Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[C:18]([Cl:20])[C:15]([C:16]#[N:17])=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:13]=2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:20][C:18]1[C:15]([C:16]#[N:17])=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=2)[CH:19]=1
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
Acetyl chloride (0.013 mL, 0.181 mmol) was added to a suspension of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (48 mg, 0.121 mmol, from Step 3 of Example 199) and Hunig's base (0.084 mL, 0.483 mmol) in dichloromethane (1 mL) at room temperature. After 90 min at room temperature, additional acetyl chloride (0.05 mL) was added. After additional 23 h, the reaction was stopped and the mixture purified by silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, to give N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide as yellow solid (24.9 mg, 47% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (2H, δ, J=8.78 Hz), 8.00-8.03 (2H, m), 7.79 (1H, s), 7.68 (2H, δ, J=8.53 Hz), 7.35-7.44 (3H, m), 7.19 (1H, t, J=7.40 Hz), 7.08-7.15 (4H, m), 2.23 (3H, s); MS (ES+) m/z: 440 (M+H); LC retention time: 4.668 min (analytical HPLC Method A). Unreacted starting material was also recovered (13.7 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([CH3:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[N:20]([CH3:32])[C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([CH3:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc3c(c2)c(C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
12.36 g (3173 mmol) 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-methyl-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 15, were dissolved in 158 mL N,N-dimethylformamide. 1.62 g (40.61 mmol) sodium hydride (as a dispersion in mineral oil) were added and the mixture stirred for 20 minutes. 2.37 mL (38.08 mmol) methyl iodide were added and the mixture stirred for 2.5 hours. The solvent was distilled off under vacuum and the residue was taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Purification with column chromatography afforded 5-(3,5-dicyano-1,2,6-trimethyl-1,4-dihydro-pyridin-4-yl)-3-methyl-indazole-1-carboxylic acid tert-butyl ester (10.56 g, 82.5%). 1H-NMR (DMSO-D6): δ=8.06 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H), 4.56 (s, 1H), 3.22 (s, 3H), 2.54 (s, 3H), 2.25 (s, 6H), 1.64 (s, 9H) ppm. MS (ES+): 404.45 (M++1, 75%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]=[C:24]2[S:28][C:27](=[O:29])[N:26]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[C:25]2=[O:30])[CH2:19][CH2:18]1
Reactant: CN1CCN(C=C2SC(=O)NC2=O)CC1
Reactant: ClCCCCSc1cccc2nccn12
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCN(C=C2SC(=O)N(CCCCSc3cccc4nccn34)C2=O)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 241 mg (1.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 227 mg (1.0 mmol) of 5-(1-methylpiperazin-4-yl)methylene-thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 3 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/ethanol=50/1) to yield 330 mg (76.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:10]>>[CH:8]1[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:1]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: C#CCCCCC#C
Reactant: CCOC(=O)C#N
Product: CCOC(=O)c1cc2c(cn1)CCCC2
Yield: 20.6 %

Procedure:
A solution of 1,7-octadiyne (4.00 ml, 30.1 mmol) and ethyl cyanoformate (2.95 ml, 30.1 mmol) in dry degassed 1,4-dioxane (500 ml) under argon at rt was treated with cyclopentadienyl-Cobalt(I)-dicarbonyl (0.814 g, 4.52 mmol) and then heated at reflux for 18 h. Reaction was then evaporated, treated with toluene (100 ml), re-evaporated, dissolved in DCM (100 ml), filtered through a short pad of Kieselguhr, eluting with DCM, organic extracts evaporated, chromatographed (0-100% DCM:40-60 Petroleum ether then 0-10% methanol/DCM) to give product as an impure brown oil (1.27 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([Cl:1])[C:3]([C:13]([F:14])([F:16])[F:15])=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3ccccc3)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3:Rf=0.58) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.81–7.86 (m, 1H), 7.36–7.44 (m, 4H), 6.42–6.48 (d, 1H), 6.34–6.38 (dd, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62–3.82 (m, 4H), 3.12–3.22 (m, 4H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:16]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccccc1

