Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccncc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran and under an atmosphere of nitrogen was cooled to -30° C. in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.30 mole) was added over 1 hr and the mixture was stirred for an additional 30 min at -30° C. The reaction mixture was allowed to warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of 4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid was collected. The aqueous mixture was extracted with several portions of methylene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (67.9% yield) of title compound as a white, crystalline solid: mp 158°-159.5° C.
Reaction SMILES: [Si](OCC[C:11]1[CH:27]=[N:26][C:14]2[S:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[N:18]([CH2:19][O:20][CH3:21])[C:13]=2[N:12]=1)(C(C)(C)C)(C)C.[O:28]1CC[CH2:30][CH2:29]1>>[CH3:21][O:20][CH2:19][N:18]1[C:17]2[CH:22]=[C:23]([CH2:30][CH2:29][OH:28])[CH:24]=[CH:25][C:16]=2[S:15][C:14]2[N:26]=[CH:27][CH:11]=[N:12][C:13]1=2
Reactant: COCN1c2ccccc2Sc2ncc(CCO[Si](C)(C)C(C)(C)C)nc21
Reactant: C1CCOC1
Product: COCN1c2cc(CCO)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
463 mg of 8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 5 ml of tetrahydrofuran. After adding 1.3 ml of n-tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran), the resulting mixture was stirred at room temperature for 1 hour and then at 4° C. for additional 13 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 281 mg of the title compound as a pale orange solid.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>C1COCC1.[Cl-].[Na+].O>[C:10]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of BOC-Leu-OH (15.09 g, 65 mmol, 1 equiv) in THF (150 mL) at 0° C. was added BH3. THF (163 mL of a 1.0 M solution in THF, 163 mmol, 2.51 equiv). The reaction mixture was stirred at 23° C. for 3 h and then cooled to 0° C. Brine (100 mL) was added carefully, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (gradient elution, 25-35% EtOAc in hexanes) to afford BOC-L-Leucinol as a colorless oil (12.59 g, 89%): IR (cm−1): 3434, 1699, 1256, 739; 1H NMR (CDCl3) δ 0.93 (dd, 6H, J=6.6, 1.5), 1.29-1.31 (m, 2H), 1.45 (s, 9H), 1.60-2.05 (m, 2H), 3.47-3.53 (m, 1H), 3.65-3.72 (m, 2H), 4.56 (s, br, 1H); Anal. (C11H23NO3) C, H, N.
Reaction SMILES: CI.[CH3:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]2([CH3:7])[C@H:5]1[C:24]([O-:26])=[O:25])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[CH:27](N(C(C)C)CC)(C)C.[I-]>C(#N)C>[CH3:27][O:25][C:24]([C@H:5]1[C@H:4]([CH3:3])[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]12[CH3:7])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)=[O:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)[O-]
Agent: [I-]
Solvent: CI
Solvent: CC#N
Product: COC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 2 h

Procedure:
Methyl iodide (7.9 ml) is added to a solution of 16α-methylandrosta-4,9(11)-dien-3-one 17β-carboxylate (7.9 g) and diisopropylethylamine (17.5 ml) in acetonitrile (175 ml). The mixture is allowed to stand at 20°-25° for 2 hr and then a second addition of amine (9 ml) and iodide (4 ml) is made. The mixture is allowed to stand overnight at 20°-25° and then concentrated under reduced pressure. The residue is partitioned (water and methylene chloride) and the extract is concentrated and chromatographed on silica gel (750 g). Elution is performed with acetone/methylene chloride (2-5%/98-95%). The appropriate fractions are pooled and concentrated to give the title compound, m.p. 127.5° (acetone-hexane)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[N:16][CH:17]=2)[N:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[N:36]=1)[CH:9]=[CH2:10]>N1C=CC=CC=1>[CH2:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[N:16][CH:17]=2)[N:12]1[C:35]1[N:36]=[C:37]([NH:41][C:5](=[O:7])[CH3:6])[CH:38]=[CH:39][CH:40]=1)[CH:9]=[CH2:10]
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(NC(C)=O)n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
0.2 mL of acetic anhydride was added to pyridine (2 mL) solution of 50 mg of 2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 50, and stirred at 50° C. for 6 hours. After this was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution was added thereto, extracted with chloroform, and the organic layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through preparative basic thin-layer chromatography (chloroform/methanol=40/1) to obtain 47 mg of the entitled compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: c1nc[nH]n1
Product: Nc1ccc(-n2cncn2)c(C(F)(F)F)c1

