Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]=[C:3]1[CH:10]2[CH2:11][C:6]3([O:13][C:14](=[O:22])[C:15]([F:21])([F:20])[S:16]([OH:19])(=[O:18])=[O:17])[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[Cl-].[C:24]1([S+:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C(#N)C>[O:2]=[C:3]1[CH:10]2[CH2:11][C:6]3([O:13][C:14]([C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:17])=[O:18])=[O:22])[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:37]1([S+:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)O)(C3)C2
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C2

Procedure:
To 5.4 parts (35.6% purity) of the sodium salt of difluorosulfoacetic acid-4-oxo-1-adamantyl ester, a mixture of 16 parts of acetonitrile and 16 parts of ion-exchanged water was added. To the mixture, a solution of 1.7 parts of triphenylsulfonium chloride, 5 parts of acetonitrile, and 5 parts of ion-exchanged water was added. The resultant mixture was stirred for 15 hours, then concentrated, and extracted with 142 parts of chloroform. The organic layer was washed with ion-exchanged water, and the resulting organic layer was concentrated. The concentrate was washed with 24 parts of tert-butyl methyl ether, giving 1.7 parts of triphenylsulfonium 4-oxo-1-adamantyloxycarbonyldifluromethanesulfonate (B1) in the form of a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[CH3:10][C:11]([S:14]([NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:18]#[CH:19])=[O:15])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(O)CCC.O>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:19]=[C:18]([C@H:17]([NH:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[N:3]=[N:2]1)[CH3:9]
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)Cn1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stir bar were added ethyl azidoacetate (0.193 g, 1.495 mmol), 2-methyl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]prop-2-yn-1-yl}propane-2-sulfinamide (0.500 g, 1.495 mmol), freshly made 1.0 N sodium ascorbate (0.150 ml, 0.150 mmol), and 1.0 N Cu2SO4 (0.150 ml, 0.150 mmol) into 6.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 50-80% ethyl acetate in hexanes, gradient) gave the title compound as a light yellow solid (0.365 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.291 (d, J=2.93 Hz, 1H), 7.634 (s, 1H), 7.452 (d, J=8.79 Hz, 1H), 7.247 (ABq, J=3.03 Hz, 1H), 5.879 (d, J=5.50 Hz, 1H), 5.349 (d, J=5.31 Hz, 1H), 5.125 (ABq, J=7.49 Hz, 2H), 4.381 (q, J=7.87 Hz, 2H), 4.255 (q, J=7.14 Hz, 2H), 1.290 (t, J=7.14 Hz, 3H), 1.271 (s, 9H). ES-MS [M+1]+: 464.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][OH:22])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][O:24][C:25]([CH3:27])=[CH2:26].C(=O)([O-])O.[Na+]>C1COCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:21][O:22][C:25]([O:24][CH3:23])([CH3:27])[CH3:26]
Reactant: CCc1ccc(Cc2cccc3cc(CO)c(Br)cc23)cc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cccc3cc(COC(C)(C)OC)c(Br)cc23)cc1
Yield: 100 %

