Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:10]3[CH2:11][CH:12]([CH2:14][NH:35][CH:36]4[CH2:38][CH2:37]4)[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CNC1CC1)O2
Temperature: 50 °C
Yield: 16 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added aminopropane (0.5 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (10 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1 H) 7.26-7.34 (m, 1 H) 7.01 (s, 1 H) 6.80-6.87 (m, 1 H) 4.98-5.07 (m, 1 H) 4.59-4.69 (m, 1 H) 3.81 (s, 3 H) 3.23 (dd, J=16.42, 9.35 Hz, 1 H) 2.93-3.05 (m, 2 H) 2.86 (dd, J=16.42, 7.07 Hz, 1 H) 2.20-2.27 (m, 1 H) 1.34 (dd, J=5.94, 1.14 Hz, 6 H) 0.36-0.54 (m, 4 H); LCMS for C20H26N4O3 m/z 371.20 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])([CH3:3])[CH3:2].[C:11]([Si](C)(C)C)#[N:12].C(N(CC)C(Cl)=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)#[N:12]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1cccc[n+]1[O-]
Agent: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
A mixture of 2-isopropylpyridine-N-oxide (104, 1.33 g, 9.7 mmol), cyanotrimethyl-silane (TMS-CN) (1.42 mL, 1.06 g, 11.0 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 5 min. Then, diethylcarbamoylchloride (Et2NCOCl, 1.23 mL, 9.7 mmol) was added and the mixture was stirred at room temperature under inert atmosphere. After 2 days, a aqueous solution of potassium carbonate (10%) was added and the stirring was continued for 10 min. The organic layer was separated, and the water layer was extracted twice with 1,2-dichloroethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (Hexanes/AcOEt, 3:1) to give 1.06 g (74%) of the title compound: m/z=147 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.OC1C=C(C=CC=1[C:32]([O:34][CH3:35])=[O:33])N.ClC1N=C(Cl)C(F)=CN=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:32]([O:34][CH3:35])=[O:33])=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(O)c3)n2)cc1O
Yield: 41 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis-[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (105 mg, 41%). 1H NMR (DMSO-d6): δ 3.90 (s, 3H), 3.93 (s, 3H), 7.31 (dd, J=2.4, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.7 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 8.28 (d, J=3.6 Hz, 1H), 9.72 (s, 1H, NH), 9.82 (s, 1H, NH), 10.77 (s, 1H, OH), 10.80 (s, 1H, OH); 19F NMR (282 MHz, DMSO-d6): δ −161.74; LCMS: ret. time: 31.47 min.; purity: 96.03%; MS (m/e): 428.99 (MH+).
Reaction SMILES: CO.C[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: CO
Product: O=Cc1ccc(O)cc1

Procedure:
The reactions are carried out in a manner similar to Examples 1 to 19. However, water is added but no methanol. The starting material and reaction product and the blanketing stream of nitrogen are passed downward over the fixed-bed catalyst by the co-current method. With the aid of this downward-flow procedure, it is also possible to convert liquid phases. At 200° C., for example, the water will be in the form of steam but p-methoxybenzaldehyde (boiling point 248° C.) will still be substantially in the form of a liquid. In this case too, the desired p-hydroxybenzaldehyde is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[OH:9])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(C)cc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cc2c(C)cc(C)cc2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3,5-dimethylphenol (12 g) were added lithium hydroxide monohydrate (4.2 g) and 4-methoxybenzyl chloride (14 mL) at 85° C., and the mixture was stirred 1.5 hours. The reaction mixture was cooled to ambient temperature and purified by column chromatography on silica gel (eluent: dichloromethane) to give 2-(4-methoxybenzyl)-3,5-dimethylphenol (5.1 g).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[C:20]([N:24]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)[CH2:25][CH2:26][CH3:27])[S:21][C:22]=1[CH3:23]>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[C:20]([N:24]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:32]=[CH:31]3)[CH2:25][CH2:26][CH3:27])[S:21][C:22]=1[CH3:23]
Reactant: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(ccn2CC(=O)OC)c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C

Procedure:
