Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[Hg]Cl)(=[O:3])[CH3:2].[Cl:12][C:13](=[CH2:16])[C:14]#[N:15].[BH4-].[Na+]>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:16][CH:13]([Cl:12])[C:14]#[N:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCC[C@H]1[Hg]Cl
Reactant: C=C(Cl)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@@H]1CCC[C@H]1CC(Cl)C#N
Reaction time: 1 h

Procedure:
16.1 g of trans-1-acetamido-2-chloromercuriocyclopentane are suspended in 200 ml of ethanol. 10.7 ml of 2-chloroacrylonitrile are added, followed by 1.7 g of sodium borohydride in 40 ml of ethanol as rapidly as possible while cooling in ice. After 1 hour at room temperature, the mixture is filtered with suction through kieselguhr, the filtrate is evaporated, the residue is taken up with methylene chloride, this solution is washed twice with 1N sodium hydroxide solution, and the organic phase is dried over sodium sulfate and evaporated. Chromatography on silica gel (mobile phase ethyl acetate) produces 2.2 g of crystalline product, melting point 114°-117° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:16][CH2:15]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Dissolve {2-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (3.8 g, 9.16 mmol, 1 eq.) in dichloromethane (20 mL). Add trifluoroacetic acid (41.2 g, 27.8 mL, 366.4 mmol, 40 eq.). Stir at room temperature for 1.5 hr. Partition the reaction mixture between aqueous 5N NaOH (pH aqueous layer=14) and dichlormethane. Separate the layers. Extract the aqueous layer with dichloromethane (2×50 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate to afford the title preparation (3.04 g, 100% yield). MS (loop): m/z=316.3 [M+H].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:37].[Na+].[Na+]>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([C:25](=[O:35])[CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)=[CH:19][CH:20]=4)[C:15](=[O:37])[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A solution of 9.0 g (0.019 mole) 2,7-bis(4-piperidinobutyryl)fluorene, 7.54 g (0.0253 mole) sodium dichromate and 300 ml of glacial acetic acid is stirred and refluxed for 1 hour. The reaction mixture is evaporated to semi-dryness and made basic using concentrated ammonium hydroxide. The solid which precipitates is filtered, washed with water and chromatographed on alumina using chloroform as the eluant. The solvent is removed from the fraction collected, leaving a solid residue which is recrystallized three times from chloroform-acetone to yield 2,7-bis(4-piperidinobutyryl)fluoren-9-one, M.P. 168°-170°C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>CO>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:10](=[O:11])[C:9]([F:16])([F:15])[F:8]
Reactant: CNCCCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: CN(CCCCO)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a 250 mL round bottom flask, charged with 10.0 g (96.9 mmol) of the amine, 4-methylaminobutanol, in 100 mL of dry methanol, was added 17.5 mL (147 mmol) of ethyl trifluoroacetate. The mixture was stirred at room temperature for 24 hours and then concentrated to afford 18.55 g of the product as a near colorless oil (96%): 1H-NMR (200 MHz, D2O); 3.63 and 3.50 (2t's, 4H), 3.20 and 3.05 (d and s, 3H), and 1.82-1.47 (m, 4H) ppm.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]cnn1-c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnn(-c2ccc(Br)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dry NaH (67.8 mg, 2.83 mmol) under an Argon atmosphere was added a solution of compound 84b (532 mg, 1.88 mmol) in anhydrous DMF (5 mL) slowly over 2 min. The mixture was stirred at rt for 1 h and then cooled to 0° C. 2-(Trimethylsilyl)ethoxymethyl chloride (0.612 mL, 3.391 mmol) was added dropwise over 2 min. After stirring at rt for 1 h, the mixture was quenched carefully with 1 mL of saturated aqueous NH4Cl and poured into brine (75 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined extracts were washed with water (2×25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a faintly yellow crystalline solid. The solid was purified by flash column chromatography on silica gel (0-40% EtOAc-heptane) to give compound 84c as a white solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2Si, 392.1/394.1 (M+Na). found 392.2/394.1.
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=1>>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:29]1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(CO)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) and 3-amino-1-methyl-pyrazole to give a white solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1 H) 7.33-7.45 (m, 5 H) 7.30 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (d, J=1.01 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 4.95-5.03 (m, 1 H) 3.81 (s, 3 H) 3.73-3.79 (m, 1 H) 3.27 (dd, J=16.17, 9.60 Hz, 1 H) 3.03 (dd, J=16.29, 7.20 Hz, 1 H) 2.13 (t, J=6.44 Hz, 1 H); LCMS for C21H21N3O4 m/z 380.00 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(F)ccc2N1
Product: CC(=O)N1C(=O)Cc2cc(F)ccc21
Temperature: 25 °C

