Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al].II.[CH2:4](Br)[C:5]#[CH:6].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:30])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1.[Cl-].[NH4+]>O1CCCC1.[Hg]Cl>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[C:23]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1)[CH2:6][C:5]#[CH:4]
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: C#CCBr
Agent: Cl[Hg]
Agent: II
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
1.05 g (39 mmol) of aluminum flakes, a spatula tipful of mercury chloride and an iodine crystal are warmed at 40° C. for one hour in 5 ml of absolute tetrahydrofuran under a nitrogen atmosphere. The mixture is heated to 60° C. and 6.9 g (58 mmol) of propargyl bromide in 10 ml of absolute tetrahydrofuran are added dropwise. The mixture is subsequently stirred at 60° C. for 60 minutes and then cooled to -60° C. A solution of 10 g (29 mmol) of 1-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-2-(1,2,4-triazol-1-yl)-ethan-1-one in 20 ml of absolute tetrahydrofuran is then added dropwise and the mixture is subsequently allowed to react first for 1 hour at 0° C. and then for 2 hours at room temperature. 20 ml of a saturated aqueous ammonium chloride solution are added, the precipitate obtained is filtered off with suction, and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, and the resulting solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. In this manner, 8.8 g (80% of theory) of 4-(2-chloro-4-(4-chlorophenoxy)-phenyl)-5-(1,2,4-triazol-1-yl)-pent-1-yn-4-ol are obtained in the form of a solid of melting point 124° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:17]#[N:18])[CH2:13][CH2:12]1)(C)(C)C.[OH:27]S(O)(=O)=O>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:17]([NH2:18])=[O:27])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(Cl)cc2)CC1
Reactant: O=S(=O)(O)O
Product: NCCCN1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1
Yield: 79 %

Procedure:
(+)-3-(3-(4-Aminocarbonyl-4-(4-chloro)phenylpiperidin-1-yl)-propyl)aminocarbonyl-4-(3,4-difluoro)phenyl-2-oxazolidinone: 3-(4-(4-chlorophenyl)-4-cyanopiperidin-1-yl)propylcarbamic acid tert-butyl ester (0.150 g, 5.39 mmol) in conc. H2SO4 (1 mL) was stirred at room temperature for 30 hours. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.185 g (79%) of 1-(3-aminopropyl)-4-(4-chlorophenyl)piperidine-4-carboxamide which was used as such for the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2
Yield: 94 %

Procedure:
10-Bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 181 mg (94% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1ccc(C2(O)CCCCC2)cn1Cc1ccccc1
Yield: 109.9 %

Procedure:
A mixture of 5-(1-hydroxycyclohexyl)-2-methoxy pyridine (26.3 g), benzyl bromide (21.7 g) and potassium carbonate (35 g) was heated in 500 mL of refluxing acetonitrile for 17 hours. The mixture was cooled and filtered, and the solids were washed with methanol. The filtrate was concentrated to give 39.5 g of an oil. HPLC on silica gel (elution with ethyl acetate) afforded 20.8 g of solid.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:17]3[CH:18]=[CH:5][C:4]4[C:16](=[CH:17][CH:18]=[CH:2][CH:3]=4)[CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: C1CCOC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(-c2nc(-c3ccc4ccccc4c3)c[nH]2)cc1
Temperature: 20 °C

Procedure:
A suspension consisting of 31.3 g (0.20 mol) of benzamidine hydrochloride, 10.8 g (0.20 mol) of sodium methylate, and 150 mL of tetrahydrofuran was heated under reflux for one hour. After cooling to 20° C., a solution consisting of 49.8 g (0.2 mol) of ω-bromo-2-acetonaphthone and 100 mL of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 30° C. After completion of addition, 10.8 g (0.20 mol) of sodium methylate was added, and the mixture was heated under reflux for one hour. Next, the reaction mixture was cooled to room temperature, insoluble matters were filtered off, and the filtrate was evaporated to dryness in vacuo. The residual solid was successively washed with water and toluene and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from acetonitrile to obtain 32.8 g (yield: 60.7%) of a colorless crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8](Cl)=[O:9])#[N:2].O=S(Cl)Cl.[K+].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19]C([O-])=O.[Mg+2].[Cl-].[Cl-]>C1(C)C=CC=CC=1.CC#N.CCN(CC)CC.CN(C=O)C>[CH2:25]([O:24][C:18](=[O:23])[CH2:19][C:8]([C:7]1[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[F:12])=[O:9])[CH3:26]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: N#Cc1ccc(F)c(C(=O)Cl)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(C#N)ccc1F

Procedure:
Prepared from 5-cyano-2-fluoro-benzoyl chloride [prepared from the corresponding acid [CAS-No. 146328-87-21 by treatment with SOCl2, cat. DMF in toluene at 80° C.] by reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a light yellow solid (3.85 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[N:14][CH:13]=1)[C:5]([NH2:7])=[O:6].Cl.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH2:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:34][CH:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25]2)=[N:14][CH:13]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC1Cc2ccccc2C1
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)c(F)c1
Agent: Cl
Product: NC(=O)c1ccc(Oc2cnc(CNC3Cc4ccccc4C3)c3ccccc23)c(F)c1

