Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C=CC(O)(c2ncccn2)C=C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Reaction time: 15 h
Yield: 51 %

Procedure:
2.11 g of the compound of step 1 of Example 25 was dissolved in 30 ml of pyridine, then 1.0 ml (1.4 equivalents) of phosphorus oxychloride was added under ice cooling and the result was agitated for 15 hours. The pyridine was distilled off under reduced pressure, an aqueous solution of 10% sodium hydroxide was added and extraction was performed by methylene chloride. The organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate, then the solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the above-referenced compound in an amount of 1.01 g (yield of 51%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[CH3:22][NH:23][C:24](=[O:31])[CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CO.[H-].[Na+]>CN(C)C=O.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:3]=[C:25]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[C:24](=[O:31])[N:23]([CH3:22])[C:5]=2[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=CN(C)C)C(=O)c2ccncc2)cc1
Reactant: CNC(=O)Cc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(-c3nccs3)c(=O)n(C)c2-c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one (2.53 g), N-methyl thiazol-2-ylacetamide (1.70 g) and methanol (0.73 cm3) in dry dimethylformamide (20 cm3) was added via cannula at room temperature to a stirred suspension of sodium hydride (55% in oil; 0.80 g) in dry dimethylformamide (10 cm3) under nitrogen. The mixture was stirred at 40° C. for 18 hours, then poured into water (200 cm3). The resulting yellow precipitate was collected and recrystallised from ethyl acetate to give 3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one as a yellow powder (2.18 g; 62%) m.p. 224-225° C. (EtOAc). Found: C, 66.9; H, 4.45; N, 11.2. C12H17N3O2S requires C, 67.2; H, 4.6; N, 11.2%. δH (360 MHz; CDCl3) 3.50 (3 H, s, NCH3), 3.74 (3 H, s, OCH3), 6.70 (2 H, d, J 9, methoxyphenyl H-2), 6.93 (2 H, d, J 9, methoxyphenyl H-3), 7.15 (2 H, d, J 6, pyridyl H-3), 7.50 (1 H, d, J 3, thiazolyl H-5), 7.96 (1 H, d, J 3, thiazolyl H-4), 8.64 (2 H, d, J 6, pyridyl H-2) and 8.72 (1 H, s, pyridone H-4); m/z (ESP+) 376 (MH+; 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2F)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (4.56 g, 32.10 mmol) in anhydrous 1,2-dimethoxyethane (25 ml) is added sodium methoxide (1.91 g, 35.10 mol) in one portion. After stirring at room temperature for 10 minutes a second solution of 5-bromo-2-fluorobenzaldehyde (5.93 g, 29.10 mmol) in anhydrous 1,2-dimethoxyethane (45 ml) is added dropwise, followed by stirring at 0° C. for a further 45 minutes. The reaction mixture is quenched with 2M hydrochloric acid (50 ml), then diluted with diethyl ether and the two phases separated. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined, washed with brine and dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (9.30 g, 96%) as a yellow gum.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15].[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C:26]1=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C:26]1([C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOc1ccc(C)cc1Br
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