Procedure:
At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred for 3 h in 10 mL (98 mmol) acetic anhydride. After cooling to RT the mixture was poured onto 200 mL ice water, the precipitated substance was suction filtered and washed with 100 mL water. The solid was recrystallised from 100 mL water and 50 mL ethanol at boiling temperature. The precipitated product was suction filtered, washed with 30 mL water and dried in the CAD.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:24]([O:30][CH2:31]I)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:13])[CH3:3]
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Yield: 72.5 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.17 g) was dissolved in dry DMF (1.7 ml) and the solution was ice-cooled. Thereto was gradually dropped pivaloyloxymethyl iodide (0.12 g) in dry DMF (1.2 ml) and the mixture was stirred. Thirty minutes later, ethyl acetate was added thereto and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2˜ethyl acetate only) to give [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g, yield 70%).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 40 °C

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in ethanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. and a solution of trifluoroacetic acid in ethanol (10 ml in 100 ml) was added over a period of 1 hour. The reaction mass was refluxed for 18-24 hours and cooled to 40° C. The reaction mass was concentrated under vacuum to obtain a residue and water (1500 ml) was added. The mixture was cooled to 10-15° C. and pH of the reaction mass was adjusted to 8 using 5% sodium bicarbonate solution and stirred. The resulting solid was filtered and dried at 50-55° C. under vacuum to obtain title compound (Yield: 93 g, HPLC Purity: 99%)
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)CC=C)[CH2:17][CH2:18]C>CN(C=O)C.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>[CH2:18]([C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)[CH:17]=[CH2:16]
Reactant: COC(=O)Cn1nc(C(F)(F)F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Temperature: 120 °C
Yield: 38.4 %

Procedure:
Methyl 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (420 mg, 1.47 mmol), tri n-butyl allyltin (729 mg, 2.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) were dissolved in DMF (10 mL). The solution was degassed with argon for 10 min and then heated at 120° C. overnight. After the solution was cooled to room temperature, the volatiles were removed under vacuum. The resulting residue was purified by silica gel chromatography (loading with toluene, eluting with dichloromethane/hexanes) to afford methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (140 mg, 38%) as a clear oil. MS (m/z): 249.1 [M+H]+; HPLC retention time 3.51 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13](N)=[O:14])[CH:12]=1)[CH3:2].[OH-:27].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([OH:27])=[O:14])[CH:12]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(CO)c(C)nc12
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(CO)c(C)nc12
Yield: 59.8 %

Procedure:
8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine-6-carboxamide (0.02 g, 0.057 m mol) and sodium hydroxide (0.02 g, 0.29 mmol) were solved in ethanol (95%) (1 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and to the residue was added water (1 ml). The pH was adjusted to 5 by addition of acetic acid and the solid that precipitated was isolated by filtration, washed with water and dried to give 0.012 g (60%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 91 %

Procedure:
A solution of Example 39H (0.050 g, 0.105 mmol), acetic anhydride (0.011 mL, 0.116 mmol), and pyridine (0.068 mL, 0.840 mmol) in methylene chloride (2 mL) was stirred at 25° C. for 4 hours. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.046 g, 90%). 1H NMR (300 MHz, DMSO-d6): 5 ppm 0.43 (m, 1H) 0.77 (m, 7H) 1.33 (m, 1H) 1.56 (m, 3H) 2.06 (m, 4H) 2.23 (m, 1H) 7.53 (m, 1H) 7.66 (m, 1H) 7.77 (m, 3H) 8.16 (m, 1H) 8.29 (m, 1H) 10.38 (m, 1H) 13.84 (m, 1H).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])([CH3:3])[CH3:2].C([Li])(CC)C.Cl[C:25]([O:27][CH3:28])=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH3:28][O:27][C:25]([C:10]1[O:9][C:8]([CH3:12])=[C:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17])[CH:11]=1)=[O:26]
Reactant: COC(=O)Cl
Reactant: Cc1occc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triisopropyl-(2-methyl-furan-3-ylmethoxy)-silane (14) (10.0 g) in tetrahydrofuran (300 mL) was cooled to −78° C. with stirring was treated drop-wise with sec-butyllithium (3.0 M in cyclohexane, 37 mL). After 1 hour the reaction mixture was treated drop-wise with a solution of methyl chloroformate (5.2 g) in tetrahydrofuran (30 mL) over 10 mins and stirring was continued at −78° C. for 1 hour. The reaction mixture was then treated with saturated ammonium chloride solution (300 mL) and allowed to warm to ambient temperature. The two layers were separated and the organic phase washed with brine (300 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:9 by volume) to give compound 15 as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Nc1ccccc1F
Reactant: CC1(O)CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C2(C)CCCCC2)cc1F
Temperature: 70 °C

