Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Reactant: CCCBr
Product: CCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 38 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-9a) and 1-bromopropane. Yield: 38%. MS M+H calculated 409.19; found 409.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][P:13]([CH2:16][NH2:17])(=[O:15])[OH:14]>N1C=CC=CC=1>[C:1]([NH:11][CH2:12][P:13]([CH2:16][NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCP(=O)(O)CN
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCP(=O)(O)CNC(=O)c1ccccc1)c1ccccc1
Yield: 78.5 %

Procedure:
Benzoyl chloride (1.8 ml; 15.49 mmol) is added slowly with stirring at 0° C. to a solution of bis(aminomethyl)phosphinic acid hydrochloride (1.20 g; 7.48 mmol) in pyridine (8 ml). The reaction mixture is concentrated under reduced pressure. The residue is taken up in 5% hydrochloric acid (60 ml). The aqueous phase is extracted with ethyl acetate (3×60 ml). The combined organic phases are dried (sodium sulfate) and concentrated under reduced pressure. The phosphinic acid 2 (1.95 g) is obtained as a crude product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>[OH-].[Li+]>[NH2:2][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N[C@@H](CCCCN=Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
L-lysine, monohydrochloride (130 g.) is dissolved in 2N lithium hydroxide (360 ml.) solution in a 2-liter, 3-necked, round bottom flask, equipped with an overhead stirrer, addition funnel and thermometer. Benzaldehyde (76.4 ml.) is added dropwise to this vigorously stirring solution at a temperature of about 5°. The reaction mixture turns cloudy at first and then becomes a thick mass of white precipitate. The rest of the benzaldehyde is added along with toluene (300 ml.) to improve the difficult stirring. The reaction mixture is stirred at about 5° for three hours. The mixture is filtered in a coarse sintered glass funnel. The solid is washed with ice cold water (50 ml.), ice cold ethanol (2×115 ml.), and then extensively with anhydrous ether. The product is dried in vacuo over 16 hours to give (S)-2-amino-6-[(benzylidene)amino]hexanoic acid as a white powder; m.p. 196°-200°.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][C:11]#[CH:12])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:20]>C(O)(=O)C.O>[C:11]([CH2:10][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:8]=[O:9])(=[O:20])[CH3:12]
Reactant: C#CCC(C=O)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC(C=O)(c1ccccc1)c1ccccc1
Yield: 103.9 %

Procedure:
A solution of 2,2-diphenyl-2-(2-propynyl)acetaldehyde (83.0 g) in acetic acid (83 ml) was added dropwise to a solution of mercuric acetate (3.1 g) and sulfuric acid (18.3 g) in a mixture of acetic acid (300 ml) and water (75 ml) over a period of 2 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and aqueous solution of sodium bicarbonate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[CH:16]=2)=[O:11])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=[C:14]2[C:32]#[N:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A mixture of 3-{[7-(2-chloro-4-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.08) in (½) TFA/CH2Cl2 (3 mL) was stirred at room temperature for 4 h. Reaction mixture was concentrated. The residue was dissolved in water (30 mL) and the pH was adjusted to 10 by 1 N NaOH. It was then acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 24 mg (0.053 mmol) in 66% yield. LC-MS ESI−: 456.05 (M−1)−.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:23]1([CH2:22][N:16]2[CH2:17][CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)/C=C\c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 1.98 g (12.2 mmol) of methyl (Z)-cinnamate and 5.80 g (24.4 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine in 30 mL of CH2Cl2 at 0° C. was treated with 20 drops of trifluoroacetic acid and stirred cold for 1 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 100 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 20:1 v/v CH2Cl2/ether as the eluant afforded 2.61 g (72%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.83 (t, J=8.7, 1H), 3.09-3.19 (m, 6H), 3.16 (s, 3H), 3.46-3.51 (m, 1H), 3.73-3.79 (m, 3H), 7.19-7.42 (1OH). Mass Spectrum (NH3 -CI): m/z 296 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]=2[CH:29]=[CH:28]1>C(Cl)Cl>[NH:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]([C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[O:12])[C:30]=2[CH:29]=[CH:28]1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: c1cc2c([nH]1)CCCCN2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]ccc32)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a mixture of 1-acetyl-piperidine-4-carboxylic acid (822 mg, 4.8 mmol, 1.2 eq.), EDC (920 mg, 1.2 eq.), HOBt (648 mg, 1.2 eq.) in DCM (15 mL) was added TEA (1.3 mL, 2 eq.) and 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (550 mg, 4 mmol). The mixture was stirred at rt for 2 days. The reaction was diluted with DCM, washed with water, sat. NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.1 g of 1-[4-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-piperidin-1-yl]-ethanone as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11][CH2:10]3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[OH:36]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Clc1cncc(N[C@@H]2CCCc3ccccc32)n1
Product: COc1cc(-c2cncc(N[C@@H]3CCCc4ccccc43)n2)ccc1O
Yield: 46.7 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine (139 mg, 0.536 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (147 mg, 0.59 mmol) furnished the product (87 mg, 47%).
Reaction SMILES: [CH3:1][N:2]([O:15][CH3:16])[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(#N)C>Cl>[CH3:16][O:15][N:2]([CH3:1])[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:5]=1
Reactant: NC1CCCC1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CC#N
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(NC2CCCC2)c1
Yield: 92.1 %

