Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:18][CH:19]2[CH:20]3[CH2:28][CH:24]4[CH2:23][C:22]([OH:29])([CH2:27][CH:26]2[CH2:25]4)[CH2:21]3)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 3-(6-bromo-pyridin-3-yloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 444 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12](Br)=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CN(C1C=CC=CN=1)[CH:26]=[O:27]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12]([CH:26]=[O:27])=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Br)c(Br)cc(OCc2ccccc2)c1=O
Reactant: CN(C=O)c1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1c(C=O)c(Br)cc(OCc2ccccc2)c1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a −78° C. solution of 3-(benzyloxy)-5,6-dibromo-1-methylpyridin-2(1H)-one (1.5 g, 4.02 mmol) in THF (20 mL) was added 2 M isopropylmagnesium chloride in THF (4.02 mL, 8.04 mmol) dropwise. This mixture was stirred at −78° C. for 15 minutes under nitrogen, and N-methyl-N-pyridin-2-ylformamide (1.4 mL, 12.06 mmol) was added. The mixture was allowed to slowly warm to room temperature overnight. Volatiles were removed under reduced pressure, and the resulting residue was partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate, and purified by silica gel chromatography to afford 5-(benzyloxy)-3-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (1.09 g, 3.38 mmol, 84% yield). ES-MS (M+H)+=323.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][N:25]3[CH3:28])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:27]=2)[C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
A solution of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid methyl ester (1.1 g, 2.6 mmole) in 14 mL of a 1:1 THF/methanol mixture was treated with a solution of 0.44 g of lithium hydroxide monohydrate in 5 mL of water and stirred at 40° C. for 6 hours. The mixture was diluted with 20 mL of water and the pH was adjusted to 2.0 with 2N HCl solution. The mixture was extracted with three 20 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by preparative tlc (SiO2, 25% ethyl acetate in hexanes) to yield 0.875 g of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid as a pale yellow oil. MS (EI): (M++1): 410.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:31](=[O:33])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: COc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1
Reaction time: 0.5 h
Yield: 144 %

Procedure:
To a solution of 2-methyl-N1-(4-{[3-(methyloxy)phenyl]oxy}phenyl)alaninamide (Intermediate 72, 1.33 g) and triethylamine (3.70 mL, 26.6 mmol) in dry dichloromethane (80 mL) at 0° C. was added dropwise a solution of triphosgene (600 mg, 2.022 mmol) in dry dichloromethane (20 mL) and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with a saturated solution of ammonium chloride (100 mL) and two phases were separated. Aqueous layer was extracted with dichloromethane (100 mL) and the two organic phases were collected, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP cartridge) using as eluent a gradient and cyclohexane/ethyl acetate from 80/20 to 40/60 to afford the title compound as a white solid (950 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].C(O)(=O)C.Cl>O>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc(N)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 51.3 %

Procedure:
A mixture of ethyl 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (2.68 g, 7.92 mmol), acetic acid (20 ml) and concentrated hydrochloric acid (20 ml) was heated under reflux for 3 hours. After cooling there action solution with ice, water (200 ml) was poured therein and the precipitated crystals were filtered out. After washing with excess water, a small amount of cold ethanol and excess diethyl ether in that order, the crude crystals obtained were purified by recrystallization in a mixed solvent of chloroform/methanol and then dried under a reduced pressure. 1.26 g (51%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11](C(O)=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C.Cl>O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a nitrogen inlet tube was charged 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (1 gm, 4 mmol), N,N′-carbonyldiimidazole (CDI) (0.97 g, 6 mmol) and dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 45° C. for about 1 hour then cooled to room temperature. Glycine methyl ester hydrochloride (1.15 g, 12 mmol) is added followed by the dropwise addition of diisopropylethylamine (3.2 mL, 19 mmol). The mixture was then stirred for 2.5 hours at room temperature after which water (70 mL) was added. The contents of the reaction flask was cooled to 0° C. to 5° C. and 1N HCl was added until the solution pH is approximately 2. The solution was extracted with dichloromethane (100 mL) and the organic layer was dried over MgSO4 for 16 hours. Silica gel (3 g) is added and the solution slurried for 2 hours after which the solids are removed by filtration. The filtrate is concentrated to dryness under reduced pressure and the resulting residue was slurried in methanol (10 mL) for two hours. The resulting solid was collected by filtration and washed with cold methanol (20 mL) then hexane and the resulting cake is dried to afford 0.85 g of the desired product as an off-white solid. The filtrate was treated to afford 0.026 g of the desired product as a second crop. The combined crops afford 0.88 g (68% yield) of the desired product. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).
Reaction SMILES: C(=O)C1C=CC=CC=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:9][C:10]5[CH:17]=[CH:16][C:13]([CH3:14])=[CH:12][CH:11]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Reactant: Cc1ccc(C=O)cc1
Solvent: O=Cc1ccccc1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with p-methylbenzaldehyde and using the acid (1) (R=ethyl) described in example 13 one obtains 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-p-methylbenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=ethyl-Z=p-methylphenyl).
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17]>C1(C)C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[N:17]=[C:16]([CH2:15][C:14]#[N:18])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Reactant: N#CCC#N
Solvent: Cc1ccccc1
Product: N#CCc1nc(C(=O)c2ccc(Cl)cc2)no1
Yield: 27.8 %