Procedure:
2-Fluoro-N-methoxycarbonylaniline (3.38 g, 20.0 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (20 g) to prepare a solution. 1-Methylcyclohexyl alcohol (2.28 g, 20.0 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for 5 hr. Subsequently, the reaction solution was cooled to room temperature. n-Hexane (100 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (100 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 843 mg of 2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline as a target compound (yield 15.8%, 4-substituted compound: 5-substituted compound=100:0).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:19])=[CH:29][CH:28]=3)[CH2:23][CH2:24][CH2:25]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)ccc21
Temperature: 40 °C
Yield: 30.8 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (59.7 mg, 0.21 mmol, 1.0 equiv; Example 31, Step 1) in dichloromethane (2 mL) was added 6-fluoro-1,2,3,4-tetrahydro-quinoline (34.9 mg, 0.23 mmol, 1.1 equiv; [CAS RN 59611-52-8]), triethylamine (42.5 mg, 59 μL, 0.42 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (59.0 mg, 0.23 mmol, 1.1 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at 40° C. over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 27 mg (31%) of the title compound. MS (ISP): 417.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH4-].[Na+].[ClH:31]>CO>[ClH:31].[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][CH:10]([CH3:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NCCCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1cccc(C(F)(F)F)c1)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-2-propanone (102 mg, 0.50 mmol), 3-phenyl-1-propylamine (86 mg, 0.64 mmol), glacial acetic acid (8 mg, 0.13 mmol), and MeOH (2 mL) was allowed to stir at room temperature for 0.5 h. To this mixture was added over a 4-h period sodium borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room temperature for 20 h. The solvents were removed by warming under reduced pressure to give a small amount of an oil which was cooled and treated with 10% HCl. The crude product separated as a white solid, 122 mg (68%), mp 135-145° C. The crystals were dissolved in H2O and the solution was extracted with Et2O. The H2O portion was separated, the H2O was evaporated, and the crystals reformed; recrystallization from acetone gave 66 mg (37%) of colorless crystals, mp 167-169° C.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[CH3:6][N:7]1[C:12](=[O:13])[CH2:11][C:10](=[S:14])[N:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]1=[O:19]>O>[CH3:6][N:7]1[C:12](=[O:13])[C:11]2[CH:1]=[CH:2][S:14][C:10]=2[N:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:8]1=[O:19]
Reactant: CC(C)CN1C(=O)N(C)C(=O)CC1=S
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reaction time: 5 h
Yield: 94.7 %

Procedure:
Sodium acetate (38.9 g) was added to a stirred suspension of 3-methyl-1-(2-methylpropyl)-6-thioxo-pyrimidine-2,4(1H,3H)-dione (25.42 g) in water (1 l). After 5 hours, the mixture was filtered. Aqueous chloroacetaldehyde solution (50 wt. %, 142 ml) was added to the filtrate and the mixture was stirred for 16 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×500 ml). The combined organic extracts were washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was purified by column chromatography over silica, eluting with isohexane:ether (1:1) to give the title compound (26.78 g) as a solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.C(N(CC)CC)C>ClCCl>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:14]
Reactant: O=Cc1ccccn1
Reactant: CC(C)CC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(N=Cc1ccccn1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-methylpentanoic acid tert-butyl ester hydrochloride (5.00 g, 22.35 mmol), pyridine-2-carboxaldehyde (2.12 mL, 22.35 mmol) and triethylamine (3.11 mL, 22.35 mmol) in dichloromethane (75 mL) was heated under reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature, washed with water and brine, dried over MgSO4 and evaporated to give the title compound as an oil.