Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:28]N1C(=O)CCC1=O>C1COCC1.C1CCCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:28])=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]cc(Br)c23)CC1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of 0.4 g (1.32 mmole) 4-(1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL THF was added 0.83 mL (1.65 mmole) 2M n-butyl lithium in cyclohexane. The reaction mixture was stirred for 5 min and then cooled to −70° C. A solution of 0.26 g (1.44 mmole) N-bromosuccinimide in 6 mL THF was added and the mixture was stirred at 0° C. for 0.5 hr. The mixture was diluted with 10 mL water and extracted with 25 mL ether. The organic phase was washed with 5 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to column chromatography over silica gel eluting with hexane/chloroform/ethyl acetate (50:48:2) to afford) 4-(3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a foam, 0.46 g. Nmr (deuteriochloroform) ppm δ: 1.50 (s 9H), 3.08 (m, 4H), 3.71 (m, 4H), 6.72 (dd, 1H), 7.14 (m, 3H), 8.42 (brs, 1H).
Reaction SMILES: [H-].[Na+].C(#N)[CH:4]([CH2:6][C:7]#[N:8])O.Br[C:11]1[N:16]=[CH:15][C:14]([N:17]2[C:26]3[N:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]4=[N:29][C:25]=3[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:36])=[CH:13][CH:12]=1.[N:37]1C=CC=CC=1>>[C:7]([CH:6]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:26]3[N:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]4=[N:29][C:25]=3[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:36])=[CH:15][N:16]=1)[C:4]#[N:37])#[N:8]
Reactant: N#CCC(O)C#N
Reactant: COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Br)nc4)c3n2c1
Reactant: c1ccncc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(C(C#N)C#N)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
Sodium hydride (2.5 equiv., 0.950 mmol, 0.038 g (60%)) was added to a solution of malonitrile (1.2 equiv., 0.456 mmol, 0.030 g) in dry pyridine (1 ml) under Ar atmosphere. The catalyst—prepared as described above—was injected, and the mixture was stirred at room temperature for 5 min. 6-(6-Bromo-pyridin-3-yl)-9-methoxypyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (39) (1.0 equiv., 0.380 mmol, 0.160 g) was then added and the reaction mixture was heated at 85° C. for 2 h. After destruction of the excess of sodium hydride with methanol, the solvent was concentrated under vacuum. The residue was purified by column chromatography (gradient elution: dichloromethane/methanol (7M NH3) 9:1→8:2) to give α-cyano-5-[5,6-dihydro-9-methoxy-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-6-yl]-2-pyridineacetonitrile (52) (0.030 g, yield=19%, purity (LC)=99%).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.CN1CCOCC1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[F:39][C:40]([F:49])([F:48])[C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:40]([F:39])([F:48])[F:49])[CH:42]=1)=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
mono-Benzyl malonate (10 g) was dissolved in THF (100 ml), 4-methylmorpholine and cooled to −22° C. prior to the slow addition of diphenyl chlorophosphate (14 ml) and 3-trifluoromethyl-phenylamine (19 ml). After the reaction was warmed to rt overnight, it was heated to gently reflux for 0.5 h. After the reaction was cooled to rt, the solid was filtered off. The filtrate was concentrated. EtOAc was added along with 1N HCl solution. The organic layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid benzyl ester (8.0 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 3.56 (s, 2H),5.26 (s, 2H), 7.40 (m, 7H), 7.75 (d, 1H), 7.83 (s, 1H), 9.43 (s, br, 1H). (21b) A portion (6 g) of the above derivative (21a) was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (4 g). A hydrogen balloon was added and the solution was stirred overnight. The palladium was filtered off and the solution was concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid (1.75 g). MS found: (2M−H)−=493.3. (21c) Derivative (21b)(65 mg) was incorporated into example (1e), to give the title compound (80 mg). MS found: (M+H)+=494.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.[ClH:29]>CC(=O)OCC>[ClH:29].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C