Procedure:
A mixture of 38 g of 4-chlorophenylglyoxylohydroxamyl chloride and 112 g of malononitrile in one liter of toluene was refluxed for 48 hours under N2. The cooled mixture was filtered and concentrated in vacuo. The residue was taken up in Et2O, washed with water (8×) and brine, and dried over MgSO4. Concentration gave an oil which was purified by high pressure liquid chromatography using 5% hexane/CH2Cl2 as an eluent to give 12 g (28%) of an oil which solidified on standing, m.p. 81°-84°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][F:27])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][F:27])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(OCF)c2)C1
Solvent: C1CCOC1
Product: FCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1

Procedure:
(R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluoromethoxy-phenyl)-piperidin-1-yl]-methanone (0.13 mmol, 50 mg) was treated with BH3 THF according to the above general procedure. Flash chromatography gave the title compound.
Reaction SMILES: [Br:1][C:2]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:26]O>S(=O)(=O)(O)O>[Br:1][C:2]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:26])=[O:17])[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: CO
Reactant: O=C(O)CCC(c1cccc(Cl)c1)C1(Br)C(=O)Nc2cc(Cl)ccc21
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(c1cccc(Cl)c1)C1(Br)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoic acid (Example 62, Step E) (5.38 g, 12.14 mmol) in MeOH (120 mL) at room temperature was added one drop of concentrated sulfuric acid. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+].[OH-].[NH4+:14].[Cl-].[NH4+].Cl[O-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:14][N:4]1[CH:5]=[CH:6][C:2]([Br:1])=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]ccc1Br
Reactant: [NH4+]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)c1c(Br)ccn1N
Yield: 32.1 %

Procedure:
Methyl 3-bromo-1H-pyrrole-2-carboxylate (1.74 g, 8.53 mmol) was treated with an aqueous solution of sodium hydroxide (32%, 25 mL, 172.3 mmol), ammonium hydroxide solution (8M, 8 mL, 63.5 mmol), ammonium chloride (2.74 g, 51.2 mmol), aliquat 336 (312 μl, 0.68 mmol) and a 10% aqueous solution of sodium hypochlorite (10%, 56 mL, 75.4 mmol) according to the method of Preparation 4c to give 600 mg (23% yield) of the title product. Purity 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:6]([C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: COc1ccc(OC)cc1
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
3-Methoxyphthalic anhydride (17.8 g, 0.1 mole) was suspended in 100 ml. dry methylene chloride (previously distilled over anhydrous potassium carbonate). To the suspension was added anhydrous aluminum chloride (30.5 g, 0.23 mole) in one portion. The suspension quickly became bright yellow and was stirred at room temperature for 2 hours. A solution of p-dimethoxybenzene (27.6 g, 0.2 mole) in methylene chloride (100 ml) was added slowly to the vigorously stirred solution. The reaction mixture was stirred overnight at 25° and poured onto ice (300 g) and concentrated hydrochloric acid (50 ml). The slurry was stirred for 30 minutes and extracted with chloroform (4 × 150 ml). A white precipitate suspended in the aqueous layer is collected by filtration. The organic extract was washed once with water (200 ml) and washed with saturated sodium bicarbonate (4 × 150 ml). The aqueous bicarbonate extract was washed once with chloroform (150 ml) and acidified with concentrated hydrochloric acid, the mixture cooled on an ice bath and filtered. The residue was washed well with water and dried under reduced pressure and combined with the white precipitate to yield 2-(2',5'-dimethoxybenzoyl)-6-methoxybenzoic acid (I) as a pale yellow solid (13 g, 41% yield), m.p. 180°-182° C. (from ethanol); IR (KBr) 2.95, 5.72μ; NMR (CDCl3) δ, 7.60-6.80 (m, 6H), 6.10 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([NH:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CC(C)CNc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and and Isobutylamine (49% yield, off white foam, MS (m/e): 484.5 (M+H, 100%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14]OC1C=CC=C(C)C=1S([O-])(=O)=O>O>[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: FC(F)(F)C(F)(F)CCCN1CCNCC1
Yield: 70.7 %

