Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.C(O)(=O)C.[I:21]I>O>[I:21][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: II
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(I)c(C)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 236.9 %

Procedure:
To 1,3-dimethyl-2-nitro-benzene (68.5 g, 453.2 mmol) is added sulfuric acid (27.2 mL, 510 mmol), acetic acid (543.8 mL, 9.49 mol), iodine (46 g, 181.3 mmol) and HIO4 (91.9 g, 403.3 mmol). The reaction is heated to 90° C. for 7 days. The reaction mixture is cooled to ambient temperature and water (500 mL) is added. The resulting solid is collected by filtration and washed with cold water. The solid is dried under reduced pressure at 45° C. overnight to afford the title compound as a yellow solid (119 g, 95%). 1H NMR (300.16 MHz, CDCl3): δ 7.80 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 2.37 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH3:3].C(N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:3]([NH:2][CH:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C=C1CCCC1=O
Product: O=C1CCCC1=CNCc1ccccc1
Yield: 73.5 %

Procedure:
Using 2-dimethylaminomethylenecyclopentanone (50 mmol) and benzylamine (50 mmol) and proceeding according to the abovementioned method C, 2-benzylaminomethylenecyclopentanone (7.4 g, efficiency: 70%) is produced in the form of a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)#[N:10]>C(O)(C)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:14][C:13]2[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CC(C)O
Product: N#Cc1cccc(C=Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
88 ml of para-fluoroaniline are added dropwise to 12 g of meta-cyanobenzaldehyde in 60 ml of isopropanol. After 1 h at 60° C., the product precipitates out. The mixture is allowed to warm to room temperature and filtered off, and the residue is washed with isopropanol. Drying gives 11 of m.p. 101° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.NN.[OH-].[K+]>C(O)COCCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)c2nccc3ccccc23)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCc1ccc(Cc2nccc3ccccc23)cc1
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 55.3 %

Procedure:
The compound of Example B3 (1.7 g, 6.0 mmol), hydrazine monohydrate (836 mg, 17 mmol), and potassium hydroxide (769 mg, 14 mmol) were added to diethylene glycol (8.5 ml), and this mixture was stirred at 80° C. for 1 hour, at 160° C. for 3.5 hours, then at 200° C. for 1 hour. The mixture was cooled to room temperature, ice water was added, and this was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (914 mg).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>O>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:15])([CH3:14])[C:4]([OH:16])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Cc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 3-(4-fluorophenyl)-2,2-dimethyl-propionic acid ethyl ester (10.0 g, 44.6 mmol) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated to reflux for 18 hours. The resulting solution was cooled to room temperature, then was stirred on ice and acidified to about pH 1 with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under vacuum. The solid was stirred in dichloromethane, and the mixture was filtered to remove a residual gelatinous solid. The filtrate was concentrated to provide a pale yellowish solid (7.60 g, 87%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.14 (m, 2H), 6.98 (t, J=8 Hz, 2H), 2.88 (s, 2H), 1.22 (s, 6H). Mass spec (ES−) m/z 195.2 (M−H−, 100%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[BrH:17]>C1CCCCC1>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCCCCCCCCCCCCCO
Reactant: Br
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCBr
Yield: 67 %

Procedure:
1,14-Tetradecandiol (1.5 g) was dissolved in 16.5 ml of cyclohexane, and 57% aqueous hydrobromic acid solution (16.5 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 14-bromotetradecan-1-ol as white crystals at a 67% yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[Cl:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1>>[Cl:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:16])=[CH:15][CH:14]=3)=[O:13])[CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 75.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(3,5-dichloropyridin-2-yl)piperazine (229 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (340 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][CH2:47][C:48]([NH:50][NH2:51])=[O:49]>O.CN(C)C=O>[CH3:45][O:46][CH2:47][C:48]([NH:50][NH:51][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:14])=[O:49]
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.40 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.28 g) at room temperature. The mixture was stirred for 10 min, and methoxyacetohydrazide (0.19 g) was added. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.29 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 148-149° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].[H-].[Na+]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:30][N:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)[CH2:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH3:29]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)c1ccc(-c2csc(NCCc3cccs3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCN(CCc1cccs1)c1nc(-c2ccc(C(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a THF solution of [4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amine (100 mg, 0.3 mmol) and ethyl bromopropionate (42 μL, 0.33 mmol) was added NaH (18 mg, 60%, 0.45 mmol). The mixture was stirred at room temperature for 30 min, and the excess NaH was quenched with brine and extracted into ethyl acetate (3×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate, concentrated and purified on silica gel column to afford 3-[[4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amino]-propionic acid ethyl ester (98 mg). LCMS m/z: 430 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([NH:6][C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH3:8])=[CH:10][CH:11]=1
Reactant: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: CC(NC(=O)C(C)(C)Cn1ccnc1)c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 6 h