Procedure:
Under a nitrogen stream, to a solution of [3-bromo-5-[(4-ethylphenyl)methyl]-naphthalen-2-yl]-methanol (326.2 mg, 0.92 mmol) and pyridinium p-toluenesulfonate (4.6 mg, 0.02 mmol) in THF (3.0 mL) was added 2-methoxypropene (0.44 mL, 4.6 mmol) under ice-cooling, and the resultant mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added thereto. The resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to thereby obtain the titled compound (393.2 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([N:10]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)[C:11](=[O:23])[CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[CH2:4][C:3]1([CH3:36])[CH3:35].[H-].[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:32][N:27]1[C:26]([CH3:34])([CH3:33])[CH2:25][CH:24]([N:10]([CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:36])([CH3:35])[CH2:4]2)[C:11](=[O:23])[C:12]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])[CH2:29][C:28]1([CH3:31])[CH3:30]
Reactant: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
With stirring, a solution of 20 g of benzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide in 50 ml of toluene and 100 ml of dimethylformamide is added dropwise in the course of about 1/2 hour to a suspension of oil-free sodium hydride (0.97 g) in toluene (20 ml). After the addition of the amide, the reaction mixture is stirred for a further 20 hours at 60° C. until all the sodium hydride is reacted. A solution of 7.7 g of benzyl bromide in 10 ml of toluene is then added dropwise to the reaction mixture at room temperature in the course of 40 minutes, the temperature is raised to 70° C. and stirring is continued for 12 hours at this temperature. For working up, the reaction solution is filtered warm to remove precipitated sodium bromide, the residue is washed well with chloroform and the combined filtrates are freed as completely as possible from all solvents by rotary evaporation. The residue is dissolved in 400 ml of chloroform, the solution is extracted repeatedly with water, dried over sodium sulphate and the solvent removed in vacuo. The crystalline residue is recrystallised once in toluene and once in benzene, affording dibenzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide with a melting point of 275°-277° C. (Stabiliser 4).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.17 g, 0.44 mmol), 4-(6-(methyl)pyridin-3-yl)pyridin-2(1H)-one (90 mg, 0.48 mmol) and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.5 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.12 g, 0.66 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (20 mL), and the resulting solution was washed with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (53 mg, 25%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.10-8.08 (m, 1H), 7.76 (d, J=6.5 Hz, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.03-7.01 (m, 1H), 6.84 (s, 1H), 6.71 (d, J=7.0 Hz, 1H), 4.60 (s, 2H), 3.77-3.66 (m, 5H), 3.01-2.99 (m, 2H), 2.54 (s, 3H), 1.99-1.86 (m, 2H), 1.36-1.30 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[CH2:16][C:17]([OH:19])=[O:18].Cl[C:21]([O:23][CH:24]1[CH:31]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2)=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:8][CH2:9][N:10]([C:21]([O:23][CH:24]3[CH:25]4[CH2:33][CH:29]5[CH2:28][CH:27]([CH2:32][CH:31]3[CH2:30]5)[CH2:26]4)=[O:22])[CH2:11][CH2:12]1)[CH2:6][CH:5]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1ccc2c(c1)C(CC(=O)O)CC21CCNCC1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Product: Cc1ccc2c(c1)C(CC(=O)O)CC21CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1

Procedure:
The title compound was prepared from 2-(5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid and 2-adamantyl chloroformate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.24 min, m/z=0.438; 1H NMR (CDCl3) δ=7.06 (m, 2H), 7.00 (s, 1H), 4.88 (s, 1H), 4.19 (t, 2H), 3.61 (m, 1H), 3.03 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[C:21](O)=O.S(Cl)([Cl:26])=O.[BH4-].[Na+]>CO>[Cl:26][CH2:21][C:10]1[N:11]([CH3:20])[C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3ccccc23)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(CCl)n(C)c(=O)c3ccccc23)c(C)c1
Temperature: 70 °C
Yield: 5.3 %

