Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N:3](CCCC(NC1C=C(/C=C/C2C=CC=CC=2Cl)N=C2C=C(Cl)C=CC=12)C)CC.Cl[C:33]1[C:34]2[CH2:42][N:41](C3C=CC=CN=3)[CH2:40][CH2:39][C:35]=2[N:36]=[CH:37][N:38]=1>>[N:36]1[C:35]2[CH:39]=[CH:40][N:41]=[CH:42][C:34]=2[C:33]([NH2:3])=[N:38][CH:37]=1
Reactant: Clc1ncnc2c1CN(c1ccccn1)CC2
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Product: Nc1ncnc2ccncc12

Procedure:
Appropriate 6-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[4,3-d]pyrimidin-4-amine derivatives are prepared starting from 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinoline derivate is reacted with appropriate alkylating agent to give the N-substituted nitroquinoline, which is reduced using standard procedures known in the art to yield 7-aminoquinoline derivative. The resulting aminoquinoline derivated is then condensed with the appropriate 4-chloro-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine to give the desired 6-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[4,3-d]pyrimidin-4-amine derivative. As a representative example, preparation of the N-morpholionethyl derivative is depicted in Scheme 6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B using 1-(4-tert-butylphenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 447.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]1([S:18]([NH:21][C:22](=[NH:25])SC)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:12]1([S:18]([NH:21][C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])=[NH:25])(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC(=N)NS(=O)(=O)c1ccccc1
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=N)NS(=O)(=O)c1ccccc1
Yield: 20.4 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.93g.) and N-benzenesulphonyl-S-methylisothiourea (8.0g.) in acetonitrile (100 ml.) was heated under reflux for 24 hours. Concentration, followed by chromatographic purification on a column of silica gel with benzene - methanol (10:1) and recrystallisation from aqueous ethanol and then acetonitrile afforded N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.5 g.) m.p. 149°-150°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 150 °C
Yield: 100.3 %

Procedure:
A solution of 4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][N:49]=1)[C:43]([NH:45][CH3:46])=[O:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][N:49]=2)[C:43]([NH:45][CH3:46])=[O:44])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1ccnc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 56.2 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (1.30 g), 2-bromo-N-methylisonicotinamide (310 mg) and tetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound (480 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:9]1=[O:32])[CH2:5][CH2:6][CH3:7].[Li+].[OH-]>O1CCOCC1.O>[O:32]=[C:9]1[N:8]([C@H:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:33])=[O:2])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=2[CH3:29])[N:22]([CH3:31])[CH:21]=1
Reactant: CCC[C@H](C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@H](C(=O)O)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (50 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and water (2 mL) is added LiOH (5.4 mg, 0.22 mmol) at room temperature. The solution is stirred at 60° C. for 4 hours. The solution is concentrated and water is added to the residue. The solution is acidified by 12N HCl in an ice-bath. The precipitated white solid is collected by filtration and is dried under vacuum to afford the title product. : LCMS (ESMS): m/z 434.89 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH2:14][N:15]=[N+]=[N-].C(O)(=O)C>C(O)C.[Pd]>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]2[C:5]=1[CH2:14][NH:15][C:3]2=[O:2]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(F)cc2c1CNC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is added in 46 ml of ethanol and 3.4 ml of glacial acetic acid and mixed with 256.6 mg of Pd/C. After stirring overnight at room temperature under hydrogen atmosphere, the catalyst is suctioned off via a glass-fiber filter, and the filtrate is evaporated to the dry state. The residue, 1.18 mg (97.5%) of the desired compound, is further incorporated in crude form.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH:20]([CH3:22])[CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH:20]([CH3:21])[CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1C(C)C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C(C)C
Yield: 80.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111c) (0.31 g, 0.91 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.39 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.24 g of the title compound as a colorless solid (77%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:5]1O[CH:6]1[CH3:7].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1CCCCC1>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:7]=[CH:6][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1CO1
Agent: C=CC=C
Agent: O=C1CCCCCO1
Solvent: C1CCCCC1
Product: C=Cc1ccccc1
Reaction time: 0.42 h

