Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]1[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10]1)(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH2:10][CH:9]([CH2:8][CH2:7][CH2:6][N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)[C:13]=2[CH:14]=1
Reactant: CS(=O)(=O)OCCCC1COc2ccc(F)cc21
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: Fc1ccc(C2CCN(CCCC3COc4ccc(F)cc43)CC2)cc1

Procedure:
The title compound, 11a, was prepared from 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate (4.2 g) and 4-(4-fluorophenyl)piperidine (5.5 g) by the method described in EXAMPLE 2. Yield: 1.8 g, mp: 83-85° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([N:17]([CH:21](N(CCC)CCC)OC(C)(C)C)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:21]=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:15][CH3:16]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: CCCN(CCC)C(OC(C)(C)C)N(CCC)CCC
Product: CCCN(C=Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])CCC
Reaction time: 2 h
Yield: 85.8 %

Procedure:
For two hours, 5.5 g of 2,3-dinitrotoluene is heated with 13.0 g of bisdipropylamino-tert-butoxymethane to 60° C. After cooling, the reaction mixture is freed of volatile components under a high vacuum, thus obtaining 7.6 g of β-dipropylamino-2,3-dinitrostyrene as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[F:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.36) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.19 g, 79%). MS (ISP) 479.0 [(M+H)+]; mp 212° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.[ClH:26]>CCOCC.O1CCOCC1>[ClH:17].[Cl:26][C:19]1[CH:20]=[C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[CH:9][C:8]=4[C:2]3=[N:25]2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CCCc2ccncc2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1CC2CCCc3ccncc3C2=NN1c1ccc(Cl)c(Cl)c1

Procedure:
Prepared according to the method described in Example 1 from 9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-8-acetic acid and 4-chlorophenylhydrazine, the compound being dissolved in ether and hydrogen chloride in dioxan added to precipitate the hydrochloride salt.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH2:10][CH3:11])[C:7](Br)=[O:8].[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]1=[O:22]>C(=S)=S>[Br:5][CH:6]([CH2:10][CH3:11])[C:7]([C:19]1[CH:20]=[CH:21][C:16]2[S:15][C:14](=[O:22])[N:13]([CH3:12])[C:17]=2[CH:18]=1)=[O:8]
Reactant: CCC(Br)C(=O)Br
Reactant: Cn1c(=O)sc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A mixture of aluminum chloride (120 g) and 2-bromobutyryl bromide (48 g) in carbon disulfide (120 ml) was stirred for 30 minutes at ambient temperature. To the resultant mixture was added 3-methyl-2-benzothiazolinone (23 g) and the mixture was stirred for an hour at ambient temperature. The solvent was removed by evaporation at 60°-70° C. and stirred for an hour under the same condition. The reaction mixture was poured into ice-water (360 g) and extracted with chloroform (100 ml×2). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel (300 g) by eluting with benzene. The fractions containing the desired compound were combined and the solvent was removed by distillation to give 5-(2-bromobutyryl)-3-methyl-2-benzothiazolinone (27.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[C:12]2([CH2:14][CH2:2][CH2:3][CH3:4])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH2:6]2
Reactant: COc1ccc2c(c1)CNC2=O
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc2c(c1)CN(Cc1ccc(C)cc1)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
5-Methoxy-2,3-dihydroisoindol-1-one (40 mg, 0.25 mmol), Cs2CO3 (239 mg, 0.74 mmol), 1-bromomethyl-4-methylbenzene (68 mg, 0.37 mmol) in acetonitrile (4 mL) was allowed to stir at room temperature for 18 hours and at 70° C. for 4 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (30% EtOAc/Hexanes) to afford a white solid (15 mg). 1H NMR (300 MHz, CDCl3): δ 7.81 (d, 1H), 7.18 (q, 4H), 7.00 (dd, 1H), 6.87 (s, 1H), 4.75 (s, 2H), 4.21 (s, 2H), 3.87 (s, 3H), 2.34 (S, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[OH-].[K+]>CS(C)=O.O>[CH3:9][C:4]1[S:3][C:2]([NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([C:7]#[N:8])[CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-methylthiophene-3-carbonitrile (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR: (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7.56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6.96 (m, 1H), 6.80 (s, 1H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH:10]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[N:11]([CH2:23][CH2:24][CH2:25][OH:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:35].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH:10]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:23][CH2:24][C:25]([OH:35])=[O:26])[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N(CCCO)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(CCC(=O)O)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Reaction time: 4 h