Procedure:
A suspension of 4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (21.6 g) in thionyl chloride (218 mL, 2987 mmol) was heated at 70° C. for 2 hours. The mixture was concentrated, dissolved in tetrahydrofuran (THF) (15 mL), and treated with sodium borohydride (0.929 g, 24.56 mmol). The resulting mixture was heated to 70° C. for 2 hours until LCMS indicated complete reaction. The mixture was cooled to 0° C. and methanol was added until gas evolution ceased. The mixture was concentrated, diluted with water and then extracted three times with dichloromethane. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was treated with thionyl chloride (20 mL) and heated at 70° C. for 2 hours. The mixture was concentrated and then purified on silica gel (0-70% EA/Hexane) to afford the title compound (1.17 g, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46-8.59 (m, 1 H) 7.47-7.57 (m, 2 H) 7.05-7.24 (m, 3 H) 6.87-6.99 (m, 1 H) 4.43-4.55 (m, 1 H) 4.31-4.41 (m, 1 H) 3.86 (s, 3 H) 2.43 (s, 3 H) 2.01 (s, 3 H). LC/MS (m/z) ES+=312 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1nccnc1N1CCNCC1
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dichloropyrazine (1.35 g, 15.32 mmol), piperazine (2.34 g, 27.2 mmol) and K2CO3 (1.25 g, 9.04 mmol) in acetonitrile (5.5 mL) was stirred at 110° C. for 1.25 h in a sealed tube. The reaction mixture was diluted with CH2Cl2, filtered, and concentrated to give a yellowish semisolid residue which was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. The obtained solid was redissolved in CHCl3 and applied to a short (3 cm) plug of alumina. Elution with ether/CHCl3 (9:1) afforded 1.24 g (69%) of the title product as a white solid: mp 47-53° C. HRMS m/z calcd for C8H11CIN4 (M)+ 198.0672, found 198.0673.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: OB(O)c1ccccc1F
Product: Nc1c(F)cc(-c2ccccc2F)cc1Cl
Yield: 74.4 %

Procedure:
The title compound (0.392 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.2 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51 (td, J 1.7, 7.8, 1H), 7.38-7.32 (m, 1H), 7.28 (s, 2H), 7.27-7.22 (m, 2H), 5.62 (s, 2H).
Reaction SMILES: FC1C([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=2[F:25])=C(C=CC=1F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[F:25][C:14]1[CH:15]=[C:16]([C:19]#[C:20][Si:21]([CH3:22])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:13]=1[NH2:12]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 139 %

Procedure:
The product of Step B, 3,4-difluoro-2-[[2-fluoro-4-(trimethylsilylethynyl)phenyl]amino]benzoic acid (3.99 g, 11.0 mmol), was dissolved in MeOH (200 mL), to which was added K2CO3 (3.03 g, 22.0 mmol). This mixture was stirred at room temperature for 15 hours, then the reaction solvent removed under reduced pressure. The resulting residue was dissolved in water (50 mL), to which was added 1 M HCl until the pH=4. The resulting pale brown precipitate was collected by filtration and dried to afford the desired product (3.17 g, 99%); m.p. (EtOAc/hexanes) 160-162° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.82 (ddd, J=9.2, 6.1, 2.1 Hz, 1 H), 7.38 (dd, J=12.0, 1.9, 1 H), 7.21 (ddd, J=8.4, 1.9, 0.8 Hz, 1 H), 7.16 (td, J=9.5, 7.3 Hz, 1 H), 6.96 (ddd, J=8.9, 8.4, 5.4 Hz, 1 H), 4.15 (s, 1 H). Anal. Calcd for C15H8F3NO2: C, 62.4; H, 3.1; N, 4.7. Found: C, 62.4; H, 3.2; N, 4.6. Step D: Preparation of 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1.C([Li])CCC.[CH3:23][C:24]1([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26](=[O:32])[CH2:25]1.O>O1CCCC1.C(OCC)(=O)C>[CH:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:26]3([OH:32])[CH2:25][C:24]([CH3:23])([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27]3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: Brc1ccccc1N1CCN(CC2CC2)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(c2ccccc2N2CCN(CC3CC3)CC2)C1
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 1-(2-bromophenyl)-4-cyclopropylmethylpiperazine (700 mg, 2.37 mmol) produced in Example (108a) in anhydrous tetrahydrofuran (7 mL) was added dropwise n-butyllithium (1.60 M solution in hexane, 1.63 mL, 2.61 mmol) over a period of 3 minutes at an external temperature of −70° C. After stirring for 45 minutes under the same conditions, 3,3,5,5-tetramethylcyclohexanone (0.49 mL, 2.85 mmol) was added dropwise to the reaction mixture over a period of 4 minutes at an external temperature of −70° C. Stirring was continued for 15 minutes under the same conditions, and then for 18 hours and 30 minutes while warming until the external temperature reached room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 765 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33].CN(C)P(N(C)C)(N(C)C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Yield: 92.1 %