0.093 g of 55% sodium hydride in oil and then 0.95 ml of methyl bromoacetate are added, at 0° C., to 0.8 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(indol-5-yl)-N-propylamino]thiazole obtained above (EXAMPLE 7) in solution in 20 ml of dimethylformamide. After stirring for twelve hours at room temperature, the reaction mixture is poured into ice-water. The mixture is extracted with ethyl acetate and the organic phase is washed a number of times with water, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 9/1 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of a white solid (Y=95%); M.p.=80° C. 1H NMR (DMSO): 0.84 (t, 3H), 1.51-1.62 (m, 2H), 1.94 (s, 3H), 3.68 (s, 3H), 3.79 (s, 3H), 3.75-3.82 (m, 2H), 5.17 (s, 2H), 6.50 (d, 1H), 6.91-7.58 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[BH4-].[Na+].C(O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([OH:17])[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(=O)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2C(O)c3ccc(OC)cc3C3CCCCC32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (58.0 mg, 0.17 mmol), sodium borohydride (52.0 mg, 1.40 mmol), ethanol (3.0 mL), tetrahydrofuran (3.0 mL), stir, and reflux under a nitrogen atmosphere. After 2 hours, cool to ambient temperature, and concentrate in vacuo. Add ethyl acetate to reaction mixture, wash with sat ammonium chloride solution(aq), Brine, and dry over sodium sulfate. Concentrate to yield the titled compound (57.0 mg, 99%) as a white solid. TLC Rf=0.12 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.50 (d, 1H, J=8.8 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.4 Hz), 6.80 (dd, 1H, J=8.6, 2.4 Hz), 6.66 (m, 1H), 4.77 (d, 1H, J=9.7 Hz), 3.82 (m, 6H), 3.05 (m, 1H), 2.85 (m, 1H), 2.35 (m, 1H), 1.75 (m, 4H), 1.40 (m, 5H).
Reaction SMILES: Cl[S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([NH:18][S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 5-(chlorosulfonyl)-2-furoate (3.0 g) in DCM (100 mL) was added tert-butylamine (3.6 mL). After stirring at room temperature for 2 days the mixture was filtered through a pad of celite, washing with DCM (2×10 mL). The filtrate was evaporated to dryness in vacuo. The resulting crude residue was purified by column chromatography using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a foam. Yield: 2.75 g.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:36]#[C:37]Br>ClCCl.O>[C:37]([N:2]1[CH2:3][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:5]1)#[N:36]
Reactant: N#CBr
Reactant: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 45 °C

Procedure:
To a stirring mixture of N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (21) (200 mg, 0.487 mmol), potassium carbonate (202 mg, 1.46 mmol) and cyanogen bromide (103 mg, 0.974 mmol) in dichloromethane:water (1:1, 15 mL) were heated at 45° C. for 1.5 hours. The reaction was cooled to room temperature and the layers were separated. The aqueous layer was washed with 3 times with DCM and dried over anhydrous sodium sulfate. The combined organics were concentrated. The resulting solid was washed with hexanes to give N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82). MS m/z 400.14 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Cl:14])=[N:11][C:10]([C:15]([O:17]CC)=[O:16])=[N:9]2)=[C:4]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Cl:14])=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[C:4]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[CH:3]=1
Reactant: CCOC(=O)c1nc(CCl)n(-c2ccc(Br)cc2C(=O)c2ccccn2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc(CCl)n(-c2ccc(Br)cc2C(=O)c2ccccn2)n1

Procedure:
According to the same manner as in Preparative Example 5, ethyl 1-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate is hydrolyzed with sodium hydroxide to give 1-[4-bromo-2-(2-pyridinecarbonyl)-phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as crystals. Recrystallizations from ethanol gives colorless prisms, melting at 215° C to 217° C. (decomposition).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:18]=2)[N:9]=1.[CH3:35][C:36]([CH3:38])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:36]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:18]=2)[N:9]=1)([CH3:38])[CH3:35]
Reactant: c1ccc2c(CNc3cc(-c4cc5nccn5c(N5CC6CC5CN6)n4)ccn3)cccc2c1