Procedure:
A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (500 mg, 1.29 mmol) in 5N HCl in EA (20 mL) was stirred at room temperature for 2 hours, then concentrated to give curd product as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl.[CH3:10][O:11][C:12]1[C:30]([O:31][CH3:32])=[CH:29][C:15]([CH2:16][CH2:17][NH:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:14][C:13]=1[OH:33].[BH4-].[Na+]>CO>[CH3:32][O:31][C:30]1[CH:29]=[C:15]2[C:14](=[C:13]([OH:33])[C:12]=1[O:11][CH3:10])[CH:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[NH:18][CH2:17][CH2:16]2
Reactant: COc1cc(CCNC(=O)Cc2ccc(F)cc2)cc(O)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(c(O)c1OC)C(Cc1ccc(F)cc1)NCC2
Temperature: 55 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Phosphoryl chloride (370 μl, 3.97 mmol) was added to a chloroform (6 ml)solution of N-(4,5-dimethoxy-3-hydroxyphenethyl)-4-fluorophenylacetamide (437 mg, 1.31 mmol) at room temperature, and the mixture was stirred undera nitrogen atmosphere at 55° C. for 8 hours. The solvent and the excess phosphoryl chloride were removed under reduced pressure and the resultant residue was dissolved in methanol (25 ml). Sodium borohydride (65 mg, 1.72 mmol) was added to this methanol solution under ice cooling and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, brine (50 ml) was added to the resultant residue, and the mixture was extracted three times with chloroform (30 ml). The organiclayer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resultant residue was recrystallized from ethyl acetate-hexane to give 199 mg (yield: 48%) of the captioned compoundas a colorless solid. Melting point: 195°-200° C. FAB-MS (m/z, (C18H20NO3F+H)+): 318 1H-NMR (300MHz, CD3OD, δ ppm): 2.97-3.08 (3H, m), 3.22-3.34 (1H, m), 3.46-3.55(2H, m), 3.78 (3H,(2H, m), 7.34-7.38 (2H, m)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].CCN(C(C)C)C(C)C.O>O1CCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Yield: 78.8 %

Procedure:
A solution of 4-Fluoro-3-nitro-aniline (2.00 g, 12.8 mmol), 3-Trifluoromethyl-benzoyl chloride (1.895 mL, 12.8 mmol), Hunig's base (4.463 mL, 25.6 mmol) in tetrahydrofuran (50 ml) was stirred at room temperature for 1 hour. Afterwards water (450 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound (3.311 g, 97%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][C:12]([O:14]C)=[O:13])=[C:9]2[C:4]([N:5]([CH3:19])[C:6](=[O:18])[N:7]([CH3:17])[C:8]2=[O:16])=[N:3]1.OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][N:2]1[C:10]([CH2:11][C:12]([OH:14])=[O:13])=[C:9]2[C:4]([N:5]([CH3:19])[C:6](=[O:18])[N:7]([CH3:17])[C:8]2=[O:16])=[N:3]1
Reactant: COC(=O)Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc2c(c1CC(=O)O)c(=O)n(C)c(=O)n2C

Procedure:
A mixture of Step 6 intermediate (1.0 g, 3.755 mmol) and 6 N H2SO4 (9.3 ml) in dioxane (9.3 ml) stirred at reflux temperature for 2 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue obtained was triturated in diethyl ether, solid obtained was collected by filtration to give 330 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.17 (s, 3H), 3.34 (s, overlapping with DMSO, 3H), 3.79 (s, 3H), 4.11 (s, 2H), 12.95 (br s, 1H) and 1H NMR (300 MHz, CDCl3): δ 3.39 (s, 3H), 3.50 (s, 3H), 3.88 (s, 3H), 4.10 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][S:31]([CH:34]=[CH2:35])(=[O:33])=[O:32].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCS(C)(=O)=O)C3)cc1
Yield: 27.4 %