Procedure:
Combine N-[methyl]N-[methoxy]3-fluoro-4-nitrobenzamide (2.3 g, 10 mmol), cyclopentylamine (12.3 mL, 100 mmol) and acetonitrile (50 mL) and stir at room temperature for 6 hours. Dilute with 1N HCl and extract with ethyl acetate. Wash the organic layer sequentially with water and saturated aqueous sodium chloride, then dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound as an orange solid (2.7 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N-:14]1.[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[O:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 91.5 %

Procedure:
4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) and potassium 1,3-dioxoisoindolin-2-ide (2.0 g, 10.9 mmol) were placed in microwave vial (0.5-2 ml) and NMP (12.0 ml) was added. The reaction mixture was heated at 200° C. using microwave (Biotage, Initiator) for 1 min. After cooling to rt, the reaction mixture was added dropwise to stirring water which resulted in formation of precipitate. The solid was collected, washed with water and dried under stream of nitrogen to afford the title compound (2.89 g, yield: 92%). 1H-NMR (400 MHz, CDCl3) δ 7.26 (s, 2H) 7.43 (d, 2H) 7.81-7.87 (m, 3H) 7.91 (dd, 2H) 7.95-8.05 (m, 3H) 8.33 (d, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1.[CH:19]([Mg]Br)=[CH2:20].[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH:19]=[CH2:20])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1
Reactant: C=C[Mg]Br
Reactant: C=C(c1ccccc1)c1nc(Cl)nc(Cl)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)c1c(Cl)nc(Cl)nc1C(=C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4-dichloro-6-(1-phenylvinyl)pyrimidine-5-carbaldehyde (200 mg) in THF (3.6 mL) at −78 C. was added vinylmagnesium bromide (0.79 mL, 1M solution in THF) dropwise, and the reaction mixture was stirred at −78° C. for 20 min. Saturated NH4Cl was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate (×3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give the title compound (156 mg) as a colorless oil. The crude product was used directly for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNC(=O)Nc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (919 mg, 2.76 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (300 μL, 2.76 mmol) and Et3N (0.77 mL, 5.51 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as a white powder. m.p. 180-182° C.;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5](=[O:19])[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][N:22]([CH3:21])[C:16]([C:6]1[C:5](=[O:19])[C:4]([O:3][CH3:2])=[CH:9][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: CNOC
Reactant: COc1cn(-c2cccnc2)nc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (1.0 g, 3.5 mmol), N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), TEA (1.5 ml, 11 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.2 g, 3.9 mmol) in DMF (15 ml) was stirred at room temperature overnight. The mixture was diluted with AcOEt. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed on basic silica gel (0/100-20/80 MeOH/AeOEt) to give the title compound (0.81 g, 79% yield) as white crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.48 (1H, dd, J=8.3, 4.5 Hz), 7.97 (1H, s), 8.00-8.05 (1H, m), 8.67 (1H, dd, J=4.5, 1.3 Hz), 8.91 (1H, d, J=2.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:21][CH:22]([OH:24])[CH3:23]>>[OH:24][C:22]([CH:9]1[CH2:8][CH2:7][CH:6]([CH2:2][NH:3][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)[CH2:5][CH2:10]1)([CH3:23])[CH3:21]
Reactant: Cc1noc2ccc(Oc3ncccc3C(=O)O)cc12
Reactant: CC(C)O
Product: Cc1noc2ccc(Oc3ncccc3C(=O)NCC3CCC(C(C)(C)O)CC3)cc12

Procedure:
Prepared from 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid and trans-2-Aminomethyl-cyclohexyl)-propan-2-ol. mp 135-7° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([O:24]CC)=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:21][CH2:20]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1.[OH-].[Na+].C(O)C>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:20][CH2:21]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCN(C)CC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(F)c(N2CCN(C)CC2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 60.2 %