Procedure:
Cyclohexane was charged to a 26-oz. beverage bottle equipped with a perforated Crown cap over a self-sealing rubber gasket, and the bottle and cyclohexane were then purged with nitrogen. Styrene and tetrahydrofuran were added and then the n-butyllithium was added. The temperature was adjusted to 70° C. and the bottle and its contents were tumbled in a constant temperature bath for 20 to 30 minutes, after which time the styrene polymerization was essentially complete. 1,3-Butadiene was then charged to the bottle and the polymerization was continued for one hour with continued agitation at 70° C. At the end of this time, polymerization of the 1,3-butadiene was essentially complete. Propylene oxide was then added to the polymerization reaction mixture and the mixture was agitated for 10 minutes while the temperature was reduced from 70° C. to 30° C. Epsilon-caprolactone was added and polymerization was allowed to proceed at 30° C. for 5 minutes with continued agitation. Five minutes after the epsilon-caprolactone had been charged, the polymerization reaction was terminated by the addition of 10 ml of 0.1 M hydrochloric acid. After termination was complete, one part of 2,6-di-t-butyl-4-methylphenol per 100 parts of total monomers was added as a 10 weight percent solution in 50:50 toluene:isopropanol, the contents of the bottle were emptied into a beaker, and the styrene-butadiene-epsilon-caprolactone block terpolymer was isolated by steam stripping. The recovered polymer was dried at 60° C. for about 15 hours under reduced pressure. Properties of the recovered polymers are shown in Table II.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=[O:18])[CH2:16][CH3:17].Cl>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:15]([OH:18])[CH2:16][CH3:17]
Reactant: COc1cccc(F)c1
Reactant: CCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1c(F)cccc1OC
Reaction time: 1 h
Yield: 85.6 %

Procedure:
66.7 ml (106.8 mmol) of a 1.6N butyllithium solution in hexane were added at -78° to a solution of 12 g (95.14 mmol) of 3-fluoroanisole in 240 ml of anhydrous tetrahydrofuran and the mixture was stirred for one hour. Subsequently, 21 ml (288 mmol) of propionaldehyde were added dropwise thereto at -78°, the mixture was stirred for one hour and the solution was left to come to room temperature. The mixture was poured into 240 ml of 1 N HCl and extracted twice with 250 ml of diethyl ether each time After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). There were obtained 15 g (86%) of 1-(2-fluoro-6-methoxy-phenyl)-propan-1-ol as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]2=[O:27])=[C:17]([F:30])[CH:16]=1.[CH3:31][S-:32].[Na+]>CN(C=O)C.ClCCl>[CH:12]1([CH2:11][N:7]2[C:6]3[CH:5]=[CH:4][C:3]([C:15]4[CH:29]=[CH:28][C:18]([CH2:19][N:20]5[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]5=[O:27])=[C:17]([F:30])[CH:16]=4)=[C:2]([S:32][CH3:31])[C:10]=3[N:9]=[N:8]2)[CH2:14][CH2:13]1
Reactant: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Br)cc2F)C1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1c(-c2ccc(CN3CC(=O)N(C)C3=O)c(F)c2)ccc2c1nnn2CC1CC1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-{4-[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]-2-fluorobenzyl}-3-methylimidazolidine-2,4-dione (10 mg, 0.021 mmol) in DMF (0.18 mL) was added sodium thiomethoxide (5.6 mg, 0.080 mmol, 4 equiv.). The mixture was stirred at 120° C. for 3.5 hours, cooled to ambient temperature and diluted with dichloromethane, which was washed with water and brine. The organic extract was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound: 1H NMR (400 MHz, CDCl3) 7.39-7.45 (m, 2H), 7.34 (d, 1H, J=8.4 Hz), 7.18-7.24 (m, 2H), 4.70 (s, 2H), 4.53 (d, 2H, J=7.1 Hz), 3.90 (s, 2H), 3.06 (s, 3H), 2.85 (s, 3H), 1.40-1.46 (m, 1H), 0.67-0.71 (m, 2H), 0.50-0.54 (m, 2H) ppm. LRMS m/z (M+H) 440.2 found, 440.1 required.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[C:50]([CH3:52])[N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[N:48]5[CH:49]=[C:50]([CH3:52])[N:51]=[C:47]5[CH:46]=[CH:45][CH:44]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: Cc1cn2c(Br)cccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1cn2c(-c3nc(N4CCOCC4)c4sc(CN5CCN(C(C)(C)C(N)=O)CC5)cc4n3)cccc2n1
Temperature: 150 °C
Yield: 49 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-yl methyl)piperazin-1-yl]isobutyramide (150 mg, 0.21 mmol), 5-bromo-2-methyl-imidazo[1,2-a]pyridine (55 mg, 0.26 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (8 mg, 0.04 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 693 as a white solid (55 mg, 47%). LCMS (Method E): RT 4.99 min; [M+H]+ 535. 1H NMR (400 MHz, CHCl3-d): δ 8.98 (s, 1 H); 7.92-7.89 (m, 1 H); 7.68 (d, J=8.8 Hz, 1 H); 7.39 (s, 1 H); 7.27-7.23 (m, 1 H); 7.09 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.09-4.04 (m, 4 H); 3.94-3.87 (m, 4 H); 3.87 (s, 2 H); 2.62 (m, 8 H); 2.54 (s, 3 H); 1.29-1.23 (m, 6 H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CCO>[CH:18]1([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (158 mg, 0.658 mmol) and cyclohexylmethylamine (0.100 mL, 0.790 mmol) were stirred in 3 mL of EtOH containing triethylamine (0.140 mL, 0.987 mmol) at 75° C. for 24 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 217 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.98-1.09 (m, 2H), 1.17-1.28 (m, 3H), 1.31 (s, 9H), 1.65-1.73 (m, 2H), 1.74-1.80 (m, 2H), 1.82-1.84 (m, 1H), 1.85-1.88 (m, 1H), 3.15 (dd, J=6.64, 5.47 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.23 (br.s, 1H), 7.82 (dd, J=9.18, 2.54 Hz, 1H), 8.10 (d, J=2.54 Hz, 1H), 8.11-8.13 (m, 1H).
Reaction SMILES: [N:1]#CBr.[CH2:4]([N:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:7]C)[CH3:5]>CCOCC>[CH2:4]([N:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:7]#[N:1])[CH3:5]
Reactant: CCN(CC)c1cccc2ccccc12
Reactant: N#CBr
Solvent: CCOCC
Product: CCN(C#N)c1cccc2ccccc12
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A mixture of cyanogen bromide (3.32 g, 31.3 mmol) and N,N-diethyl-1-naphthylamine (5 g, 25 mmol) was heated at 100° C. for 4 hours under nitrogen. It was then allowed to cool to room temperature, ether was added, and the insoluble N,N-diethyl-1-naphthylamine hydrobromide was filtered off. The ether layer was washed with 15% aqueous HCl solution (2×50 ml), water (2×50 ml), and dried over MgSO4. It was filtered, concentrated and the residue was flash chromatographed on silica gel to give N-ethyl-N-(1-naphthyl)-cyanamide (2.34 g, 48%) as a yellow thick liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17].[C:19](Cl)(=O)[CH3:20].C(Cl)(=O)CCC>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH2:17][CH2:19][CH3:20]
Reactant: COc1ccc2ccccc2c1CONC(C)=O
Reactant: CC(=O)Cl
Agent: CCCC(=O)Cl
Product: CCCC(=O)NOCc1c(OC)ccc2ccccc12