Procedure:
A mixture of 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide (5.0 g) and imidazole (6.2 g) was heated at 125° C. with stirring for 6 hours. Excess imidazole was removed by azeotropic distillation with toluene under reduced pressure. The residue was dissolved in 5M hydrochloric acid and washed with dichloromethane. The acid layer was basified with 5M sodium hydroxide solution and extracted with dichloromethane. The combined extracts were washed with water, dried and evaporated to give N-[1-(4-chlorophenyl)ethyl]-3-(imidazol-1-yl)-2,2-dimethylpropionamide which was used directly in (c) below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:7]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.O>C1COCC1>[Cl:20][C:5]1[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:7][C:2]2[NH:1][C:27](=[O:28])[O:21][C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(O)cc2Cl)c1=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Reaction time: 1 h
Yield: 62.6 %

Procedure:
0.6 g (1.9 mmol) of 3-(5-amino-2-chloro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.35 g (2.2 mmol) of CDI were dissolved in 5 ml of THF, followed by stirring for 1 hour under heating and refluxing. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.41 g (yield: 63%) of the desired product. Melting point: 263-265° C. 1H-NMR (400 MHz, CDCl3) δ value: 3.78(3H,s), 6.84(1H,s), 6.85(1H,d), 7.28(1H,s), 7.46(1H,d)ppm.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[NH4+].[Cl-]>C(OCC)C>[CH3:16][CH:15]([CH3:17])[CH2:14][CH:13]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: CC(C)CC=O
Reactant: Ic1cnccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CC(O)c1cnccn1

Procedure:
To a solution of 2-iodopyrazine (10.0 g, 48.5 mmol) in diethyl ether at −50° C. was added dropwise n-BuLi (2.5 M in hexanes, 25 mL, 60.7 mmol), immediately followed by addition of isovaleraldehyde (8.13 mL, 6.48 g, 75 mmol) over 5 minutes. The mixture was allowed to reach room temperature and was added to a saturated NH4Cl solution. The aqueous phase was extracted with TBME (3×100 mL) and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting oil was filtered over a plug of silica to afford 3-methyl-1-(pyrazin-2-yl)butan-1-ol as a yellow-brownish oil (5.5 g; 68%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH3:3]>[Pd]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCOc1ccc(CCCCCCC(=O)O)cc1
Yield: 93.1 %

Procedure:
This compound was synthesized from 7-(p-propoxyphenyl)-6-heptenoic acid (1.31 g, 5 mmol) by a hydrogenation reaction using Pd/c(130 mg). Crystallization (petroleum ether) afforded the product (1.23 g, 93%) as white crystals (mp: 49-50° C.). IR: 3450-2550, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.37 (m, 4H), 1.60 (m, 4H), 1.79 (m, 2H), 2.36 (t, 2H), 2.53 (t, 2H), 3.87 (t, 2H), 6.95 (q, 4H), 9.80 (bs, 1H). Anal. Calcd. for C16H24O3 : C, 72.69, H, 9.15%; Found: C, 72.79, H, 9.16%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 0 °C