Procedure:
A mixture of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (ca) (0.35 mmol), methyl-sulfonylethene (3.5 mmol), DIPEA (1 mL), in a mixed solvent of THF/DMF (30 mL, 10:1) was stirred at 40° C. overnight. The solvent was removed in vacuum and the residue was purified by preparative TLC (Hexanes:ethyl acetate=1:2) to give 48.2 mg (yield: 27%) of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(2-(methylsulfonyl)ethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (yg). 1H NMR (D6-DMSO, 400 MHz): δ 8.60 (s, 1H), 8.13 (d, J=7.2, 2H), 7.44 (d, J=7.2, 2H), 6.12 (t, J=2.5, 1H), 4.18-3.33 (m, 11H), 3.19-2.63 (m, 11H), 1.20 (d, J=6.8, 3H), 1.04 (t, J=7.2, 3H). LC-MS: m/z=+503 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:20]=2)=O)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([O:38][CH2:39][C:40]([F:42])([F:43])[F:41])=[CH:9][C:8]2[N:7]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)[CH:20]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from [2′-fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M22) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (50 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A149) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:3]1.C[Li].[C:16]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[NH4+].[Cl-].[O:29]1CCCC1>>[C:19]1([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[C:4]([NH:3][C:2]([CH3:13])([CH3:1])[CH2:6][OH:5])=[O:29])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH:18]=1
Reactant: C1CCOC1
Reactant: O=C1CCCc2ccccc21
Reactant: CC1(C)COC(c2ccncc2)=N1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Product: CC(C)(CO)NC(=O)c1ccncc1C1=CCCc2ccccc21
Reaction time: 2 h
Yield: 17.6 %

Procedure:
Preparation of: ##STR39## To a stirred and cooled (-78° C.) solution of 26.4 g of 4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)pyridine in 200 ml of tetrahydrofuran (distilled over LiAlH4) there were added 70 ml of methyl lithium under a nitrogen atmosphere. Stirring was continued for 2 hours at 0° C. At -78° C., there was added a solution of 22 g of 3,4-dihydro-1(2H)naphthalenone in 50 ml of tetrahydrofuran. After stirring overnight at room temperature, the reaction mixture was poured into a saturated NH4Cl solution. The product was PG,25 extracted with diethyl ether and the extract was dried, filtered and evaporated. The residue was recrystallized from acetonitrile, yielding 8.5 g (17.6%) of 3-(3,4-dihydro-1-naphthalenyl)-N-(2-hydroxy-1,1-dimethylethyl)-4-pyridinecarboxamide; mp. 156.8° C. (comp. 3.031).
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]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:8]([CH3:25])[CH2:7][C:6]2=[O:26].[CH:27](OCC)=[O:28].[O-]CC.[Na+].[H-].[Na+]>C1C=CC=CC=1.C(O)C>[OH:28][CH:27]=[C:7]1[C:6](=[O:26])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]1[CH3:25]
Reactant: CCOC=O
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O