A 1.6 M hexane solution of n-butyl lithium (11 ml) was added dropwise to a solution of 3-bromo-4-ethoxytoluene (3.6 g) in THF (50 ml) at −78° C. and the mixture was stirred for 15 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (7.6 g) in THF (10 ml) was added dropwise to the reaction mixture and the mixture was stirred for 2.5 hours. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The resulting precipitates were collected by filtration to obtain 2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose (3.53 g).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH2:58][O:59][C:60](=[O:62])[CH3:61])[CH:53]([NH:63][C:64](=[O:79])[CH2:65][C:66]2[N:67]=[C:68]([C:71]4[C:76]([OH:77])=[CH:75][CH:74]=[CH:73][C:72]=4[OH:78])[S:69][CH:70]=2)[C:52]3=[O:80])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[C:60]([O:59][CH2:58][C:57]1[CH2:56][S:55][CH:54]2[N:51]([C:52](=[O:80])[CH:53]2[NH:63][C:64](=[O:79])[CH2:65][C:66]2[N:67]=[C:68]([C:71]3[C:76]([OH:77])=[CH:75][CH:74]=[CH:73][C:72]=3[OH:78])[S:69][CH:70]=2)[C:50]=1[C:48]([OH:49])=[O:47])(=[O:62])[CH3:61]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Yield: 87.9 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8e (181 mg, 0.270 mmol), Et3SiH (0.431 mL, 2.70 mmol), and trifluoroacetic acid (0.832 mL, 10.8 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9e (120 mg, 88%) as a white solid after crystallization from EtOAc/CH2Cl2 /hexane. mp 145° C. (dec); IR (KBr) 3650-2500 (br), 1775, 1736, 1466, 1237 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.43 (1H, d, J=18.1 Hz ), 3.58 (1H, d, J=18.1 Hz), 3.76 (2H, s, CH2), 4.64 (1H, d, J=12.8 Hz), 4.95 (1H, d, J=12.8 Hz), 5.05 (1H, d, J=5.0 Hz), 5.64-5.70 (1H, m), 6.42 (2H, d, J=8.0 Hz), 7.07 (1H, t, J=8.0 Hz), 7.41 (1H, s), 9.12 (1H, d, J=8.1 Hz, NH), 12.17 (2H, br s, OH), 13.60 (1H, br s, CO2H); FDMS m/z 505 (M+), 506 (M+ +1); Anal. Calcd for C21H19N3O8S2 : C, 49.89; H, 3.79; N 8.31. Found. C 50.15; H 3.79; N 8.60.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][CH2:23][CH2:24][C:25]2[NH:26][CH:27]=[N:28][CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(F)(F)F)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.CO.O.[Li+].[OH-]>C1COCC1>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:22][CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[N:28][CH:29]=3)[C:2]([Br:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
N-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-trifluoro acetamide (1 g, 1.9 mmole) was dissolved in THF (10 ml), MeOH (10 ml) and water (5 ml) and LiOH (455 mg) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for two days, the solvent removed under reduced pressure The residue was dissolved in ethyl acetate and water and extracted with ethyl acetate (3×). The combined organic layers were combined and dried over magnesium sulfate. After evaporation of the solvent one obtains 350 mg of N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-y)-ethyl]-pyrimidine-2,4-diamine. ESI-MS: 375.
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]([OH:28])=O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=C[N:31](C(N2C=NC=C2)=O)C=1.NC1C=CC(C(N2CC3(C)CC2CC(C)(C)C3)=O)=CC=1>C1COCC1>[C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]([NH2:31])=[O:28])=[N:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: NC(=O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
To a solution of (2-trityl-2H-tetrazol-5-yl)-acetic acid (0.82 g, 2.20 mmol) in dry THF (50 ml) was added CDI (0.4 g, 2.39 mmol) and the resulting mixture was stirred for 10 min. To this mixture was added (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.5 g, 1.84 mmol) and the stirring was continued for 18 hrs. at room temperature. The mixture was evaporated and the residue purified by column chromatography (silica gel) using EtOAc-Heptane (4:1) as eluent. Pure fractions were collected and evaporated to dryness affording 150 mg (13%) of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-2-(2-trityl-2H-tetrazol-5-yl-acetamide which was dissolved in THF (25 ml) followed by addition of 20% aqueous HCl (20 ml). The mixture was stirred for 2 hrs. at room temperature at which time the volatiles were removed in vacuo. The aqueous residue was extracted with EtOAc (2×50 ml), dried (Na2SO4), filtered and evaporated in vacuo affording 30 mg (4%) of the title compound as a solid.