Procedure:
To a solution of phenol (3.16 g, 33.6 mmol) in acetonitrile, was added ethyl 4-bromobutyrate (4.8 ml, 33.6 mmol), potassium carbonate (4.64 g, 33.6 mmol) and tetrabutylammonium iodide (370 mg, 1 mmol). The reaction mixture was stirred vigorously and heated to reflux for 2 days before being cooled, filtered, dried (MgSO4) and concentrated in-vacuo to yield 4-phenoxy-butyric acid ethyl ester. 4-Phenoxy-butyric acid ethyl ester was hydrolyzed to its corresponding carboxylic acid using sodium hydroxide mediated hydrolysis to yield 4-phenoxy-butyric acid. To a solution of 4-phenoxy-butyric acid (7.67 g, 29.6 mmol) in anhydrous dichloromethane was added oxalyl chloride (4.4 ml, 50.3 mmol) and one drop of dimethyl formamide and the reaction mixture stirred at room temperature for 30 minutes. Reaction mixture was concentrated in-vacuo and the residue dissolved in 1,2-dichloroethane (90 ml). This solution was added drop wise to a suspension of aluminum trichloride (4.73 g, 35.5 mmol) in 1,2-dichloroethane (50 ml) at 0° C. Reaction mixture was left stirring in ice bath which rose to room temperature overnight. The reaction mixture was poured over conc. hydrochloric acid (30 ml) stirred into 100 g ice, and then stirred for a further 90 minutes until the ice fully melted. The aqueous phase was washed with dichloromethane 3 times, before the organics were combined, dried (Na2SO4) and concentrated in-vacuo. Purification by triturating with diethyl ether gave 3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A stirred solution of 5.2 g (0.017 mol) of 3-(2-chloro-5-trifluoromethylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 4 g (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 mL of water and the oil globules which separated slowly solidified on standing. Filtration yielded 4 g of crude product which was recrystallized from benzene/ligroin yielding 3.3 g (62.9%) of fine white crystalline product, mp 132°-133° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>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]>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.00 g (7.14 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyrimidine (4) in 16 mL of dioxane-degassed water 1:1 were added 132 mg (0.14 mmol) of Pd2dba3 followed by 242 mg (0.58 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.2 g (21.42 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 100 mL of water and extracted with two portions of 75 mL of ethyl acetate. The aqueous layer was acidified with HCl (pH 2-3) and then extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure to afford the expected product as a light yellow crystals: yield 1.62 g (100%). 1H-NMR (CDCl3) δ 5.76 (s, 2H), 2.47 (s, 6H), 2.20 (s, 6H); 13C-NMR (CDCL3) δ 154.15, 149.87, 145.13, 128.74, 107.32, 18.40, 13.50.
Reaction SMILES: [Cl-].[OH:2][C@@H:3]([C@H:5]1[C:25](=[O:26])[N:7]2[CH:8]([C:12]([O:14]CC3C=CC([N+]([O-])=O)=CC=3)=[O:13])[C:9](=O)[CH2:10][C@H:6]12)[CH3:4].[CH3:27][N:28]([CH3:39])[C:29]([C@@H:31]1[CH2:35][C@H:34]([SH:36])[CH2:33][N+:32]1([CH3:38])[CH3:37])=[O:30]>C(#N)C.C(N(C(C)C)CC)(C)C.O1CCCC1.P([O-])([O-])([O-])=O.[Pd]>[CH3:38][N+:32]1([CH3:37])[CH2:33][C@@H:34]([S:36][C:9]2[CH2:10][C@@H:6]3[C@@H:5]([C@H:3]([OH:2])[CH3:4])[C:25](=[O:26])[N:7]3[C:8]=2[C:12]([O-:14])=[O:13])[CH2:35][C@H:31]1[C:29](=[O:30])[N:28]([CH3:27])[CH3:39]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)C[N+]1(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(=O)N(C)C)[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h
Yield: 22.5 %

Procedure:
126 μl of diisopropylethylamine and 132 μl of diphenylphophoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 218 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate dissolved in 3 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time a solution of 243 mg of the crude (2S, 4S)-2-(N,N-dimethylcarbamoyl)-1,1-dimethyl-4-mercaptopyrrolidinium salt [prepared as described in Example 4-(1)] in 2 ml of dry acetonitrile and 144 μl of diisopropylethylamine were added to the mixture, whilst ice-cooling. The mixture was then allowed to stand at the same temperature for 5 hours and then for 2 days in a refrigerator. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 6. The crude product was dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2 hours in the presence of 200 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified in a similar manner to that described in Example 6, to afford 56 mg of the title compound.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)N3CCC3)nc2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (2.67 mL, 20 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (6.18 g, 15.3 mmol) in DCM (100 mL) and the reaction stirred at RT for 50 mins. 2-Amino-5-methylpyrazine (3.34 g, 30.6 mmol) and pyridine (2.5 mL, 30.6 mmol) were added and the reaction stirred overnight. The solvent was removed in vacuo, and the residue taken up in ethyl acetate (350 mL). The organic phase was washed with water (2×100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-75% ethyl acetate in isohexane, to give the desired material (4.01 g). 1H NMR δ (CDCl3): 2.28 (quin, 2H), 2.49 (s, 3H), 4.18 (t, 2H), 4.63 (t, 2H), 5.05 (s, 2H), 6.78 (s, 1H), 7.10 (s, 1H), 7.25-7.37 (m, 7H), 8.04 (d, 1H), 8.07 (s, 1H), 8.25 (s, 2H), 9.46 (s, 1H); m/z 496 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[O:18][CH3:19])=[CH:15][CH:14]=[CH:13][C:12]=2[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[OH-].[Na+].Cl>CO.O1CCCC1>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:18][CH3:19])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])[N:9]=1)#[N:28]
Reactant: COC(=O)CNC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)NCC(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Yield: 79.5 %

