Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:5])[CH2:4][CH2:3]1.[O:6]=[C:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[O:13][C:14](=O)[O:15]N1C(=O)CCC1=O.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[CH3:1][C:2]1([O:5][C:14](=[O:15])[O:13][N:8]2[C:9](=[O:12])[CH2:10][CH2:11][C:7]2=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(O)CC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 19.5 %

Procedure:
To a solution of 1-methyl-cyclopropanol (1.25 g, 17.4 mmol) in acetonitrile (44 mL) was added carbonic acid bis-(2,5-dioxo-pyrrolidin-1-yl) ester (6.68 g, 26.1 mmol) and triethylamine (7.3 mL, 52.3 mmol). The reaction was stirred at room temperature for 21 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica (15→50%→100% Hex/EtOAc) to provide carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 1-methyl-cyclopropyl ester (722.8 mg, 19%): 1H NMR (CDCl3, 300 MHz) δ 2.83 (s, 4H), 1.63 (s, 3H), 1.10 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:23][C:24]([F:35])([F:34])[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26]>O.C(OCC)(=O)C>[C:10]1([CH2:9][CH2:8][CH2:7][NH:33][CH:30]2[CH2:29][CH2:28][N:27]([C:25](=[O:26])[C:24]([F:23])([F:34])[F:35])[CH2:32][CH2:31]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCc1ccccc1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CCC(NCCCc2ccccc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.38 mL of (3-bromopropyl)benzene, 0.76 g of potassium carbonate and 0.64 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thereto were further added 2 mL of N,N-dimethylformamide, 0.40 g of 1-(trifluoroacetyl)piperidine-4-amine dihydrochloride and 0.60 g of potassium carbonate, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.99 g of a yellow oily substance, N-(3-phenylpropyl)-1-(trifluoroacetyl)piperidine-4-amine. (2) To 3 mL of a dichloromethane solution containing 0.99 g of N-(3-phenylpropyl)-1-(trifluoroacetyl)piperidine-4-amine, 0.82 g of di-tert-butyl dicarbonate was added under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Thereto was further added 0.20 g of di-tert-butyl dicarbonate, and the mixture was left to stand at room temperature overnight. The solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 0.63 g of a colorless oily substance, tert-butyl (3-phenylpropyl) (1-(trifluoroacetyl)piperidin-4-yl)carbamate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccccc1C1CCNCC1
Reaction time: 1 h
Yield: 102.5 %

Procedure:
4-(2-Cyano-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g) was dissolved in a solution of hydrogen chloride in dioxane (4 M, 2 mL) and the mixture stirred for 1 hour. The solvent was evaporated under vacuum, and the resulting solid triturated from diethyl ether to give the title compound as a grey solid (0.1 g). LCMS m/z 187.2[M+H]+. R.T.=1.90 min (Analytical Method 4).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[O:5])[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[C:18]([C:17]1[C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=[CH:21][C:20]=1[O:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])#[N:19]
Reactant: CCNC(=O)NCC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCNC(=O)NCC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 47 %

Procedure:
Prepared as in Example 215c from 1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)urea (Example 227d) and 2,6-dinitrobenzonitrile in 47% yield. MS 321 (MH+).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([S:11][CH3:12])=[N:9][N:8]=[C:7]1[CH:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.S(=O)(=O)(O)O>>[CH3:20][CH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:4]=[CH:5][N:6]2[C:10]([S:11][CH3:12])=[N:9][N:8]=[C:7]12
Reactant: CCOC(Cn1c(SC)nnc1C(C)c1ccccc1)OCC
Agent: O=S(=O)(O)O
Product: CSc1nnc2n1C=Cc1ccccc1C2C

Procedure:
12.5 g of the 4-(2,2-diethoxyethyl)-3-(α-methylbenzyl)-5-methylthio-4H-1,2,4-triazole prepared in Reference Example 10 was added to cold concentrated sulfuric acid and the cyclization reaction mixture was treated by a procedure similar to that described in Example 2. By the above procedure was obtained 11-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:35])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH:10]([O:35][C:42](=[O:44])[CH3:43])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:15]=2)=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
2-Fluoro-4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-benzonitrile (as described in Step B above) (4.05 g, 8.81 mmol), pyridine (2.14 mL, 26.4 mmol), and acetic anhydride (12.5 mL, 132 mmol) were stirred in anhydrous DMF (60 mL) for 3 h under Ar. The reaction was concentrated in vacuo, diluted with EtOAc (250 mL), washed with H2O (2×), brine, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:8]3[C@:18]([F:22])([C@@H:19]([OH:21])[CH2:20][C@:4]2([CH3:5])[C:3]=1[S:24][CH2:25][CH3:26])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:8]3[C@:18]([F:22])([C@@H:19]([OH:21])[CH2:20][C@:4]2([CH3:5])[C:3]=1[S:24]([CH2:25][CH3:26])=[O:35])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3
Reactant: CCSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)C1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C