Procedure:
methanesulfonyl chloride (3.130 g, 2.115 mL, 27.32 mmol) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol) and Et3N (5.027 g, 6.924 mL, 49.68 mmol) in DCM (50 mL) cooled to 0° C. on an ice-bath. The reaction was allowed to warm to ambient temperature over 3 hours. The reaction mixture was washed with water and 1M HCl, dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate as a yellow oil (7.9 g, Quantitative yield—some residual solvent). 1H NMR (400.0 MHz, CDCL3) δ 1.49 (s, 9H), 1.60-1.57 (m, 1H), 2.04-1.79 (m, 3H), 3.08 (s, 3H), 3.38-3.32 (m, 1H), 3.50-3.43 (m, 1H), 3.70-3.60 (m, 2H) and 4.74 (br s, 1H) ppm;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25]
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Cc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 19.20 min.; purity: 94%; MS (m/e): 360 (M|); 1H NMR (CDCl3): δ 7.93 (1H, d, J=3.1 Hz), 7.54 (1H, d, J=2.6 Hz), 7.30 (1H, t, J=2.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.02 (3H, m), 6.78 (1H, s), 6.61 (1H, dd, J=7.9 Hz, J=2.1 Hz), 2.26 (3H, s).
Reaction SMILES: C(=N/[OH:9])\C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=O)[C:14]=1[C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[C:27]([OH:9])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20](=[O:22])[C:19]2([CH3:25])[CH3:26]
Reactant: CCOC(=O)C#Cc1c(Cl)cccc1C(C)(C)C(=O)OCC
Reactant: O/N=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of (E)-benzaldehyde oxime (234 mg, 1.93 mmol) in dry DMF (9 mL) was added to a suspension of NaH (46 mg, 1.93 mmol) in dioxane (9 mL) at room temperature. The mixture was stirred for 30 minutes and then cooled to 0° C. A solution of ethyl 3-(2-chloro-6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)phenyl)propiolate (520 mg, 1.61 mmol) in dry DMF (9 mL) was added, and the mixture was stirred at 0° C. for 3 hours and then at room temperature for 1 hour. The mixture was quenched with water and then washed with EtOAc (2×). The aqueous layer was made acidic with 10% HCl and then extracted with EtOAc (2×). The extracts were dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography to give 210 mg of ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate as a colorless oil. MS m/e=295 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:25](=[O:26])[CH2:24][Cl:23])=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(CCl)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution under N2 of 6-(4-fluorophenyl)indole (10.0 g, 47.4 mmol) in dioxane (36 mL) was added pyridine (5.80 mL, 71.8 mmol) and the solution was heated to 60° C. A solution of chloroacetyl chloride (5.66 mL, 71.1 mmol) in dioxane (12.5 mL) was added over one hour. The reaction mixture was stirred for one hour at 60° C., then was cooled to ambient temperature and partitioned between H2O and ether. The resulting orange precipitate was filtered off, recrystallized from ethanol, and rinsed with cold ether to give 6-(4-fluorophenyl)-3-chloroacetylindole (2.78 g, 20% as an orange solid.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH:27]=[CH2:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[OH:24][CH2:23][C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:26][CH:27]=[CH2:28]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
N-methylmorpholine (15.25 ml) and ethyl chloroformate (12.60 ml) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (25.0 g) in THF (250 ml) at −15° C. After stirring the mixture at −15° C. for 15 minutes, the generated insoluble matter was filtered off. A solution of sodium borohydride (3.23 g) in water (32 ml) was added to the filtrate at −15° C., and the mixture was stirred at −15° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added thereto to separate the organic layer. The organic layer was washed with a 0.5 N aqueous potassium hydrogensulfate solution, water, a 0.5 N aqueous sodium hydroxide solution, and a saturated sodium chloride solution; and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, oily substance (11.93 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(I)cnn1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-5-methyl-1H-pyrazole (870.0 mg, 2.069 mmol) in THF (20 mL, 200 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (6.367 mL, 8.278 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.696 mL, 10.35 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=0.12 (s, 6H), 0.97 (s, 9H), 1.33 (s, 9H), 1.60-1.75 (m, 4H), 1.83-1.92 (m, 2H), 2.32-2.40 (m, 2H), 2.47 (s, 3H), 4.07-4.21 (m, 2H), 7.58 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[N+:12]([O-])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].[H][H]>O.[Pd]>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(=O)O)ccc[n+]1[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ncccc1C(=O)O

Procedure:
Sixteen grams (88.4 mmol) of 2-acetylnicotinic acid N-oxide (J. Chem. Soc., 1961, 5216) is added to a solution of sodium hydroxide (3.5 g, 88.4 mmol) in 300 ml of water. The pH is adjusted to 9 by the addition of 6N NaOH, and 10% palladium on carbon (1.6 g) is added. The mixture is then hydrogenated until a 20% excess of hydrogen is taken up. The reaction mixture is filtered through Celite, and the pH of the filtrate is adjusted to 2.5 with 6N HCL. The solvent is removed by rotoevaporation and the residue is taken up in methanol. The mixture is filtered and the filtrate is evaporated to give a pale beige solid, 2-acetylnicotinic acid.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:19])[CH3:20])=[CH:11][CH:10]=1
Reactant: CC(C)NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)NC[C@H](O)COc1ccc(O)cc1
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
A solution of (S)-1-(4-benzyloxyphenoxy)-3-(1-methylethyl)amino-2-propanol (53.4 g) in 500 ml methanol was hydrogenated over 5 g 10% palladium on carbon (room temperature; 1 atmosphere). Within 40 minutes the uptake of nitrogen stopped abruptly after the absorption of 4,300 ml. The mixture was filtered through Celite and the filtrate was concentrated to dryness under reduced pressure. The resulting colorless solid residue was crystallized from acetone to give 35.2 g of (S)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol, mp 127°-129°; [α]D25 -20.67° (c, 1.0, 0.1N hydrochloric acid).