Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Yield: 59.5 %

Procedure:
A solution of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.0 g.) in ethanol (70 ml.) containing potassium hydroxide (7.0 g.) was heated under reflux for 30 minutes. The solution was then poured into water (250 ml.) and the aqueous solution was extracted with ether (2×150 ml.). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The solid which was thus precipitated was separated, washed with water, dried in vacuo and then recrystallised from a 6:2:3 v/v mixture of toluene, propan-2-ol and petrol (60-80) to give 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (3.9 g.), m.p. 186° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32](O)=[C:31]([CH3:37])[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOCC.CCCCCC>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][O:27][C:32]2[C:33]([CH3:35])=[CH:34][C:29]([Br:28])=[CH:30][C:31]=2[CH3:37])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 118.9 %

Procedure:
A solution of diethyl azodicarboxylate (16.1 mL, 102.2 mmol) in tetrahydrofuran (50 mL) was added dropwise during 1.5 hours to an ice cold solution of (S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine (20.0 g, 92.9 mmol), 4-bromo-2,6 dimethylphenol (18.7 g, 92.9 mmol), and triphenylphosphine (26.8 g, 102.2 mmol) in tetrahydrofuran (300 mL), while maintaining the temperature below 10° C. After the addition was complete, the reaction was stirred at room temperature for 48 hours and partitioned between ethyl acetate (1 L) and water (1 L). After extracting the aqueous phase with additional ethyl acetate (2×200 mL), the combined ethyl acetate layers were washed with brine (250 mL), dried over magnesium sulfate, and concentrated to afford a thick yellow oil. The oil was combined with hexane (500 mL) and ether (50 mL) and stirred for 30 minutes. The resulting white precipitate was removed by filtration and washed with additional hexane (50 mL). The combined filtrates were concentrated to give crude (S)-N-(tert-butoxycarbonyl)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine as a clear yellow oil (44 g).
Reaction SMILES: [CH3:1][CH2:2]CC[O-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.O>C(O)CCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH2:33][CH2:1][CH3:2])=[O:30]
Reactant: CCCC[O-]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
50 ml of a sodium n-butylate solution in n-butanol (prepared from 0.3 g of 80% strength sodium hydride and 50 ml of n-butanol) were added to a solution of 4.4 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethen-1-yl)-phenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 50 ml of n-butanol, and stirring was carried out for 5 hours at room temperature. Thereafter, the mixture was neutralized with 10% strength hydrochloric acid at 0-5° C. and the resulting solution was stirred into 100 ml of water at 0-5° C. The aqueous phase was extracted with 100 ml of toluene, and the combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. The oil obtained was chromatographed over silica gel (dichloromethane), and the oil obtained therefrom was stirred with petroleum ether. The resulting solid was filtered off, washed with petroleum ether and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Li].CI.O>C1COCC1.C(OCC)C.C(OCC)(=O)C>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][S:9]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:24])(=[O:10])=[O:11]
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(Br)c2)c(OC)c1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)C(C)c2cccc(Br)c2)c(OC)c1
Reaction time: 0.08 h

Procedure:
Under inert gas, 3.50 g of C-(3-bromophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −76° C., 10.93 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred for 5 minutes. After the addition of 1.24 g of methyl iodide, the reaction mixture was allowed to come to room temperature. The reaction solution was admixed with water and ethyl acetate, and the aqueous phase was reextracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (2.83 g) with a molecular weight of 414.3 g/mol (C17H20BrNO4S).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([O:22][CH:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[O:14]1)(=[O:41])[CH3:40]
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
To a solution of 1.0 g (3.4 mmol) 1′-benzyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one in 34 ml dichloromethane at −78° C. were added 6.8 ml (6.8 mmol) diisobutylaluminum hydride solution (1 M in n-hexane). After 45 min were subsequently added 0.80 ml (10 mmol) pyridine, a solution of 0.83 g (6.8 mmol) 4-N,N-dimethylaminopyridine in 2 ml dichloromethane and 1.9 ml (20 mmol) acetic anhydride. The reaction mixture was stirred at −78° C. for 14 h. The reaction was quenched with 34 ml aqueous saturated ammonium chloride solution and 26 ml 1 M aqueous sodium potassium tartrate solution and stirred for 30 min. Addition of saturated aqueous sodium hydrogen carbonate solution was followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (0.8 g; 70%) as a light yellow solid.
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCO)=CN2)C1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:26]([O:37][CH3:38])=[C:27]2[C:31]=1[NH:30][CH:29]=[C:28]2[CH2:32][C:33](OC)=[O:34]>>[F:22][C:23]1[CH:24]=[C:25]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:26]([O:37][CH3:38])=[C:27]2[C:31]=1[NH:30][CH:29]=[C:28]2[CH2:32][CH2:33][OH:34]
Reactant: COC(=O)Cc1c[nH]c2c(F)cc(-c3ccccc3)c(OC)c12
Agent: OCCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: COc1c(-c2ccccc2)cc(F)c2[nH]cc(CCO)c12
Yield: 69 %

