Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH:46]([CH3:48])[CH2:45][C:44]=3[CH:49]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH:46]([CH3:48])[CH2:45][C:44]=3[CH:49]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogen carbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C. for 30 min, 4′-{[2-ethyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.3 g, 49%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[C:23]([O-:25])=[O:24])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:7]=1[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C(=O)[O-])n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1c(C(=O)O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 96.7 %

Procedure:
To a solution of 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.40 g, 9 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added sodium hydroxide (1.08 g, 27 mmol). The obtained mixture was refluxed under heating for 3 h. The reaction mixture was pouted into water, and, after making the mixture acidic with 1N hydrochloric acid, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (3.04 g, 96.8%) as crystals.
Reaction SMILES: [CH2:1]1[C@H:8]2[NH:9][C@H:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][N:12]=1>>[O:6]=[C:5]1[CH2:4][CH:3]2[N:9]([C:11]3[N:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][N:12]=3)[CH:8]([CH2:1][CH2:2]2)[CH2:7]1
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C1CC2CCC(C1)N2c1ncc(B(O)O)cn1
Yield: 48.1 %

Procedure:
Prepared from nortropan-3-one (2.00 g, 16.0 mmol) and (2-chloropyrimidin-5-yl)-boronic acid (2.53 g, 16.0 mmol) in accordance with General Method C to give the title compound (1.90 g, 48%) as a pale orange oil. δH (DMSO-d6) 8.93 (s, 2H), 8.70 (s, 2H), 4.95-4.90 (m, 2H), 3.68-3.60 (m, 2H), 2.65-2.59 (m, 2H), 2.35-2.26 (m, 2H), 2.12-2.07 (m, 2H), 1.75-1.68 (m, 2H). LCMS (pH 3): MH+ (248.8), RT 0.87 minutes.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:21]1[C:25]2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN>CN(C)C=O.CCOC(C)=O.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH:21][CH3:25])=[O:16])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (25 mg) in N,N-dimethylformamide (0.375 mL) were added 1-hydroxybenzotriazole (19.5 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22.5 mg) and methylamine hydrochloride (9.8 mg). The mixture was stirred at 55° C. for 1 hour. To the solution were added water and EtOAc and the mixture was extracted with EtOAc. The extract was washed with water, dried over MgSO4, filtrated and evaporated The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (5 mg), as a pale yellow powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:22][CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[OH:23])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (136 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (182 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OCCCCl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35].[I-].[Na+]>COCCO.ClCCl>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:3][CH2:4][CH2:5][O:6][C:19]2[N:18]=[C:17]([NH:16][C:3]3[C:4]4[O:8][CH2:7][O:6][C:5]=4[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])=[CH:10][C:2]=3[Cl:1])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCNCC1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2nc(OCCCN3CCN(C(C)=O)CC3)nc3ccc(OC)cc23)c2c1OCO2
Temperature: 105 °C
Yield: 145 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.158 g) was dissolved in 2-methoxyethanol (5 ml) and then N-acetylpiperazine (0.600 g) was added and the mixture heated to 105° C. A small amount of sodium iodide was added to the reaction mixture, and heating continued for a total of 2½ hours. The reaction mixture was cooled to room temperature and then diluted with dichloromethane. The mixture was washed with a water/brine (5/1) mixture followed by brine and then dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.136 g) as a pale yellow foam. NMR Spectrum: (CDCl3) 2.10 (quin, 2H), 2.43 (m, 2H), 2.47 (m, 2H), 2.57 (t, 2H), 3.46 (s, 3H), 3.47 (m, 2H), 3.49 (s, 3H), 3.62 (t, 3H), 3.98 (s, 3H), 4.25 (t, 2H), 4.35 (s, 2H), 6.08 (s, 2H), 7.06 (s, 1H), 7.20 (s, 1H), 7.28 (s, 2H), 8.62 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].O>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:27](=[O:29])[CH3:28])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
To ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methanamine (0.464 mmol, 150 mg) in dichloromethane (5 ml) at 0° C. were added triethylamine (0.466 mmol, 65 μl) and acetyl chloride (0.510 mmol, 36.4 μl). After stirring at room temperature for one hour water was added. The organic layer separated, dried (Na2SO4) and concentrated in vacuo to give N-(((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methyl)acetamide (96 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([S:12](Cl)(=[O:14])=[O:13])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a solution of (5-bromopyridin-2-yl)methanamine (250 mg, 1.34 mmol) in CH2Cl2 (3 mL) is added ethyl sulfonyl chloride (95 mg, 0.74 mmol) followed by triethylamine (0.3 mL, 2.0 mmol). The reaction is stirred at room temperature for 1.5 hours. The reaction is directly injected onto a 12 g silica gel column and chromatographed eluting from 100% hexanes to 50:50 ethylacetate:hexanes to afford the title compound (158 mg): m/z (Cl) M+H 279+281.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:20](=[O:27])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C(=O)c1ccccc1
Yield: 72 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a was reacted with benzoyl chloride (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 59.5 mg of 390 after RP-HPLC, purification (72% yield). MS (Q1) 485.3 (M)+
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH2:8]([NH:10][C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: O=C(Cl)C1CCC1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)C1CCC1
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
Cyclobutanecarbonyl chloride (4.0 mL, 35 mmol) was added slowly to an ice-cooled solution of ethylamine [20 mL, 2M solution in tetrahydrofuran (THF)] and triethylamine (4.85 mL, 35 mmol) in anhydrous methylene chloride (25 mL) at 0-5° C. under nitrogen. After stirring for 20 min the mixture was warmed to 20-25° C. and stirred for an additional 5-7 h. The reaction was quenched by pouring the mixture into 5-10% aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and the solvent was evaporated to give cyclobutanecarboxylic acid ethylamide as a pale yellow liquid, which solidified upon standing at RT.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.Br>>[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[OH:2])[CH2:8][CH2:9][NH:10]1
Reactant: COc1cccc2c1CNCC2
Agent: Br
Product: Oc1cccc2c1CNCC2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Combine 8-methoxy-tetrahydroisoquinoline (665.7 mg, 4.08 mmol) and 48% HBr at room temperature. Reflux the reaction for 3 hours and then cool to room temperature. Recrystallize the product from EtOH and diethyl ether to afford 754.2 mg, 3.28 mmol (80% yield) of the title compound as a tannish white solid: 1H NMR (500 MHz, DMSO-d6); 2.9 (2H, t, J=6.16, 5.86 Hz), 3.2-3.4 (2H, m), 4.0 (2H, s), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m), 8.8-9.1 (2H, br m), 9.9 (1H, s); MS m/z 148 (M−1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:24][CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[C:32]3[C:37]([CH:38]=[CH:39][C:28]=2[N:27]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[C:32]5[C:37]([CH:38]=[CH:39][C:28]=4[N:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(CCCl)nc2ccc3ccccc3c21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(CCN2CCN(c3ccc(Cl)cc3)CC2)nc2ccc3ccccc3c21
Yield: 89.7 %

Procedure:
6.5 g (0.024 mole) of 1-(4-chlorophenyl)-piperazine dihydrochloride and 8.43 cc (0.06 mole) of triethylamine are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole in 100 cc of ethanol. The reaction mixture is then heated at reflux temperature and maintained under an argon atmosphere for 23 hours. By evaporating the solvent, grinding the residue with water and filtering, a raw product is obtained, which is recrystallized from methylisopropylketone, yielding 4.36 g (90% yield) of pure compound. M.p. 213°-15° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(OCC)(=O)C.CCCCCC>CS(C)=O>[CH3:21][C:19]1[CH:20]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a suspension of NaH (3.22 g, 80.6 mmol) in DMSO (20 mL) was added diethyl malonate (12.9 g, 12.2 mL, 80.6 mmol) dropwise. The reaction mixture was heated at 60° C. for 30 min. A solution of 2-fluoro-4-methyl-1-nitro-benzene (5.00 g, 32.2 mmol) in DMSO (6 mL) was added and the reaction mixture heated at 60° C. for 2 h. The reaction was quenched with saturated ammonium chloride (20 mL), acidified (pH˜1) with 1N HCl and extracted into ether. The product was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (0-60% ethyl acetate/hexane) provided diethyl 2-(5-methyl-2-nitrophenyl)malonate as a yellow solid (9.50 g, 99% yield). LC/MS m/z 296.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 8.05 (d, J=8.4 Hz, 1H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 7.30 (d, J=1.2 Hz, 1H), 5.36 (s, 1H), 4.22-4.14 (q, 1H), 2.43 (s, 3H), 1.18 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].C(Cl)Cl.[CH3:20][O-:21].[Na+].CO>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:15])[C:12]([O:21][CH3:20])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[O-]