Procedure:
To (11β)-16-chloro-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4,16-trien-3-one (100 mg; see Example 1A) in dichloromethane (15 ml) is added a solution of 85% m-chloroperbenzoic acid (56 mg) in dichloromethane (5.0 ml) over a period of 2 minutes. After 1 hour the solution is washed with a dilute sodium carbonate solution and water, dried (anhydrous MgSO4) and evaporated to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:21](C)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][N:11]([CH3:21])[CH2:10][C@H:9]1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1CNCC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CO[C@@H]1CN(C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Tert-butyl((3R,4R)-3-methoxy-piperidin-4-yl)-carbamate (2.88 g) is dissolved with formaldehyde (1.79 mL, 37% solution in H2O) and acetic acid (100 μL) in DMF. Then Na(OAc)3BH (12.59 g) is added. After 20 h the reaction mixture is combined with aqueous NaHCO3 solution (saturated with NaCl) and extracted 5 times with EtOAc. The combined organic phase is dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. The residue is used in the next reaction step without any further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:16])=[CH:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>[OH-].[Na+]>[C:17]([O:1][C@@H:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:16])=[CH:3]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@H]1C(C)=C[C@H](OC(C)=O)CC12CCCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A part of the crude trans-methyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate obtained (4.0 g) was treated with acetic anhydride (3.5 ml, 37.4 mmol) and sodium acetate (1.46 g, 17.8 mmol). The resulting mixture was stirred at 80° C. for 4 h, poured into cold 2N aqueous NaOH (20 ml), and extracted twice with MTBE (30 ml). The combined organic phases were washed with water (30 ml), with a saturated aqueous solution of NaCl (30 ml), dried (MgSO4), concentrated giving crude trans-methyl 9-acetoxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (4.4 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:22]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
Dissolve 4-(2-amino-ethyl)-benzonitrile hydrochloride (300 mg, 1.65 mmol) into saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over Na2SO4 and concentrate in vacuo to obtain 4-(2-amino-ethyl)-benzonitrile (205 mg, 85%). Dissolve 4-(2-amino-ethyl)-benzonitrile (200 mg, 1.37 mmol) in DCM (2 mL), add triethylamine (54 μL, 0.38 mmol) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (169 μL, 1.37 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (182 mg, 58%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].C1COCC1.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C=O)C.O>[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:39]([CH3:40])[CH3:38])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CNC
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to 4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (150 mg, 0.40 mmol, prepared in example 4) in CH2Cl2 (10 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into THF (10 mL) and added dropwise to a stirring solution of 40% dimethylamine in water (5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into CH2Cl2 and the organic layer was washed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 167 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (97 mg, 60%) as a viscous oil. Ion spray M.S. 407.4 (M*+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:21]([CH2:20][C:19]([F:23])([F:22])[F:18])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(F)(F)F
Temperature: 75 °C
Yield: 0.1 %

Procedure:
3-(Benzyloxy)-2-methyl-4H-pyran-4-one (1.00 g, 4.6 mmol) was mixed with trifluoroethylamine hydrochloride (1.35 g, 10.0 mmol) in pyridine (10 mL). The reaction mixture was heated in a sealed flask at 75° C. for 5 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.82 mg) as beige solid. Yield=60%; 1H NMR (CDCl3, 90 MHz) δ (ppm): 7.02-7.58 (m, 6H), 6.42 (d, J=7.5 Hz, 1H), 5.20 (s, 2H), 4.30 (q, J=8.3 Hz, 2H) and 2.10 (s, 3H).
Reaction SMILES: [Mg].II.Cl[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:11][C:12]([F:45])([F:44])[C:13]1[CH:14]=[C:15]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:16][N:17]([CH2:24][C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])[C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1.C[Si](Cl)(C)C>C1COCC1.C[Mg]Br>[F:45][C:12]([F:11])([F:44])[C:13]1[CH:14]=[C:15]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:16][N:17]([CH2:24][C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH:27]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[OH:28])[C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1
Reactant: ClC1CCOCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Agent: C[Mg]Br
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCOCC2)n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a suspension of magnesium in THF was added iodine followed by 4-chlorotetrahydropyran in THF at 65° C. Small amount of methylmagnesium bromide (3 drops) was added to initiate the reaction. The mixture was stirred at 65° C. for 1.5 hours, cooled to room temperature. 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde in THF was treated with trimethylsilyl chloride and stirred at room temperature for 1 hour. The Grignard was then added to the aldehyde in THF at 0° C. via syringe. The mixture was stirred at 0° C. for 1.5 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-50% ethyl acetate in hexanes) to afford the title compound as a pale yellow foam (91.6 mg, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (d, J=13.28 Hz, 1H) 1.27-1.37 (m, 1H) 1.40-1.52 (m, 1H) 1.77-1.89 (m, 2H) 2.51 (s, 1H) 3.19-3.34 (m, 2H) 3.86 (dd, J=11.14, 3.53 Hz, 1H) 3.99 (dd, J=11.62, 3.73 Hz, 1H) 4.18 (s, 3H) 4.68-4.83 (m, 4H) 4.88 (d, J=15.35 Hz, 1H) 7.34 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 597.2, Found: 598.4 (M+1). The racemic alcohol mixture was separated by chiral chromatography using preparative HPLC (Column: Chiralcel OJ; Dimension: 5 cm×50 cm; Mobile phase: 95/5 heptane/ethanol with 0.1% DEA, Flow rate: 120 mL/minutes). The expected preparative retention times for the two enantiomers are 26 minutes (Enantiomer 1) and 36 minutes (Enantiomer 2). Enantiomer 1: MS Calc: 597.2, Found: 598.4; 100% ee. Enantiomer 2: MS Calc: 597.2, Found: 598.4; 100% ee
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.O.O.C([O-])(=O)C.[Na+]>>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(F)c1