Reactant: CC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(NCc3cccc4ccccc34)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 92 mg (0.2 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-Naphthalen-1-ylmethyl-amine in 5 mL chloroform was treated with 0.12 g (2.0 mmol) acetone, 41 mg (0.66 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][OH:18])[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1.[CH3:19][O:20][C:21](=[O:33])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27](O)=[C:26]([O:31][CH3:32])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:33])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([O:16][CH2:15][C:13]2[CH:12]=[C:11]([CH2:17][OH:18])[CH:10]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:14]=2)=[C:26]([O:31][CH3:32])[CH:25]=1
Reactant: OCc1cc(CO)cc(OCCCCCCCl)c1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCc2cc(CO)cc(OCCCCCCCl)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 47.5 %

Procedure:
2.7 g (10 mmol) [3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]phenyl] methanol (Example 6) were added to a solution of 2.6 g (12.5 mmol) (E)-4-hydroxy-3-methoxycinnamic acid methyl ester (Example 1) and 3.38 g (12.5 mmol) triphenylphosphine in 40 ml tetrahydrofuran. The colourless solution was cooled to 0° C. and then 5.2 ml (12.5 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise over a period of 2 hours. The mixture was allowed to react for 2 hours at 0° C. and then for 15 hours at room temperature. The reaction mixture was poured into an ice cold 1 M solution of HCl. The aqueous phase was extracted three times with a mixture of tert-butyl-methylether/ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated in vacuum. Purification of the residue by column chromatography on silica gel using hexane:ethyl acetate (1:1) as eluent yielded 2.2 g (48%) of (E)-3-[4-[3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]benzyloxy]-3-methoxyphenyl]acrylic acid methyl ester as an oily product that solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:21])[C:14]=1[CH2:15]OS(C)(=O)=O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([O:45][CH3:46])[CH:39]=3)[C:36]([SH:47])=[N:35][CH:34]=2)([CH3:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[Cl:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([O:45][CH3:46])[CH:39]=3)[C:36]([S:47][CH2:15][C:14]3[C:13]([F:21])=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[CH:3][C:2]=3[F:1])=[N:35][CH:34]=2)([CH3:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2S)ccc1F
Reactant: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)OC(C)(C)C)cc2F)ccc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (355 mg, 1.10 mmol) and 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazole-2-thiol (402 mg, 0.98 mmol)—prepared in a manner similar to that described for Example 3 from commercially available reagents—was suspended in acetone (4 mL) and treated with K2CO3 (223 mg, 1.6 mmol). The resulting white suspension was stirred at ambient temperature. The reaction mixture rapidly became a thick slurry, and acetone (5 mL) was added to facilitate stirring. After 75 min, the reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude product that was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 80:20) to afford the title compound (541 mg, 87% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.49-7.40 (m, 2H), 7.30-7.24 (m, 1H), 7.19 (s, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.87 (ddd, J=10.7, 9.5, 5.4 Hz, 2H), 6.28 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.85 (dd, J=7.5, 2.4 Hz, 1H), 4.20-4.07 (m, 2H), 3.46 (s, 3H), 1.57 (s, 9H), 1.54 (s, 3H), 1.46 (s, 3H); MS (EI) m/z 637 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][Br:11])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cc(CO)ccn1
Solvent: ClCCl
Product: CCc1cc(CBr)ccn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of 0.3 g of 2-ethyl-4-(hydroxymethyl)pyridine in 3.5 ml of dichloromethane is added dropwise to a solution of 1.25 g of dibromotriphenylphosphorane in 4 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The mixture is stirred to a temperature in the region of 20° C. over about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3×50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(9/1)(v/v), at a flow rate of 8 ml/minute. The fractions between 80 and 120 ml are concentrated under reduced pressure. 0.062 g of 2-ethyl-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1.O1CCOCC1.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1
