is recrystallized from acetone/hexane (treated with charcoal) to give 1.9 g of the product: m.p. 195.5°-197° C.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:41]=[CH:42][CH:43]=1)[CH2:11][N:12]([CH2:20][CH2:21][N:22]1[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:40])[CH:28]=2)[CH2:23]1)C(=O)OC(C)(C)C)(=[O:6])=[O:5])[CH3:3].[H-].[Na+].IC.[C:48](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:48][N:7]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[C:8]1[CH:9]=[C:10]([CH:41]=[CH:42][CH:43]=1)[CH2:11][NH:12][CH2:20][CH2:21][N:22]1[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:40])[CH:28]=2)[CH2:23]1
Reactant: O=C([O-])O
Reactant: CC(C)S(=O)(=O)Nc1cccc(CN(CCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N(C)c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
8.7 mg of tert-butyl 3-(2-propyl sulfonylamino)benzyl-[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]carbamate obtained in Example 131-a) was dissolved in 1 mL of THF, and 0.7 mg of sodium hydride was added thereto under ice-cooling, followed by stirring for 15 minutes. 2.6 mg of iodomethane was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction liquid was under ice-cooling, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto. The organic layer was separated, the aqueous layer was further extracted by addition of ethyl acetate, and the organic layer was combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the solvent was removed by evaporation to obtain 10.0 mg of a crude composition. The crude composition was purified by PLC to obtain 6.3 mg (yield 71%) of a desired product.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14]Br)[C:9]([CH2:12]Br)=[CH:10][CH:11]=1.[C-:16]#[N:17].O>CS(C)=O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:1]#[N:2])=[C:8]([CH2:14][C:16]#[N:17])[CH:7]=1
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC#N)c(CC#N)c1
Reaction time: 0.25 h

Procedure:
Finely ground sodium cyanide (73 gm., 1.48 m) was suspended in dimethylsulfoxide (500 ml.) by means of a "Vibro-Mixer". A solution of 4-Methoxy-α,α'-dibromo-o-xylene (113 gm., 0.384 m) in dimethylsulfoxide (200 ml.) was added dropwise to the cyanide suspension. The internal temperature was kept at 35°-38° C. by means of an ice bath. The addition took 15 minutes. Agitation of the reaction was continued for a further 11/2 hours. The reaction mixture was poured into water (4 l.). The aqueous mixture was extracted with ether (2×1 l., 3×500 ml.) and the combined ether extracts were washed with dilute hydrochloric acid (6 N) (2×500 ml.), saturated sodium carbonate solution (1×500 ml.), water (3×500 ml.) and saturated sodium chloride solution (2×500 ml.). The ether layer was dried over magnesium sulfate. The dried ethereal solution was evaporated to an oil which was distilled and the fraction with boiling range 160°- 165° (0.1 mm) was collected. wt.=53 gm. The oil obtained was crystallized from ether (650 ml.) to give 45 gm. (m.p. 51°-53°). A second drop of 5.8 gm.(m.p. 49°-51°) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[S:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+:25]([O:28][CH2:29][CH2:30][NH2:31])([O-:27])=[O:26]>>[N+:25]([O:28][CH2:29][CH2:30][NH:31][C:10](=[S:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(O)=S
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(C)(C)OC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCCO[N+](=O)[O-]
Yield: 88 %

Procedure:
The procedures of Example 1 were analogously repeated using 322 mg of (2R)-2-tert-butoxycarbonylamino-3-tert-butoxycarbonylthiopropionic acid and 186 mg of 2-nitrooxyethylamine nitrate to give 365 mg of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[O:12][CH2:11][C:10]1=[O:14]
Reactant: ClCCCI
Reactant: CC(C)c1cccc2c1OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)c1cccc2c1OCC(=O)N2CCCCl
Yield: 69.7 %

Procedure:
8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83) (0.115 g, 0.60 mmol), Cs2CO3 (0.293 g, 0.90 mmol) and 3-chloro-1-iodopropane (0.135 g, 0.66 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF98) (0.112 g, 70%). 1H NMR (CDCl3) d 7.03-6.95 (m, 2H), 6.93-6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.33-3.25 (m, 1H), 2.20-2.13 (m, 2H), 1.22 (d, J=7.2 Hz, 6H); 13CNMR (CDCl3) d 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7, 42.5, 39.3, 30.3, 27.2, 22.7.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[CH2:22][CH:16]([CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)[CH2:15]1>CC#N>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][CH2:13][N:14]2[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]3)[CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCN)C2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCNCc3ccc(C#N)cc3)C2)C1
Temperature: 40 °C
Reaction time: 32 h
Yield: 74 %

Procedure:
p-Cyanobenzylbromide (0.765 g; 3.9 mmol) was added to a stirred solution of tert-butyl 7-[2-aminoethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.04 g; 3.9 mmol; from step (a) above) in MeCN (15 mL) and the reaction mixture was stirred at 40° C. for 32 h. The solvent was evaporated and the residue subjected to column chromatography (EtOAc) to give the title compound in a 74% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[C:10]([CH3:18])=[CH:11]C2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]=[C:10]([CH3:11])[C:9](=[O:19])[NH:8]2)=[CH:6][CH:7]=1
Reactant: CC(=Cc1ccccc1)C(=O)Nc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc2ccc(Cl)cc2[nH]c1=O
Temperature: 120 °C

Procedure:
To a solution of N-(3-chlorophenyl)-2-methyl-3-phenylacrylamide (2.5 g, 9.2 mmol) in chlorobenzene (50 mL) is added AlCl3 (6.2 g, 46 mmol). The solution is heated to 120° C. After 4 hours the solution is poured onto ice. The solution is filtered. The organic layer is washed with 1N HCl, H2O and saturated NaCl. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2. The title compound is obtained as a white solid (1.5 g, 7.74 mmol). 1H NMR (d6-DMSO, 300 MHz) δ11.82 (bs, 1H), 7.73 (s, 1H), 7.52 (m, 1H), 7.21 (m, 2H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)=[O:22]>[Ni]>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=[O:22])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: O=CO
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Agent: [Ni]
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile(1.0 g) and Raney nickel(3.0 g) were suspended in formic acid(10 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=50:50→20:80). The purified product was condensed under reduced pressure to give the title compound(0.92 g) as a yellowish-white solid (yield=92%).