Reactant: Cc1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)c1c[nH]c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a solution of 5-methyl-1H-indole (1.00 g, 7.6 mmol) in diethyl ether (10 mL) at 4° C. was added a 2.0 M solution of oxalyl chloride in methylene chloride (4.0 mL, 8.0 mmol). The resulting solution was allowed to warm to room temperature and stirred for 1.5 h. The solution was cooled to −78° C. To this solution was added 25% (w/w) solution of sodium methoxide in methanol (3.65 mL, 16.0 mmol). The resulting solution was allowed to warm to room temperature. After one hour, the solution was filtered to give the title compound (1.16 g, 70%) as a light brown solid. 1H NMR (DMSO-d6) δ 8.31 (m, 1H), 7.95 (s, 1H), 7.42 (m, 1H), 7.11 (m, 1H), 3.88 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:23]([N:19]1[CH2:18][CH:17]=[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: CC1(C)CC(c2ccccc2C2=CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CC=C(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 45 %

Procedure:
To a solution of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine (130 mg, 0.44 mmol) produced in Example (102e) in tetrahydrofuran (2 mL) were added butyraldehyde (37.8 mg, 0.52 mmol), sodium triacetoxyborohydride (139 mg, 0.66 mmol) and acetic acid (52.5 mg, 0.87 mmol), followed by stirring for 13 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 70 mg of 1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].[CH:16]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]4[N:15]([CH2:14][CH2:13][O:12][CH3:11])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][CH:9]=[N:10][C:2]=5[N:1]=4)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: COCCN
Product: COCCn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2ncccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-aminonicotinic acid, 2-methoxyethylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:38][CH2:37][C:36]1=[O:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CC#N.CN(C)C=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[C:29]([N:35]2[CH2:38][CH2:37][C:36]2=[O:39])[CH:30]=1
Reactant: NCc1ccc(F)cc1N1CCC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCC1=O)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid, (0.142 g, 0.430 mmol) in CH3CN: dimethylformamide (30 mL: 5 mL) was added intermediate 120, 1-(2-(aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride, (0.100 g, 0.43 mmol), (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.207 g, 0.470 mmol) and diisopropylethylamine (280 μL, 1.72 mmol). The reaction mixture was stirred at 23° C. for 18 h. The solvents were removed in vacuo and 1N HCl (50 mL) added. This was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate as eluent to afford the title compound (0.157 g, 72% yield). 1H NMR (400 MHz, MeOD) δ ppm: 7.88 (1H, d, J=8.3 Hz), 7.76 (1H, d, J=8.0 Hz), 7.58–7.30 (4H, m), 7.10 (1H, dd, J=10.2, 2.5 Hz), 6.90 (1H, m), 5.20 (2H, s), 4.55 (2H, s), 4.04 (2H, m), 3.96 (2H, m), 3.78 (2H, t, J=4.2 Hz), 3.10 (2H, t, J=4.2 Hz), 1.58 (6H, s); LCMS (M+H)+ m/z 506.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1N=CN([C:13](N2C=NC=C2)=[O:14])C=1.CCN(CC)CC.ClC1C=C(C=CC=1OC)C[N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]([N:41]2[CH2:46][CH2:45][C:44](=[CH:47][C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=3[F:55])[CH2:43][CH2:42]2)=[O:40])[CH2:34][CH2:33]1>C(#N)C.O>[F:55][C:49]1[CH:50]=[CH:51][C:52]([F:54])=[CH:53][C:48]=1[CH:47]=[C:44]1[CH2:43][CH2:42][N:41]([C:39]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([C:13](=[O:14])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[O:40])[CH2:46][CH2:45]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccccn1)N1CCC(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
2-Aminopyridine (70.0 mg, 0.75 mmol) was dissolved in acetonitrile (4 mL), and then CDI (121 mg, 0.75 mmol) and Et3N (104 μL, 0.75 mmol) were added dropwise thereto at 0° C. After stirring at room temperature for 1 hour, the compound (250 mg, 0.67 mmol) obtained in Example 36 (1) and Et3N (312 μl, 2.25 mmol) were added to the mixture, followed by stirring at 60° C. overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50), thereby giving the title compound (80.0 mg, 24%) as a white solid.