Procedure:
The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and 1,2,4-triazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 229 (M+H)+; analytical HPLC: tret=4.14 minutes (Grad 2).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[OH-].[Na+].S(Cl)(Cl)=O.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(O)C.O.CCOCC.C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: NCc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(OCC)C(=O)NCc1ccccc1Br
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To a solution of ethyl diethoxyacetate (20.0 g, 114 mmol) in ethanol (50 ml) was added a solution of sodium hydroxide (4.56 g, 114 mmol) in water (25 ml), and the resulting mixture heated at reflux for 5 hours. The mixture was evaporated to dryness, and the residue dried in vacuo. The resulting solid (22.75 g, 0.13 mol) was dissolved in dry ether (88 ml) and to this mixture was added thionyl chloride (13.3 g, 0.11 mol) with stirring for 10 minutes at 10° C. The reaction mixture was heated at reflux for 30 minutes and then allowed to cool. A solution of 2-bromobenzylamine (20.73 g, 0.11 mol) in toluene (57 ml) and pyridine (34 ml) was poured into this reaction mixture with vigorous stirring. This was heated at reflux for 30 minutes and then allowed to cool. The mixture was poured into ice water and extracted with toluene (×3). The organic extracts were combined and washed firstly with 2% HCl and then water. The solvent was evaporated and the residue purified by flash chromatography on silica gel (9:1 hexane:ethyl acetate) to give the title compound (15.6 g, 44%).
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClN1C(=O)CCC1=O.[C:13]([C:15]1[CH:21]2[CH2:22][CH:18]([CH2:19][N:20]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH:16]=1)#[CH:14].C(N(CC)CC)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:2][C:1]1[CH:14]=[C:13]([C:15]2[CH:21]3[CH2:22][CH:18]([CH2:19][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH:16]=2)[O:4][N:3]=1
Reactant: CC=NO
Reactant: C#CC1=CCC2CC1N(C(=O)OC(C)(C)C)C2
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2=CCC3CC2N(C(=O)OC(C)(C)C)C3)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of acetaldoxime (65 mg, 1.1 mmol) in 15 mL of chloroform were added 2 drops of pyridine, followed by N-chlorosuccinimide (146 mg, 1.1 mmol). After stirring the cloudy mixture for 1 h at ambient temperature, tert-butyl 4-ethynyl-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (233 mg, 1.00 mmol) was added in 2 mL of chloroform, followed by drop-wise addition of triethylamine (0.175 mL, 1.25 mmol). The mixture was stirred at ambient temperature for 4 h and then concentrated to dryness under reduced pressure. The residue was chromatographed on a silica gel column, with a gradient of 2:1 hexane/ethyl acetate to 2:1 ethyl acetate/hexane, to give first recovered starting material, then tert-butyl 4-(3-methyl-5-isoxazolyl)-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (100 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22][NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO)C3CC3)C2=O)CC1
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CNS(=O)(=O)C3CC3)C3CC3)C2=O)CC1

Procedure:
The tile compound was prepared from methyl 1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate (35 mg, 0.068 mmol; Example 270, Step D) and cyclopropanesulfonamide (25 mg, 0.20 mmol) by a procedure similar to the one described in Example 202, Step C. Purification of the residue by chromatography on silica gel (4 g SiO2, 45% and 60% EtOAc/Hex) provided the title compound as a pale yellow.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](O)=[O:15].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[C:13]2[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(O)c1c(F)ccc(F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Br)cc1)c1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Bromophenyl)methanamine hydrochloride (0.5 g, 2.25 mmol), 2-chloro-3,6-difluorobenzoic acid (0.52 g, 2.7 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetra methyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 2.7 mmol), and N,N-diisopropyl-ethylamine (1.17 mL, 6.75 mmol) were combined in DMF (6 mL) and then stirred at room temperature for 1 h. The reaction mixture was diluted in ethyl acetate and washed once with water and twice with an aqueous saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product was suspended in hot acetonitrile and then filtered to have the pure compound N-(4-bromobenzyl)-2-chloro-3,6-difluorobenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1cc(O)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) in N,N-dimethylformamide (70 mL) was added sodium hydride (60%, oil, 1.40 g) at 0° C. and, after stirring the mixture for 15 min., 4-chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added. After stirring the mixture at 60° C. for 2 hrs., the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96 g, yield 72%) as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 123-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:36])([F:35])[C:19]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[N:20]=1.Cl.C1COCC1>C(OCC)(=O)C>[F:36][C:18]([F:17])([F:35])[C:19]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]([C:28]2[CH:29]=[CH:30][C:31]([NH:32][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])=[CH:33][CH:34]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg), 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (206 mg), WSCD hydrochloride (172 mg) and THF (3 ml) was stirred overnight at room temperature. After adding ethyl acetate, the reaction solution was washed as th water, saturated sodium bicarbonate aqueous solution, 1 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromtaography (eluent; n-hexane:ethyl acetate=7:1-5:1) to give tert-butyl 4-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenylaminocarbonyl]piperidine-1-carboxylate (279 mg) as a colorless amorphous solid. 4 N Hydrochloric acid ethyl acetate solution (2.60 ml) was added to a mixture of this solid (263 mg) and ethyl acetate (2.6 ml), followed by stirring at room temperature for 2 hours and 45 minutes. The reaction solution was concentrated under a reduced pressure, diethyl ether was added to the thus obtained residue, and the mixture was concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, [4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-4-carboxyanilide hydrochloride (201 mg) was obtained as colorless powder crystals.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1
Agent: [Pd]
Product: COc1cccc(-c2cccc3c2OC(CN)C3)c1
Yield: 80 %