Procedure:
To a mixture of [(1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (21 mg, 0.05 mmol), and methanol/tetrahydrofuran (0.9 mL, 1:3.5) was added 2N sodium hydroxide (29.2 μL, 0.06 mmol) at room temperature. The yellow solution was stirred at that temperature for fifty-five minutes before it was acidified with 1N HCl (69.1 μL) to pH=3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of methanol, dichloromethane and acetic acid (0.1%) to give the title compound as a pale brown solid (15 mg): MS: (+) m/z 378.00 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[C:22]1([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:20]=[C:31]1\[C:32](=[O:37])[NH:33][C:34]2[C:30]\1=[CH:29][C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:36][CH:35]=2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(-c4ccccc4)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 62.3 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-phenyl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 48 (41 mg, yield 62.3%) as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([CH3:15])[CH:13]([CH3:16])[NH:12][C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].CN(C)C1CCCCC1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.C(OCC)(=O)C.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([CH3:15])[CH:13]([CH3:16])[N:12]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccncc1I
Reactant: CC1NC(=O)N(c2ccc3ncsc3c2)C1C
Agent: I[Cu]I
Agent: CN(C)C1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccncc1N1C(=O)N(c2ccc3ncsc3c2)C(C)C1C
Yield: 8.8 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-4,5-dimethyl-imidazolidin-2-one (I-175b: 50 mg, 0.202 mmol) was refluxed with 3-iodo-4-methyl-pyridine (44.33 mg, 0.202 mmol), copper iodide (3.85 mg, 0.0202 mmol), N,N-dimethyl-cyclohexane-1,2-diamine (0.0095 mL, 0.061 mmol), potassium phosphate (107.2 mg, 0.506 mmol) and 1,4-dioxane (5 mL) at 120° C. for 16 hours to afford the crude product. The reaction was monitored by TLC (100% ethyl acetate). Purification by column chromatography on silica gel (60% ethyl acetate in hexane) followed by preparative HPLC afforded 6 mg of the product (8.76% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:22](=[O:32])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-])=O)[CH2:15][CH2:14]3)[C:12](=[O:33])[NH:11][CH2:10]2)=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][C:13]2([N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:10][NH:11][C:12]2=[O:33])[CH2:18][CH2:17]1)=[O:32]
Reactant: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1

Procedure:
A mixture of 9 parts of N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with ammonium hydroxide. The product is extracted twice with trichloromethane. The combined extracts are washed twice with water, dried, filtered and evaporated. The solid residue is boiled with 2-propanol and filtered. The product is allowed to crystallize from the filtrate. It is filtered off and dried in vacuo, yielding 5 parts of 2-amino-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}benzamide; mp. 194.9° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:8]NC(=O)[NH:5][C:4]1=[O:10].FC(F)(F)C(=O)C.[BrH:20]>CO>[Br:20][CH2:8][CH:3]([C:2]([F:12])([F:11])[F:1])[C:4]([NH2:5])=[O:10]
Reactant: O=C1NCC(C(F)(F)F)C(=O)N1
Reactant: Br
Agent: CC(=O)C(F)(F)F
Solvent: CO
Product: NC(=O)C(CBr)C(F)(F)F

Procedure:
One conventional method for synthesizing 5-trifluoromethyldihydrouracil comprises converting trifluoroacetone to cyanohydrin, acetylating the product, heat-decomposing the acetylated product, reacting the resulting alpha-trifluoroacrylonitrile with hydrogen bromide in methanol to form beta-bromo-alpha-trifluoromethylpropionamide, reacting the amide with urea or acetylurea, and cyclizing the resulting compound in hydrochloric acid [C. Heidelberger, D. G. Parsons and D. C. Remy, J. Med. Chem., 7, 1 (1964)].
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.[N:16]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[CH:1]=[N:16]1
Reactant: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2cn[nH]c2c1
Yield: 102 %

Procedure:
Ethyl 4-methyl-3-nitrobenzoate (105 g) was dissolved in glacial acetic acid (4 1), followed by stirring. To the solution, a solution of sodium nitrite (32 g) in water (80 ml) was added at once at a temperature of 10° C. to 15° C., and the resultant mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to remove acetic acid. Water was added to the residue, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and dried. The obtained crystals was further washed with methanol and diethyl ether, and dried to give ethyl indazol-6-yl carboxylate (90 g), m.p. 125°-126° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:33]=[CH:32][C:15]3[CH2:16][C@@H:17]([CH2:27][C:28]([O:30]C)=[O:29])[C:18](=[O:26])[N:19]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:20][C:14]=3[CH:13]=2)[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OC)=O)C(=O)N(CC(F)(F)F)CC=2C=1>O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:33]=[CH:32][C:15]3[CH2:16][C@@H:17]([CH2:27][C:28]([OH:30])=[O:29])[C:18](=[O:26])[N:19]([CH2:21][C:22]([F:23])([F:25])[F:24])[CH2:20][C:14]=3[CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCOc2ccc3c(c2)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)C3)n1
Agent: COC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Solvent: O
Product: CNc1cccc(CCOc2ccc3c(c2)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C3)n1

Procedure:
According to the method of Example 37(c), except substituting methyl (S)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the methyl (R)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as a white solid: MS (ES) m/e 452.2 (M+H)+. Anal. Calcd for C22H24F3N3O4.0.7 H2O: C, 56.94; H, 5.52; N, 9.05. Found: C, 56.80; H, 5.19; N, 8.85.