Procedure:
Piperazine (777 mg, 9.0 mmol) was added to ethanol solution (10 ml) of 4,4,5,5,5-pentafluoropentyloxytoluenesulfonate (600 mg, 1.81 mmol) and then heated under refluxing for 40 hours. After adding water, the reaction solution was extracted with ethyl acetate. The solvent was distilled off under reduced pressure from the extract to obtain 315 mg (yield: 100%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:14][CH2:15][O:16][CH3:17])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-])=O)[CH3:2]>[Pd].C(O)C>[NH2:8][C:7]1[C:6]([C:11]([NH2:13])=[O:12])=[N:5][N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Agent: [Pd]
Solvent: CCO
Product: CCc1c(N)c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
10% Palladium on carbon (100 mg) was added to a stirred slurry of 3-ethyl-2-(2-methoxyethyl)-4-nitro-pyrazole-5-carboxamide (5 g, 20.77 mmol) in ethanol (100 mL) and the mixture stirred in a pressure vessel under a hydrogen atmosphere (344.7 kPa (50 psi)) at room temperature for 6 h. The mixture was filtered and concentrated. Recrystallisation from hot ethyl acetate gave the product as white crystals (3.5 g). The mother liquor was concentrated to give a further 1.5 g of product as a grey powder.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOCc1ccc2ccccc2c1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc3ccccc3c2)CC1
Yield: 95.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.00 g) as starting compound and 5-(2-naphthylmethoxy)-pentyl chloride (1.88 g) were reacted and treated in the same manner as in Example 168 to give 1.45 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethoxy)pentyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(B(O)O)c1F
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3F)cccc2c1N
Yield: 57.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-3-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (99 mg, 57% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.93 (m, 1H), 7.83-7.69 (m, 2H), 7.22-7.14 (m, 1H), 7.10-7.00 (m, 2H), 3.93 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.74 min.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@:11]1([F:27])[CH2:25]I)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:27])[CH2:25][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CI)[C@H]1OC(=O)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-(iodomethyl)-4-methyl-tetrahydrofuran-3-yl benzoate (0.56 g, 1.15 mmol), sodium benzoate (0.825 g, 5.73 mmol) and 18-crown-6 (0.03 g, 0.115 mmol) were suspended in DMSO (20 mL), the solution was heated to 100° C. and stirred under nitrogen atmosphere for 18 h, then cooled to r.t., water (30 mL) was added into it, the mixture was extracted by EA (30 mL×3), the organic layer was washed with H2O, brine and H2O, removed solvent by reduced pressure, the residue was purified by silica gel column chromatography (PE:EA=1:2) to afford the title compound as a colorless oil (0.34 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][C:24]([OH:26])=O)[CH:6]=[C:7]([C:9]([CH3:17])([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=1.CC(N)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:17])([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:5]2[C:4]=1[C:24](=[O:26])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]12
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(N2CCCC2CC(=O)O)c1
Agent: CC(N)c1ccccc1
Product: CCCCCCC(C)(C)c1cc(OC)c2c(c1)N1CCCC1CC2=O

Procedure:
The dl-2-[1-[3-methoxy-5-(1,1-dimethylheptyl)-phenyl]pyrrolidin-2-yl]acetic acid provided in Example 54, Part A is resolved into dextrorotatory and levorotatory isomers via the alpha-methylbenzylamine salt by the methods of Examples 18 and 19. The resolved isomeric acids are then cyclized to provide the d- and l-isomers of 6-methoxy-8-(1,1-dimethylheptyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]quinolin-5-one. Cleavage of the methyl ether with hydrobromic acid/acetic acid by the procedure of Example 21 affords the title compounds.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:16])=[O:15]
Reactant: CC(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To an ice cooled solution of 37 g (46.1 ml, 0.5 mol) of isobutyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10°. The reaction mixture is then stirred for 1.5 hours at 10°. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCl, saturated KHCO3, saturated NaCl and dried (MgSO4). Solvent is removed in vacuo to yield 68 g (90%) of the isobutyl methanesulfonate as an oil.