Procedure:
Following the procedure (step 2, scheme 17) used to prepare compound 17-3, compound 22-2 gave compound 22-3 in 69% yield as a white solid. 1H NMR (CDCl3) δ ppm: 8.21 (bs, 1H), 7.58-7.62 (m, 2H), 7.39-7.45 (m, 2H), 7.30-7.35 (m, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.91 (d, J=11.3 Hz, 1H), 3.95 (q, J=6.0 Hz, 2H), 3.45 (s, 3H), 3.13 (t, J=6.0 Hz, 2H), 2.14 (t, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1
Reaction time: 3 h

Procedure:
0.150 g ethyl trans-4-[4-(E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoate (0.42 mmol, 1 eq.) is dissolved in 3 mL of a 2/1 mixture of THF/methanol. At 0° C., 0.07 g of lithium hydroxide monohydrate (1.67 mmol; 4 eq.) is added with stirring. After 3 hours at room temperature, the reaction medium is evaporated and aqueous 6% sulfur dioxide solution is added. The precipitate is filtered off and washed with water to give 0.085 g of trans-4-[4-(E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1([C:26]#[N:27])[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([CH3:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1.C(OCC)(=O)C>ClCCl.CCCCCCC>[C:26]([C:6]1([NH:5][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([CH3:25])[CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)#[N:27]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(N)(C#N)CC2)cc1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
Acetyl chloride (0.106 g, 1.356 mmol) in dichloromethane (1 ml) was added to room temperature solution of N-(4-amino-4-cyanocyclohexyl)-4-ethoxy-3-methylbenzenesulfonamide (Intermediate 124, 0.366 g, 1.085 mmol) in dichloromethane (9 ml) and the reaction was stirred 18 hours. The reaction was diluted with dichloromethane and rinsed with two volumes of saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered, and concentrated to yield 464 mg of a crude film. TLC (50% ethyl acetate in heptane) indicated a major spot Rf=0.07 by UV. The crude product was chromatographed on Biotage 25S by TLC generated gradient to yield N-(1-cyano-4-(4-ethoxy-3-methylphenylsulfonamido)cyclohexyl)-acetamide (320 mg, 0.843 mmol) as a colorless solid. Carbon-13 NMR displayed a characteristic signature for nitrile at 119.1 ppm along with a signal at 110.7 ppm for the aromatic carbon ortho to aryl ether; in addition the peaks at 169.7 ppm and 160.97 ppm represent the amide and ipso-carbon of the aryl ether (no assignment implied). LCMS [M+H]=380.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]1[O:14][C@@H:13]1[CH2:15]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:15][C@H:13]1[O:14][CH2:12]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-nitrophenol (5.95 g, 38.6 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (10.0 g, 38.6 mmol) in 150 mL of acetone was treated with 1.1 equivalents of K2CO3 (5.86 g, 42.4 mmol) and stirred at reflux for 18 hours. The suspension was cooled to ambient temperature; the solids were filtered; and the filtrate concentrated in vacuo to dryness. The resulting solids were partitioned between chloroform and water, and the aqueous layer extracted once with chloroform. The organic layers were combined and dried over Na2SO4 and concentrated in vacuo to 8.0 g (99%) of an orange solid. TLC (Rf =0.5, CHCl3) and NMR indicated >95% purity, so the material was used without further purification. NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2c1
Reactant: Cc1ccccc1O
Product: COc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3C)n(-c3ccccc3)c2c1