Procedure:
Cyclohexyl[(3-hydroxypropyl)(4-methoxybenzenesulfonyl)amino]acetic acid benzyl ester (45.8 grams, 96 mmol) and sodium periodate (92.6 grams, 433 mmol) were dissolved in a mixture of acetonitrile (345 mL), carbon tetrachloride (345 mL) and water 460 mL). While cooling in an ice bath, ruthenium trichloride monohydrate (4.4 grams, 21 mmol) was then added. The resulting mixture was mechanically stirred with ice bath cooling for 30 minutes. The bath was removed and stirring was continued at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine. After drying over magnesium sulfate, the solvents were evaporated to give a dark oil from which 3-[(benzyloxycarbonylcyclohexylmethyl)-(4-methoxybenzenesulfonyl) amino]propionic acid, a white foam (28.1 grams, 60%), was isolated by flash chromatography on silica gel eluting sequentially with chloroform and 1% methanol in chloroform.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O:15][C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18])C.C([O-])([O-])=O.[K+:27].[K+]>CO>[K+:27].[F:1][C:2]([F:12])([F:11])[C:3](=[N:18][C@H:17]([C:16]([O-:22])=[O:15])[CH:19]([CH3:21])[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)[C@H](N=C(c1ccccc1)C(F)(F)F)C(=O)[O-]
Temperature: 50 °C

Procedure:
2,2,2-Trifluoroacetophenone (4.24 g, 24.3 mmol) was added to a mixture of L-valine ethyl ester (3.21 g, 22.1 mmol) and K2CO3 (2.90 g, 20.9 mmol) in MeOH (50 mL). The mixture was warmed to 50° C. for 18 h. The mixture was cooled to 20–25° C., filtered and concentrated. The residue was suspended in TBME (100 ml) and filtered to give the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(=O)=O.CC(C)=O.[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=1>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C.CS(C)=O>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:16][CH:15]=1
Reactant: OCCCCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=CCCCc1ccncc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Oxalyl chloride (1.45 mL of a 2M solution in dry methylene chloride) was placed in an oven-dried flask and cooled to -78° C. using a dry ice and acetone cooling bath and a solution of DMSO (0.413 mL) in dry methylene chloride (1 mL) added drop by drop to the oxalyl chloride over 3 minutes and stirred for a further 3 minutes. A solution of 4-(4-pyridyl)-butan-1-ol (400 mg) in dry methylene chloride (5 mL) was added to the reaction flask over approx. 3 minutes and the reaction stirred for 15 minutes. Anhydrous triethylamine (2.03 mL) was added and the reaction mixture stirred for another 2 hours during which time the cold bath had warmed up to room temperature. The reaction was quenched by the addition of saturated brine and then partitioned with methylene chloride. The aqueous layer was discarded and the methylene chloride extract dried over anhydrous sodium sulfate powder, filtered and evaporated under reduced pressure to leave an oily residue. The product was isolated by column chromatography on silica gel using ethyl acetate as eluant (301 mg).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1([F:29])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:19]=2[O:18]1>C(Cl)(Cl)Cl>[F:29][C:17]1([F:16])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([N:12]3[CH2:13][CH2:14][C:15]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=[N:9][C:10]=4[CH2:11]3)=[O:27])[C:19]=2[O:18]1
Reactant: c1ccc(-n2cnc3c2CCNC3)cc1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Solvent: ClC(Cl)Cl
Product: O=C(c1cccc2c1OC(F)(F)O2)N1CCc2c(ncn2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of the product of Example 50, Step A (28 mg, 0.141 mmol) and TEA (23 μL, 0.169 mmol) in CHCl3 (1 mL) cooled to 0° C. was added 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (34 mg, 0.155 mmol). The reaction was warmed to room temperature and stirred overnight. The crude reaction mixture purified on 12 g SiO2 column with 0-4% NH3/MeOH CH2Cl2 to give the desired compound (43 mg, 80%). MS (ESI): mass calcd. for C20H15F2N3O3, 383.1. m/z found, 384.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.71-7.39 (m, 4H), 7.36-7.09 (m, 5H), 4.88 (s, 1H), 4.58 (t, J=1.6 Hz, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.66 (t, J=5.6 Hz, 1H), 2.86-2.74 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13].C(#N)C.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:19])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(Br)c(F)cc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A vial was charged with 7-bromo-6-fluoroquinolin-4-ol (0.460 g, 1.900 mmol) and acetonitrile (9.50 ml). Phosphoryl trichloride (0.354 ml, 3.80 mmol) was then added, and the reaction was stirred for 2 h at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous was extracted once more with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The material was then purified via silica gel chromatography eluting with 0-75% ethyl acetate in heptanes to yield 7-bromo-4-chloro-6-fluoroquinoline (0.141 g, 0.541 mmol, 28.5% yield) as a white solid. m/z (ESI) 260.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]([OH:15])[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(O[Si](C)(C)C)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(OCC)C.Cl>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:13][O:14][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15]1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](CO)OCc1ccccc1
Reactant: C[Si](C)(C)OC1=CCCCC1
Agent: Cl
Solvent: CCOCC
Product: OC[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96624.1 %