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 7, but replacing, in the acylation step, acetic acid chloride with butyric acid chloride, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)nc1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Br)nc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9 g (39 mmol) of 3-(6-bromo-pyridin-3-yl)-propionic acid, 22.5 g (195 mmol) of NEM and 12.83 g (39 mmol) of TOTU were dissolved in 30 ml of DMF and stirred at room temperature for 15 min. 3.33 g (39 mmol) of piperidine were, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium hydrogencarbonate solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 10.2 g.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:30][N:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32](Cl)=[O:33]>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:32](=[O:33])[N:31]([CH3:30])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N(C)c3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
60 mg (0.14 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 22 mg (0.14 mmol, 1.0 eq.) of methyl(phenyl)carbamoyl chloride were reacted according to General Method 3. Yield: 37 mg (69% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13]2[C:18]([C:19]=1[O:20]C(=O)C(C)(C)C)=[CH:17][CH:16]=[CH:15][N:14]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]([F:38])[F:37]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[N:12]([CH2:35][CH:36]([F:38])[F:37])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=2
Reactant: FC(F)CBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2c(F)ccc(F)c2Cl)c(O)c2cccnc2n1CC(F)F
Temperature: 120 °C

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-chloro-3,6-difluoro-phenyl)-2-oxo-1,2-dihydro-[1,8]naphthyridin-4-yl ester (Example 1.5) (0.2 g), potassium carbonate (0.211 g) and 1-bromo-2,2-difluoro-ethane (0.15 g) in N,N-dimethylformamide (3 ml) was heated to 120° C. in a microwave for 15 minutes. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. D21 of Table D as a colourless oil (24 mg).