Procedure:
From the compound of step 4, the title compound was prepared analogously as described in example 1, step 2, using 2-methylphenol. Yield: 480 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH2:28])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH:28][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:22][N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(N)cnc1CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1CNC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
The title compound (2.21 g, 5.15 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-3-methoxypyridin-2-yl)methylcarbamate (IntC16) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:28]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCCCCCCCC(=N)NO
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.547 g (2.6 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 8 mL of toluene, 0.46 g (2.8 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thick mixture, 1 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-decanimidamide (compound of Example 32; 1.0 g, 5.3 mmol) in 3 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h and further at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The combined organic layers was washed with 5 mL of 1N HCl solution, 5 of 5% sodium bicarbonate solution and 5 mL of 10% sodium chloride solution. The organic layer was distilled to yield a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=[N:41]C=2C=1.[OH-].[NH4+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([NH2:41])=[O:25])=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: O=C(O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: NC(=O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1

Procedure:
To a solution of 4-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-3,5-difluorobenzoic acid (Example 38) in NMP was added EDC, HOBT and ammonium hydroxide. After reaction complete, the mixture was concentrated and purified by reverse phase chromatography (10-100% ACN in H2O, Kromisil, C8, 30×100 mm) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:20]1[O:21][C:17]([CH3:16])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C=O)o1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Cc1ccc(CNCCCc2ccc3ccccc3c2Cl)o1
Yield: 89 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-methylfuran-2-carbaldehyde in 89% yield as a pale yellow oil.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[N:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[N:71][CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:73])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2cnccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.049 mmol), 2,5-dimorpholinopyridin-3-amine (0.098 g, 0.37 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyrazin-2-yl)quinoline (0.090 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.074 g, 0.77 mmol) in toluene (3.1 mL) at 120° C. for 5 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyrazin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 9.25 (1H, d, J=1.6 Hz), 8.67 (2H, m), 7.81 (1H, d, J=11.7 Hz), 7.65 (1H, d, J=2.7 Hz), 7.63 (1H, m), 7.02-7.10 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.42 (1H, d, J=2.3 Hz), 3.92 (4H, br. s.), 3.81 (4H, app t, J=4.3 Hz), 3.25 (4H, br. s), 3.07 (4H, app t, J=4.3 Hz), 2.25 (3H, s). Mass Spectrum (ESI) m/e=520.2 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:1]([O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C#N)c(OC(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CN)c(OC(C)C)n1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
The nitrile 32a (1.25 g, 7.12 mmol) solubilized in Et2O (20 mL) and THF (10 mL) was added in small portion to a mixture of LiAlH4 (0.54 g, 2 mol eq) in Et2O (50 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was decomposed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was separated. The organic phase was anhydrified over Na2SO4 and evaporated to dryness to obtain 33a as yellow oil (1.14 g, 6.35 mmol, 89% Yield) used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Cl[C:19]1[N:24]=[C:23]([Cl:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1>ClCCCl.CC(O)(C)C.[Zn+2].[Br-].[Br-]>[Cl:25][C:23]1[C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)[N:24]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
C2 (690 mg, 2.92 mmol) was dissolved in 10 mL DCE:t-BuOH (1:1 vol:vol), and the resultant solution was treated with ZnBr2 (1.97 g, 8.76 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (748 mg, 3.45 mmol). The resultant mixture was then treated drop-wise with TEA (406 ml, 2.92 mmol), and the mixture was allowed to stir at 25° C. for about 20 hours. The reaction mixture was concentrated, and the resultant residue was treated with EtOAc. The resultant solution was washed with water and brine, and dried over MgSO4. The mixture was then filtered, concentrated, and purified by column chromatography eluting with 22% EtOAc/Heptane. The product-containing eluents were combined and concentrated to provide C3 as a white solid. Yield: 680 mg, 56%. MS-415.2. 1H NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53 (d, 2H), 7.31 (d, 1H), 7.23 (d, 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[CH2:3].C(Cl)Cl.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C1N2CCN(CC2)C1>>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([NH:19][C:14]([NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2]([CH3:1])=[CH2:3])(=[O:12])=[O:11])=[O:15])[N:21]=1
Reactant: C=C(C)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(1-methylethenyl)benzenesulfonyl isocyanate in methylene chloride (0.9 g, 4 mmol active ingredient) was added via syringe to a nitrogen purged flask containing a 2-amino-4,6-dimethylpyrimidine and a trace (ca. 10 mg) of DABCO. The mixture was heated to reflux for 3 hours then stirred at room temperature overnight. Evaporation of the mixture left a semi-solid residue that was triturated with ether and filtered. In this manner 0.95 g of the title compound was obtained, m.p. 177°-183°.