Procedure:
Following the procedure of Examples 6-8, 9.5 g. of benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 10.95 ml. of ethyl formate and sodium ethoxide prepared from 2.57 g. of sodium hydride and 3.23 ml. of ethanol in 120 ml. of benzene gave on work-up a yellow oil which on crystallization afforded 6.0 g. of crude product, m.p. 106°-110°C. The analytical same is recrystallized several times from methanol, m.p. 116°-118°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[CH2:28][O:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[O:21][CH3:20])[C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Reactant: COc1ccccc1OCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCC(O)CN1C(=O)CCc2cc(-c3ccc(F)cc3F)ccc21
Yield: 49.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (180 mg, 0.69 mmol) (PT-012, made as in Example 1B, above) and 2-((2-methoxyphenoxy)methyl)oxirane (162 mg, 0.90 mmol) in anhydrous N,N-dimethylformamide (2 ml) was added caesium carbonate (326 mg, 1.00 mmol) in a 5 ml Personal Chemistry microwave reaction vial. The reaction vial was sealed, and subjected to microwave irradiation at 180° C. for 40 minutes. The reaction was cooled, poured into water (10 mL), extracted with ethyl acetate (2×30 mL), and the combined organic phases washed with water (30 mL), 2N sodium carbonate (30 mL), brine (40 mL), dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 6-(2,4-difluorophenyl)-1-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-3,4-dihydroquinolin-2(1H)-one (148 mg, 0.34 mmol, 49%) (compound No. 88)). LCMS mz 440.0 (M+H), 462.0 (M+Na), anal HPLC >95% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (d, J=8.6 Hz, 1H); 7.36 (m, 2H); 7.31 (bs, 1H); 6.88-7.03 (m, 6H); 4.36 (m, H); 4.27 (s, 1H), 4.26 (d, J=2.3 Hz, 1H); 4.15 (dd, J=9.8 and 5.5 Hz, 1H); 4.00-4.10 (m, 2H); 3.88 (s, 3H), 2.99 (m, 2H); 2.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].[C:49](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C.CC1C=CC=CN=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:19][CH2:18][C:17]([CH2:32][O:33][CH3:49])([CH2:22][CH2:21]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccn1
Product: COCC12CCC(N(C)C(=O)C(=O)N(C)C)(CC1)c1nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c(=O)n1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.79 %

Procedure:
To a solution of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (100 mg, 0.161 mmol) in CH2Cl2 (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (166 mg, 0.807 mmol) and trimethyloxonium tetrafluoroborate (48.5 mg, 0.807 mmol) and the mixture was stirred at room temp for 16 h. Another 5 equiv each of methylpyridine and trimethyloxonium tetrafluoroborate were added and the mixture was stirred at room temp for 5 h. The reaction was quenched by addition of 1N KHSO4 (30 mL) and stirred for 10 min and extracted with CH2Cl2 (25 mL×2). The combined extracts were dried, filtered and concentrated. The crude material was then dissolved in CH2Cl2 (1 mL) and treated with TFA (1 mL, 12.98 mmol) at room temp for 16 h. The mixture was concentrated in vacuuo and purified by preparative HPLC to afford the title compound (3.5 mg, 6.12 mmol, 3.79% yield) as a thick film. 1H NMR (500 MHz, CDCl3) δ: 12.15 (1H, br. s.), 9.59 (1H, br. s.), 7.24-7.27 (1H, m), 7.17-7.23 (1H, m), 6.90-6.97 (1H, m), 4.71 (1H, d, J=15.6 Hz), 4.58-4.65 (1H, m), 4.43-4.48 (1H, m), 3.51 (1H, d, J=15.6 Hz), 3.39-3.45 (1H, m), 3.20 (2H, d, J=5.8 Hz), 3.05 (3H, s), 3.02 (3H, s), 3.00 (3H, s), 2.27 (3H, d, J=1.8 Hz), 2.08-2.12 (3H, m), 1.76-1.83 (1H, m), 1.66-1.74 (2H, m), 1.38-1.49 (1H, m). LCMS (M+H)=544.5.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18](=[O:20])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCO)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of the carbonate (128.826 g, 0.322 moles) produced in Example 21 in 450 ml of methylene chloride was added dropwise under nitrogen to a solution of 6-amino-1-hexanol (56.6 g, 0.483 moles) and triethylamine (224.2 ml, 1.61 moles) in 2 L of methylene chloride at room temperature. After the addition the reaction was stirred overnight at room temperature. By TLC the reaction was not complete. An additional 37.7 g (0.322 moles) of 6-amino-1-hexanol and 224.2 ml (1.61 moles) of triethylamine were added and the stirring continued overnight. By TLC the reaction was complete. The reaction was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 95.0 g (78%) of a yellow oil which crystallized on standing, mp 50-52° C.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(OCc2ccc(CC(Cl)=NO)cc2)nc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (4-(5-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (246 mg, 0.846 mmol) described in Manufacturing Example 44-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (21.3 mg, 16.9%).