Procedure:
To ethyl 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (25 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. The aqueous layer is made acidic with acetic acid and then made weak alkaline with an aqueous sodium hydrogen carbonate. The resultant is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added diethyl ether. The precipitated crystals are filtered and recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (14 mg), as yellow crystals, m.p. 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.O>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([S:30]([N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1n(S(=O)(=O)c2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.17 mmol) of the compound from Example 5A were dissolved in 10 ml of THF and, at 0° C., 94 mg (2.34 mmol) of sodium hydride (60% strength dispersion in mineral oil) were added. After 20 min, 299 mg (1.17 mmol) of 3-bromobenzenesulfonyl chloride were added, and the mixture was stirred at 0° C. for 1 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1, then 1:1). This gave 181 mg (27% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:13])[CH:5]=[CH:4][C:3]1=2.[C:15](Cl)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl.Cl>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]2[CH:7]=[C:6]([NH:13][C:15](=[O:17])[CH3:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)Cl
Reactant: CC1=CCC(C)(C)c2ccc(N)cc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(C)=CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
General Procedure T A solution of 5,5,8-trimethyl-5,6-dihydro-naphthalen-2-ylamine (Compound 159, 1.47g, 7.9 mmol) in 10 mL of dichloromethane was stirred at 0° C., and acetyl chloride (1.0 mL, 1.39 g, 18 mmol) and then pyridine (1.0 mL, 1.0 g, 12 mmol) were added, and the reaction stirred at 0° C. for 1 h. The reaction mixture was then diluted with 10% HCl and extracted two times with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvents were removed in vacuo. The residual crude product was purified by silica gel chromatography (30% ethyl acetate in hexanes) to give the title compound as a white solid, which was immediately used in the next step.
Reaction SMILES: [CH2:1]1[CH2:38][O:37][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[O:2]1.[CH2:39]1[CH2:49]CN2C(=NCCC2)C[CH2:40]1.C(I)(C)C>C(#N)C>[CH2:38]1[CH2:1][O:2][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:39]([CH3:49])[CH3:40])=[O:28])[O:37]1
Reactant: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)O)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CC(C)I
Product: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
The compound (42) (1.68 g) was esterified in the conventional procedure with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 0.78 ml) and isopropyl iodide (0.35 ml) in acetonitrile (15 ml). The residue was subjected to silicagel column chromatography to give the titled compound (43). Yield: 0.908 g (88%)
Reaction SMILES: [F-].[Cs+].CN1CCCC1=O.Cl.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:36][CH:35]=1>O>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[O:41])=[CH:38][N:39]=4)[CH2:29][CH2:30]3)=[O:23])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NC1CCN(c2ccc(C(=O)N3CCOCC3)cn2)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 96 °C
Yield: 15.3 %

Procedure:
To a vial containing CsF (684 mg, 4.50 mmol) and 1-methyl-2-pyrrolidinone (NMP, 2 mL) was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide hydrochloride (247 mg) and (6-chloropyridin-3-yl)(morpholino)methanone (170 mg, 0.750 mmol). The reaction mixture was heated to 96° C. for 24 hrs. After allowing the reaction to cool to room temperature the reaction was diluted with H2O (3 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 5% MeOH: DCM) gave 6-(3-fluorophenyl)-N-{1-[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]piperidin-4-yl}nicotinamide (55 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, s), 8.53 (1H, d, J=7.7 Hz), 8.30 (1H, dd, J=8.4, 1.6 Hz), 8.23 (2 H, d, J=11.9 Hz), 8.15 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.9 Hz), 7.98 (1H, br. s.), 7.53-7.61 (1H, m), 7.26-7.37 (1H, m), 5.02 (1H, br. s.), 4.45 (1H, br. s.), 4.24 (1H, br. s.), 3.86 (1H, br. s.) 3.73 (1H, br. s.), 3.30 (3H, br. s.), 1.87-2.05 (5H, m), 1.61 (2H, br. s.), 0.75 (3H, t, J=7.3 Hz)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1>CCOC(C)=O.CO.[Pd]>[N:3]1[CH:2]=[CH:7][CH:6]=[N:5][C:4]=1[CH2:9][C:10]#[N:11]
Reactant: N#CCc1nc(Cl)cc(Cl)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1ncccn1
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a solution of 2-(4,6-dichloropyrimidin-2-yl)acetonitrile (4.10 g, 21.8 mmol) and TEA (6.07 ml, 43.6 mmol) in EtOAc/MeOH (1/1, 80 mL) was added 10% Pd/C (800 mg) and the solution was vigorously stirred for 2.5 h under H2 atmosphere (1 atm). The reaction was filtered through celite and washed the celite with MeOH. The combined filtrates were concentrated under reduced pressure and purified by flash chromatography (SiO2, 40-6% EtOAc/flexanes, gradient elution) to provide 2-(pyrimidin-2-yl)acetonitrile (1.56 g, 13.1 mmol, 60%) as a pale red liquid.