Reaction SMILES: COC1C=CC(/C=[C:16]2/[C:17]([NH:19][C:20]([S:22]/2)=[NH:21])=[O:18])=CC=1OC1CCCC1.C[I:24].[C:25](OCC)(=O)C>CN(C)C=O>[IH:24].[CH3:25][N:19]1[C:17](=[O:18])[CH2:16][S:22][C:20]1=[NH:21]
Reactant: CI
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=N)SCC1=O
Product: I
Temperature: 60 °C
Reaction time: 1 h

Procedure:
11.6 g (0.1 mol) of pseudothiohydantoin was suspended in 150 ml of dimethylformamide, and 17 g (0.12 mol) of methyl iodide was added thereto. Then, the mixture was stirred at 60° C. for one hour. After being left to cool, the reaction mixture was poured into 1000 ml of ethyl acetate, and precipitated crystals were collected by filtration to obtain 15 g of 3-methyl-2-iminothiazolidin-4-one hydroiodide as pale yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]([OH:16])(C)[CH3:14].[CH2:17]([O:35][CH2:36][CH:37]1O[CH2:38]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]CC.[ClH:40]>O>[ClH:40].[OH:16][CH:13]([CH:17]([O:35][CH2:36][CH2:37][CH2:38][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:14]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCC(OCCCN[C@@H](CCCNC(=N)N)C(=O)O)C(C)O
Yield: 2.3 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 21.2 g of N-(2-hydroxy-3-octadecyloxy)propyl-L-arginine hydrochloride (yield 4.2.3%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:30][C:26]3[NH:25][CH:29]=[CH:28][N:27]=3)[CH:17]=2)=[CH:3]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NCc4ncc[nH]4)c3)C(=O)NC2=O)c2ccccc21
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and imidazole-2-carboxaldehyde (40 mg, 0.42 mmol) in MeOH (8 mL) was stirred for 15 min., and then NaCNBH3 (40.2 mg, 0.64 mmol) was added. After stirring the reaction mixture overnight the volatiles were removed under vacuo and the residue was purified by preparatory TLC (3% MeOH/CH2Cl2) to afford 3-(1-methylindol-3-yl)-4-[3-(imidazol-2-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione (24.8 mg, 20 %). LC/MS: M+ 397(94.2%).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:19]#[N:20])([C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:21])(OC)=O.[C:22](C1CC(C2C=CC(Cl)=CC=2)(C#N)CCC1=O)(OC)=[O:23].S(=O)(=O)(O)O.[C:47](O)(=O)C>>[C:19]([C:9]1([CH2:11][C:16]2[CH:15]=[CH:14][C:13]([O:23][CH3:22])=[CH:12][CH:47]=2)[CH2:10][CH2:5][C:6](=[O:21])[CH2:7][CH2:8]1)#[N:20]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)cc2)CCC1=O
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc(CC2(C#N)CCC(=O)CC2)cc1
Yield: 71 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 41.5 gm. (0.145 mole) of 2-carbomethoxy-4-cyano-4-(p-methoxyphenyl)cyclohexanone [same as 2-carbomethoxy-4-cyano-4-(p-anisyl)cyclohexanone] (prepared in Part B, above) for the 29.8 gm. of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 940 ml. glacial acetic acid and 470 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml. respectively, and heating for 48 hours instead of 24 hours there is obtained 23.6 gm. (71% yield) of the expected 4-cyano-4-(p-anisyl)cyclohexanone which compound has a melting range at 84° to 86.5° C. An analytical sample recrystallized from diethyl ether has a melting range at 77.5° to 79.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1I)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1.CN(C=O)C.CCN(CC)CC>O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:25]#[C:24][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C#Cc2ccc(F)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine)palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) is added to a sealable tube and alternately evacuated and flushed with N2. To the tube is then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction is heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with H2O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].C([OH:10])(C)C.O=O>[Pd](Cl)Cl.O>[CH3:1][C:2](=[O:10])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:1][CH2:2][C:3](=[O:10])[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)O