Procedure:
3-Fluoroaniline (55.5 g), methyl chloroacetate (44 ml), and sodium acetate trihydrate (114 g) were treated according to the method of Intermediate 1 to give a solid (50 g), a small sample of which (ca. 1 g) was purified by FCC eluting with System B (1:3) to give a solid which was recrystallised from petroleum ether (60°-80°) to give the title compound, m.p. 68°-69°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Se]=[O:13]>C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]
Reactant: Cc1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2ncccc2c1
Temperature: 220 °C
Yield: 54.9 %

Procedure:
A mixture of 6-methylquinoline (5.72 g, 40.0 mmol) and selenium oxide (4.44 g, 40.0 mmol) was heated to 220° C. for 1 h. After cooling down the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with brine, dried over MgSO4. Evaporation of solvents provided a solid, which was recrystalized from ether-hexane (1:1) mixture to give 6-quinolinecarboxaldehyde (3.45 g, 55%).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.C(O)C(C)C>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Solvent: CC(C)CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 130 °C
Reaction time: 7 h

Procedure:
A mixture of 70 weight parts of “CROMOPHTAL Jet Magenta DMQ (produced by Ciba Japan Co., Ltd.)”, (C.I. Pigment Red 122), 290 weight parts of isobutanol and 380 weight parts of water was placed into a reaction vessel with a stirrer and stirred at 130° C. for 7 hours. Thereafter, the resulting mixture was cooled to room temperature, and the resulting precipitates were filtered off, washed with hot water, dried and pulverized to obtain a quinacridone pigment. This quinacridone pigment was designated as Quinacridone Pigment 6. The number average primary particle size, major axis direction length, minor axis direction length and a ratio of a major axis direction length to minor axis direction length of Quinacridone Pigment 6 are as shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC.[CH2:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:37]>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:41]2[CH2:42][CH2:43][N:38]([CH2:36][CH3:37])[CH2:39][CH2:40]2)=[O:8])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)c2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of 4-amino-2-trifluoromethyl-benzoic acid (15 g, 73.1 mmol), HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et3N (20.38 mL, 146 mmol), 1-ethyl-piperazine (8.35 g, 73.1 mmol) in DCM (200 mL) was stirred at 25° C. for 2 h. To the mixture was added DCM (200 mL) and then washed with H2O, 2 mol/L NaOH (2×150 mL) and brine. The organic layer was dried over Na2SO4 and concentrated to give a off white solid of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 65.2 mmol, 89.0% yield): 1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J=8.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.0, 8.0 Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33-2.31 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[S:21])[CH2:14][CH2:13]1.ClC(Cl)Cl.BrBr.[OH-].[Na+]>ClC(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]2[S:21][C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(NC(=S)NCC2CCN(CC3COc4ccccc4O3)CC2)cc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(NCC3CCN(CC4COc5ccccc5O4)CC3)sc2c1
Yield: 21 %

Procedure:
To a stirred mixture of 8.3 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea, 60 parts of trichloromethane and 240 parts of tetrachloromethane were added at once 3.1 parts of bromine. The whole was stirred and refluxed for 1 hour. After cooling, the reaction mixture was treated with a sodium hydroxide solution. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7 parts (21.0%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-6-methoxy-2-benzothiazolamine; mp. 134.7° C. (compound 68).