Procedure:
Using the procedure outlined in Example 100, 3-fluoro-4-(1-formylisoquinolin-4-yloxy)benzamide (Preparation 42) and indan-2-ylamine hydrochloride were converted to the title compound: RT=2.87 min; m/z (ES+)=428.1 [M+H]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:13]1[CH:12]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a suspension of N-iodosuccinimide (11.10 g, 49.5 mmol) in glacial acetic acid (40 ml) was added 4-trifluoromethyl phenol (8.02 g, 49.5 mmol) and, after 5 minutes, concentrated sulphuric acid (0.87 ml, 14.8 mmol). The pale brown/red suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. The organic extract was washed with water, saturated aqueous sodium thiosulphate solution, water, dried over magnesium sulphate before decolourising charcoal added. The suspension was left to stand for 10 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was evaporated in vacuo to give an oil which was purified by flash column chromatography on silica eluting with dichloromethane to give the title compound as a pale yellow oil, 9.017 g, 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[O-:21][Mn](=O)(=O)=O.[K+].OO>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:21])=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:18])[F:19])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C=O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (1.5 g, 5.3 mmol) in acetone (150 mL) was added a 0.3 M solution of KMnO4 (150 mL). The reaction mixture was stirred 3 h at room temperature and then was charged with 10% H2O2 (5 mL). After 15 minutes the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous suspension was acidified with acetic acid. The precipitates were recovered by filtration and dried under high vacuum to afford 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.99 g, 62%) as a faintly yellow powder; 1H NMR (CDCl3): δ 7.56 (dd, J=8, 3 Hz, 1H), 7.41 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 1.90 (s, 3H); MS (ESI) m/z 302 [M+H]+. To a suspension of 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.65 g, 2.16 mmol) in anhyd toluene (5.0 mL) cooled to 0-3° C. were added thionyl chloride (0.25 mL) and DMF (20 μL). The reaction mixture was allowed to warm to room temperature where it remained for 3 h and then was concentrated in vacuo. The residue was evaporated twice from 5 mL of toluene to remove thionyl chloride and then was triturated in 3 mL of hexanes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound (0.44 g, 64%) as a pale brown solid; 1H NMR (CDCl3): δ 7.59 (dd, J=8, 3 Hz, 1H), 7.44 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.51 (s, 1H), 2.17 (s, 3H), 1.89 (s, 3H); MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[CH:1]1([C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)[CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC[C@@H](c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 2-(R)-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid (290 mg, 0.8 mmol), prepared as in step 4, and triethylamine (0.14 ml, 1.0 ml) in THF (35 ml) at -25° C. was added dropwise ethyl chloroformate (0.1 ml, 1.0 mmol). Upon completion of addition, the mixture was stirred for 15 min. and warmed to 0° C. Sodium borohydride (150 mg, 4.0 mmol) was added followed by very slow addition of methanol (15 ml). The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, hexane-ethyl acetate 2:1) to afford 180 mg of 2-(R)-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)ethan-1-ol.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[Cl:16])=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1

Procedure:
2-Chloro-N-(2-chloro-4-sulphamoylphenyl)-acetamide (28.3g 0.1 mole) and aniline (18.6g, 0.2 mole) were heated together for 30 min. on a water bath (90°). The mixture was worked up as in Example 1(b) to yield 20.8 g m.p. 185°-186°
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[NH:26][C:27]([SH:30])=[N:28][CH:29]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:27]3[NH:28][CH:29]=[N:25][N:26]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ncn[nH]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 30.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (129 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2H-[1,2,4]triazole-3-thiol (202 mg, 2 mmol) following the general procedure Y
Reaction SMILES: [Li+].[Cl-].C([O:5][C:6]([C@H:8]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][C:11](=O)[N:10]([CH3:22])[C:9]1=O)=O)C.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[CH2:12][CH2:11][N:10]([CH3:22])[CH2:9][C@H:8]2[CH2:6][OH:5])=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled mixture of NaAlH4 (0.22 mol) in toluene is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH4 or after the addition of the substrate, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione. Next, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=2)[CH2:3][CH2:2]1
Reactant: OCc1csc(NC2CC2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(NC2CC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.1 g of 2-cyclopropylaminothiazol-4-ylmethanol, 3.1 g of sulfur trioxide pyridine complex, 2 g of triethylamine and 15 ml of dimethyl sulfoxide, giving the title compound as pale yellow prisms.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[Mg].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[OH:20][C:14]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C3OCCO3)cc2)CCCCC1
Temperature: 30 °C