Procedure:
Treatment of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with sodium azide (0.309 g, 4.48 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.030 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.25 g (80%) of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 152-154° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.21; H, 6.17; N, 4.46.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][C:22](C)([O-])[CH3:23].[K+].C(I)C=C.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH:1]1([CH:7]([CH2:23][CH:22]=[CH2:21])[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[O:17][CH2:18][CH2:19][O:20]3)=[CH:14][CH:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(CC1CCCCC1)c1ccc(C2OCCO2)cc1
Agent: C=CCI
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)c1ccc(C2OCCO2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
The product of Example J (1.6 g, 0.006 mole) was dissolved in 30 mls of dry DMF at room temperature under a nitrogen atmosphere and potassium t-butoxide (1.4 g) was added. After stirring for 5 minutes, 1 g of allyl iodide was added and the reaction was warmed to +50° C. for 1 hour. Another half equivalent of allyl iodide was added and the stirring was continued for 2 hours at +50° C. After cooling to room temperature the mixture was poured into 50 mls of 0.5N KHSO4 and extracted with ethyl acetate. After drying the organic layer over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel using 10% ethyl acetate/hexane to give 1 g of the title compound (54% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]#[N:9])[CH3:6]>CCO.[Ni]>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[CH2:7][CH2:8][NH2:9]
Reactant: COCCN(C)CC#N
Agent: [Ni]
Solvent: CCO
Product: COCCN(C)CCN
Reaction time: 5 h
Yield: 79.2 %

Procedure:
A mixture of nitrile 267 (3.06 g, 23.4 mmol) and Raney-Nickel (50% slurry in water, 15 g) in EtOH (100 mL) and cNH3 (10 mL) was stirred vigorously under H2 (60 psi) for 5 h. The mixture was filtered through Celite, washed with EtOH (60 mL) and the solvent evaporated, keeping the bath temperature below 35° C. to give crude diamine 268 (Pasini, C.; et al., Farmaco, Edizione Scientifica 1965, 20, 673-685) (2.45 g, 79%) as a colourless oil, which was used without further purification: 1H NMR [(CD3)2SO] δ 3.39 (t, J=6.0 Hz, 2H, CH2O), 3.22 (s, 3H, OCH3), 2.61 (br s, 2H, CH2N), 2.49 (t, J=6.0 Hz, 2H, CH2N), 2.36 (t, J=6.7 Hz, 2H, CH2N), 2.17 (s, 3H, NCH3), NH2 not observed; 13C NMR δ 59.4, 57.9, 56.3, 42.4, 38.6, 20.2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:17])[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH3:17])[CH:10]=[C:11]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:19]=1[F:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of triethylamine (107 mL, 771 mmol) and ethyl 3-(dimethylamino)acrylate (55.2 mL, 386 mmol) in toluene (250 mL) was added dropwise a toluene solution of 2,4,5-trifluorobenzoyl chloride (50 g, 257 mmol). The mixture was stirred at 90° C. for 3 h. LCMS showed completion of reaction. After cooling down, the reaction mixture was washed with water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (65 g, 216 mmol, 84% yield) as a brown oil. LCMS: (M+H)+: 302.1.
Reaction SMILES: C(OC([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(OCC)C)C.[Li]CCCC.[Br:19][C:20]1[CH:33]=[C:32]2[C:23]([O:24][C:25]3[C:26]([F:37])=[CH:27][C:28]([O:35][CH3:36])=[CH:29][C:30]=3[C:31]2=[O:34])=[CH:22][CH:21]=1>C(OCC)C>[Br:19][C:20]1[CH:33]=[C:32]2[C:23]([O:24][C:25]3[C:26]([F:37])=[CH:27][C:28]([O:35][CH3:36])=[CH:29][C:30]=3[C:31]2([C:10]2[NH:9][CH:13]=[CH:12][N:11]=2)[OH:34])=[CH:22][CH:21]=1
Reactant: CCOC(C)(OCC)n1ccnc1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(F)c2c(c1)C(O)(c1ncc[nH]1)c1cc(Br)ccc1O2
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
1-(1,1-Diethoxyethyl)-1H-imidazole (7 g, 38.0 mmol) was dissolved in diethyl ether (100 ml) and cooled to −40° C. and n-BuLi (1.6M in hexane) (23.75 ml, 38.0 mmol) was added. The solution was stirred for 10 minutes and 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (Example 5, 6.14 g, 19.00 mmol) was added in one portion. The solution was stirred one hour at −40° C., then allowed to warm to RT for 15 minutes. The solution was quenched with 2 N HCl until at pH 1, stirred for 15 minutes, then made basic with concentrated sodium carbonate and stirred for 15 minutes. The product was collected by filtration. The filtrate was also extracted with EtOAc, the extracts were concentrated and combined with the material collected by filtration. The product was loaded onto silica and purified via silica gel column chromatography (RediSep 80 g column) using 10-50% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford 7-bromo-4-fluoro-9-(1H-imidazol-2-yl)-2-methoxy-9H-xanthen-9-ol (3.4 g, 8.69 mmol) as an off white solid.