Procedure:
2,6-Dimethyl-4-(trimethylstannyl)pyridine (part g) (10.1 g) and 1.52 g dichlorobis(triphenylphosphine)palladium was added to a stirred solution of 12.13 g ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (part f) and 10 ml hexamethylphosphoramide (HMPA) in 240 ml dioxane under nitrogen. The reaction mixture was heated under reflux for 24 hours, then cooled and partitioned between water and methylene dichloride. The organic extract was washed with sodium chloride solution, dried (magnesium sulfate) and concentrated to give 12.0 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 198°-200° C.
Reaction SMILES: OCCC[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].N1CCCC([CH2:27][CH2:28][OH:29])C1>>[OH:29][CH2:28][CH2:27][CH:8]1[CH2:9][CH2:10][CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Reactant: OCCC1CCCNC1
Product: O=C(OCc1ccccc1)N1CCCC(CCO)C1

Procedure:
Prepared similarly to Intermediate 29 from 2-(3-piperidinyl)ethanol.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1

Procedure:
Synthesized as described for 52 using commercially available 4-n-butylbenzenesulfonyl chloride (0.47 g; 2 mmol), methyl 3-aminothiophene-2-carboxylate (314 mg; 2 mmol), pyridine (0.2 mL; 2.4 mmol), and anhydrous dichloromethane (10 mL). This afforded the title compound as a clear oil which later solidified (0.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH2:23][CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>O>[CH2:27]([O:26][CH:25]([O:29][CH2:30][CH3:31])[CH2:24][CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[CH3:28]
Reactant: CCOC(CCCl)OCC
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOc1ccc(C(N)=O)cc1)OCC
Temperature: 100 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask. The reaction mixture is stirred at 100° C. for 18 hours and then 5 mL of water are added. The aqueous phase is extracted with ethyl acetate, and then the organic phases are collected, washed with water and concentrated under reduced pressure. The product is obtained in the form of a powder in a yield of 89% and with a chemical purity of 95%.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[NH2:13])=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2].[N+:14]([C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH:19]=[C:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:16])=[O:15].C(OC(=O)C)C.CCCCCC>C(O)C>[C:1]([O:4][CH2:5][C:6]1[NH:13][C:26]([CH3:28])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]([C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N+:14]([O-:16])=[O:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: CCOC(=O)/C=C(\N)COC(N)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 58.1 %

Procedure:
9.4 g (50 millimoles) of ethyl 4-carbamoyloxy-3-aminocrotonate and 13.2 g (50 millimoles) of ethyl 2-(o-nitrobenzylidene)acetoacetate were dissolved in 200 ml of ethanol and reacted at a temperature of from 60° to 70° C. for 16 hours under stirring. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from ethylacetate-hexane, whereby 12.6 g (yield: 58%) of 2-carbamoyloxymethyl-6-methyl-4-(o-nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydropyridine in crystal form was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH3:19])[C:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5].B.[Na].C(O)(=O)C.[Cl-].[Na+]>C(O)C>[Cl:1][CH2:2][CH:3]([CH3:19])[CH:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[OH:5]
Reactant: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(CCl)C(O)c1ccc(Cc2cccnc2)cc1
Yield: 99 %

Procedure:
In 17 ml of ethanol was dissolved 2.28 g of 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine, and to the resulting solution was added 0.3 g of sodium boron hydride in small portions with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for one hour. To the reaction mixture were added successively 0.54 ml of acetic acid and 30 ml of a saturated aqueous sodium chloride solution, and the resulting mixture was extracted with two 20-ml portions of ethyl acetate. The extracts were combined, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:1 by volume)] to obtain 2.29 g (yield 99.0%) of colorless, oily 3-[p-(3-chloro-1-hydroxy-2-methylpropyl)benzyl]pyridine.