Procedure:
4.34 g (0.02 mol) of (2R,3R)-2-benzyloxybutane-1,3,4-triol were suspended in a mixture of 3.4 g (0.02 mmol) of 1-cyclohexenyloxytrimethylsilane and 40 ml of diethyl ether. Two drops of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for 30 minutes. The mixture was then evaporated to give 5.65 g of β(R) -benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless viscous oil; MS: m/e 292 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(C(=O)O)CC2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
128 mg of ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}piperidine-4-carboxylate (Example 83) was dissolved in 3 ml of ethanol, 0.28 ml of 12% sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for 6 hours. Ethanol was distilled off and then the obtained residue was diluted with water and the aqueous layer was washed with diethyl ether. The aqueous layer was neutralized with a 10% hydrochloric acid to pH 7 and subjected to extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with diethyl ether, and filtered and dried under reduced pressure to obtain 58 mg of the objective compound as white powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:39]([CH:40]=O)=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[C:30]([Cl:29])=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5ccccc5nc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chloroquinoline-3-carboxaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 554.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[F:13].[NH4+].[Cl-]>O1CCCC1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[F:13]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methylmagnesium bromide (22.5 mL, 31.5 mmol; 1.4 M solution in toluene/tetrahydrofuran) was added dropwise to a solution of 4-chloro-3-fluorobenzaldehyde (5.0 g, 31.5 mmol) in 100 mL of dry tetrahydrofuran at −78° C. over 15 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into saturated NH4Cl (100 mL). The aqueous layer was extracted with diethyl ether (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-(4-chloro-3-fluorophenyl)ethanol (5.50 g, 100%) as a yellow oil which was used in the next step without further purification, MS (ES) m/z 175 [M+H+].
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][CH:16]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[O:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:43]=[CH:42][C:30]([C:31]([O:33][CH2:34][CH2:35][CH2:36][CH:37]3[O:41][CH2:40][CH2:39][O:38]3)=[O:32])=[CH:29][CH:28]=2)[N:23]=1)=O)(C)(C)C>>[ClH:1].[NH2:15][CH:16]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[O:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH2:35][CH2:36][CH:37]3[O:38][CH2:39][CH2:40][O:41]3)=[O:32])=[CH:42][CH:43]=2)[N:23]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(C(=O)OCCCC4OCCO4)cc3)no2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(C(=O)OCCCC4OCCO4)cc3)no2)c1
Yield: 100 %

Procedure:
Hydrogen chloride in dioxan (4.0 M, 5 mL, 24 mmol) was added to 3-(1,3-dioxolan-2-yl)propyl 4-(5-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)-1,2,4-oxadiazol-3-yl)benzoate (0.237 g, 0.41 mmol), and the resultant solution was stirred at ambient temperature for 2 hours. The solvent was evaporated at reduced pressure to afford the title compound (0.212 g, 100%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]#[N:25])[CH:16]=[CH:15]4)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:16]=[CH:15]4)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)cs2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A mixture of {[6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetonitrile (204 mg, 0.596 mmol), prepared in the previous step, sodium azide (119 mg, 1.82 mmol) and ammonium chloride (98 mg, 1.82 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 5 h. The reaction was partitioned between 10% methanol-methylene chloride and 1 N HCl. The organic layer was separated, extracted three times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (87 mg, 37%) as a white solid, mp 226-228° C. Elemental Analysis for C21H15N5OS+0.23 H2O Calc'd: C, 64.74; H, 4.00; N, 17.98. Found: C, 63.46; H, 4.08; N, 16.95