Reactant: C=CCCCC
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Product: CCCC(=O)CC
Product: CCCCC(C)=O
Temperature: 40 °C
Yield: 20 %
Yield: 41 %

Procedure:
The operating conditions are substantially those of example 29: 0.236 mole of 1-hexene (30 cc), 65 cc of anhydrous isopropanol, 2 millimoles of palladium chloride, 4 millimoles of Cu (ClO4)2 (HMPT)4 complex and 5 cc water are introduced into a heat-insulated reactor and stirred at 40° C at a pH of about 7. After 4 hours of reaction, 25 millimoles of oxygen is absorbed; 25 millimoles of 2-hexanone (selectivity: 41%) and 12 millimoles of 3-hexanone (selectivity: 20%) is formed; 60 millimoles of 1-hexene is consumed. Thus, not only the activity is low but it is found that a mixture of two ketones is formed, instead of only 2-hexanone as in example 29.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 100 mg (0.22 mmol) of ethyl 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate and 1 ml of 1 M aqueous solution of lithium hydroxide in 6 ml of methanol and 2 ml of tetrahydrofuran was stirred for 2 hours. The mixture was concentrated in vacuum and neutralized to pH 5 by careful addition of 1 N aqueous HCl. The product was collected by filtration, washed with water and dried in high vacuum to afford 82 mg (85%) of 2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid. ESI MS m/z 423.0 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][CH2:12][C@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[ClH:21].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C@H:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][O:11][CH2:10][CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)N1CCC(COC[C@H](N)c2ccccc2)CC1
Product: CC(C)N1CCC(COC[C@H](NC(=O)c2ccc(Cl)cc2)c2ccccc2)CC1
Product: Cl

Procedure:
Using coupling method B, (R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (150 mg, 0.54 mmol) and 4-chlorobenzoyl chloride (0.14 mL, 1.1 mmol) afforded, after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) and conversion to the HCl salt by general method A, 205 mg (87%) of the title compound.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[N:5]=1.[CH:13]1([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:15][CH2:14]1.[O:20]=[C:21]1[C@:29]2([CH2:31][C@@H:30]2[C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1>>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([C@@H:30]2[C@:29]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:10][C:6]4[N:5]=[C:4]([C:3]([NH:19][S:16]([CH:13]5[CH2:15][CH2:14]5)(=[O:18])=[O:17])=[O:12])[CH:9]=[CH:8][CH:7]=4)[C:21]3=[O:20])[CH2:31]2)=[CH:39][CH:38]=1)#[N:37]
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: NS(=O)(=O)C1CC1
Reactant: N#Cc1ccc([C@H]2C[C@]23C(=O)Nc2ccccc23)cc1
Product: N#Cc1ccc([C@H]2C[C@]23C(=O)N(Cc2cccc(C(=O)NS(=O)(=O)C4CC4)n2)c2ccccc23)cc1

Procedure:
The title compound was prepared in analogy to Example 60 starting from methyl-6-(bromomethyl)picolinate, cyclopropanesulfonamide and (1R,2S) and (1S,2R)-4-(2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)benzonitrile prepared as in Scheme 1. LC/MS m/e calcd. for C27H22N4O4S: 498, observed (M+H)+: 499.2 1HNMR (400 MHz, DMSO-d6) δppm 1.02-1.15 (m, 2 H) 1.14-1.24 (m, 2 H) 2.08-2.20 (m, 1 H) 2.43-2.48 (m, 1 H) 2.99-3.15 (m, 1 H) 3.27-3.34 (m, 1 H) 5.19 (s, 2 H) 6.14 (d, 1 H) 6.72 (t, 1 H) 6.99 (d, 1H) 7.09 (t, 1 H) 7.47 (d, 1 H) 7.59 (d, 2 H) 7.79 (d, 2 H) 7.92-8.06 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])[O:19]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1OC2(CCNC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(C3)OC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (10 mg, 6%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (100 mg) obtained in Example 43(2), 3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (110 mg) and potassium carbonate (150 mg).