Procedure:
A solution of 22.9 g of 2-(p-bromophenyl)-1,3-dioxolan in 100 ml of tetrahydrofuran is added dropwise, at 60° C, to a well stirred suspension of 2.65 g of magnesium chips, which have been washed with chloroform and activated with iodine, in 100 ml of absolute tetrahydrofuran. The dropwise addition is carried out in such a manner that after the onset of the reaction, the temperature does not rise above 60° C. At the conclusion, the reaction mixture is heated for one hour, then cooled to 30° C and, while stirring, 11 g of cyclohexanone are added dropwise. After being heated for 1 hour to 50° C, the reaction mixture is evaporated in vacuo in a rotary evaporator and the residue mixed with ice and a saturated ammonium chloride solution. Extraction with ether is effected, and the ethereal extracts are dried over sodium sulphate and evaporated. The residue is distilled under a high vacuum and yields the 2-[p-(1-hydroxy-cyclohexyl)-phenyl]-1,3-dioxolan having a boiling point of 160°-170° C (0.05 mm Hg), which becomes solid on standing and melts at 95°-97° C after recrystallization from ether + petroleum ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2O)[S:9][CH:10]=1)[CH3:2].[OH:19]C1C=C(C(=S)N)C=CC=1.ClCC(=O)CC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: NC(=S)c1cccc(O)c1
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Agent: CCOC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2cccc(O)c2)n1
Yield: 78 %

Procedure:
The procedure used for the preparation of 4a was repeated with 3-hydroxybenzenecarbothioamide 3d (1.53 g, 10.0 mmol) and ethyl 4-chloroacetoacetate (1.65 g, 10.0 mmol) in dry THF (20 mL) to give 4d (2.04 g, 78%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/hexane: 30-40%) and recrystallization from EtOAc/hexane. mp 95.5°-97.2° C.; IR (KBr) 3112, 1727, 1278 cm-1 ; 1H NMR (DMSO-d6) δ 1.15 (3H, t, J=7.0 Hz, CH3), 3.81 (2H, s, CH2), 4.07 (2H, q, J=7.0 Hz, CH2), 6.81 (1H, d, J=7.3 Hz, Ar), 7.22-7.30 (3H, m, Ar), 7.46 (1H, s), 9.68 (1H, s, OH); FDMS m/z 263 (M+); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.41; H, 4.91; N, 5.30.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:15]([NH:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)CN
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCC(CC)CCCC
Temperature: 0 °C

Procedure:
128.98 Grams (1 mole) of 2-ethyl-1-hexylamine and 500 ml of toluene were charged to a flask equipped with dropping funnel, thermometer, condenser, stirrer, Dean & Stark trap and condenser. The contents of the flask were refluxed for 3 hours to remove water, then cooled to 0° C. 99.6 Grams (1 mole) of butyl isocyanate were charged to the dropping funnel and added during 1 hr. 5 min. to the stirred flask contents. The flask contents remained at 30° C. or less during the addition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[CH:14][N:13]=1>O1CCOCC1.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Fc1cc(F)c2c(Cl)ncnc2c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cc(F)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 71.4 %

Procedure:
3-Chloro-4-fluoroaniline (12 g) and 1N HCl in dioxane (40 ml) were added sequentially, each in one portion, to a mixture of 4-chloro-5,7-difluoroquinazoline (16.5 g) in IPA (250 ml) and the mixture was stirred at 80° C. under a nitrogen atmosphere for 17 hours. The reaction mixture was cooled to 0° C. and the precipitated solid was filtered and dried to leave N-(3-chloro-4-fluorophenyl)-5,7-difluoroquinazolin-4-amine as a green solid (18.2 g, 71%); Mass spectrum MH+ 310.
Reaction SMILES: NC1C=CC(OC)=C2C=1C(=O)N(C)C2.[CH3:15][N:16]1[CH2:24][C:23]2[C:18](=[C:19]([N+:29]([O-])=O)[CH:20]=[CH:21][C:22]=2[O:25][CH:26]([CH3:28])[CH3:27])[C:17]1=[O:32]>>[NH2:29][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:23]2[C:18]=1[C:17](=[O:32])[N:16]([CH3:15])[CH2:24]2
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Agent: COc1ccc(N)c2c1CN(C)C2=O
Product: CC(C)Oc1ccc(N)c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A) using 2-Methyl-7-nitro-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207B). MS (ES+): m/z 222.21 (100) [MH+]; HPLC: tR=0.93 min (UPLC, analytical).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].N[C:22](N)=[O:23].C>C1(C)C=CC=CC=1>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[NH:20][C:22]2=[O:23])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 24.7 g of 1-carbethoxy-4-(2-amino-4-chloroanilino)-piperidine and 7.2 g of urea was heated to 160°-180° C. for 3.5 hours. The melt was taken up in 250 ml of toluene and heated, while stirring, until everything had dissolved. The solution was clarified with active charcoal, filtered and concentrated to 50 ml. The product was precipitated with diisopropyl ether. Melting point: 160° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:19]([C:20]#[N:21])=[CH:18][C:6]([C:7]([N:9](C)[C:10](=O)OC(C)(C)C)=[O:8])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:10][NH:9][C:7](=[O:8])[C:6]1[CH:18]=[C:19]([C:20]#[N:21])[C:3]([CH2:2][Br:1])=[CH:4][C:5]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
After dissolving tert-butyl N-[4-(bromomethyl)-5-cyano-2-ethoxybenzoyl]-N-methylcarbamate (39.9 g) in dichloromethane (300 ml), trifluoroacetic acid (50 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (19.77 g) as a white solid.