Reactant: COC(=O)c1ccc(Cn2nccc2-c2ccc(OC)c(O[C@@H]3CCOC3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccnn2Cc2ccc(C(=O)O)cc2)cc1O[C@@H]1CCOC1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
Into a 1-neck round-bottom flask was added methyl 4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoate (330 mg, 0.808 mmol), 5 mL of 1,4-dioxane, 20 mL of water and 8 mL of 2 M aqueous sodium hydroxide. The reaction was heated at 90° C. for 1.5 hours, acidified with 1N HCl until pH˜3 and extracted with 3×20 mL CH2Cl2. The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoic acid (260 mg, 81%) as a brown solid. LCMS M+1=395.2
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Li]CCCC.[C:25]([N:32]1[C@@H:41]([CH2:42]O)[CH2:40][C:39]2[C:34](=[C:35]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:36]3=[C:37]3[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:38]3=2)[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[NH4+].[Cl-]>C1COCC1>[C:28]([O:27][C:25]([N:32]1[C@H:41]([CH:42]=[CH2:1])[CH2:40][C:39]2[C:34](=[C:35]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:36]3=[C:37]3[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:38]3=2)[CH2:33]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc2c3c(c4cc(OC)c(OC)cc4c2c1)C[C@H](CO)N(C(=O)OC(C)(C)C)C3
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@@H]1Cc2c(c3ccc(OC)cc3c3cc(OC)c(OC)cc23)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of Ph3P═CH2Br (1.43 g, 4 mmol) in THF was added n-BuLi (2M in heptanes, 1.95 mL) at 0° C. under N2. The mixture was stirred for 0.5 h before compound 8 (906 mg, 2 mmol) in THF (20 mL) was added dropwise. The mixture was then stirred for 2 h (monitored by TLC). Sat. NH4Cl was added to quench the reaction and THF was removed by evaporation. The residue was dissolved in CH2Cl2 (50 mL), washed with sat. NaHCO3 and brine, and dried over MgSO4. Column chromatography eluting with EtOAc/Hexane gave 9 (684 mg, 76%) as a light yellow foam: mp 177-179° C.; [α]23D=118.2 (c 0.56, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 5.86-5.75 (m, 1H), 5.29 (m, 1H), 5.26 (d, J=16.8 Hz, 1H), 5.16-5.04 (m, 2H), 4.59 (d, J=17.4 Hz, 1H), 4.11 (s, 3H), 4.06 (s, 3H), 4.01 (s, 3H), 3.36 (dd, J=16.2 Hz, J=6.0 Hz, 1H), 3.29 (t, J=16.5 Hz, 1H), 1.55 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 157.9, 155.3, 149.8, 148.8, 136.5, 130.4, 126.8, 124.4, 124.2, 123.9, 123.6, 123.1, 116.6, 115.2, 105.1, 104.3, 104.1, 80.3, 77.4, 56.3, 56.1, 55.7, 41.1, 29.8, 28.7 (3×C); ESI-HRMS ([M+Na]+) calcd for C27H31NO5Na 472.2100. found 472.2103.
Reaction SMILES: CC([O-])(C)C.[K+].CC(S)C.[CH3:11][CH:12]([S:14][C:15]1[C:16](C(O)=O)=[N:17][C:18]([S:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=1)[CH3:13]>CN(C=O)C>[CH3:24][CH:22]([S:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][CH:12]([CH3:13])[CH3:11])=[CH:16][N:17]=1)[CH3:23]
Reactant: CC(C)Sc1ccc(SC(C)C)c(C(=O)O)n1
Agent: CC(C)(C)[O-]
Agent: CC(C)S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(SC(C)C)nc1
Temperature: 50 °C

Procedure:
To 198 g of t-BuOK dissolved in 300 ml of DMF was added 2-propanethiol (163.47 ml) dropwise with an ice bath employed to keep the temperature below 50° C. As salt began to precipitate out an additional 50 ml of DMF was added. After addition was complete, the ice bath was removed and the mixture heated to 50° C. A solution of 100 g of methyl 3,6-dichloro-2-pyridinecarboxylate dissolved in DMF was added and the temperature during addition rose to 115° C. The temperature was then maintained at approximately 105°-110° C. until addition was completed and then the resulting mixture was heated at 100°-110° C. for 11/2 hrs. The reaction mixture was allowed to cool and the solvent removed in a rotary evaporator. The brown residue which remained was washed with ether and then dissolved in water. The solution was acidified with HCl, and the product, which oiled out, extracted with CH2Cl2. The CH2Cl2 was then removed using a rotary evaporator. Infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid had formed. The 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid was decarboxylated employing a Kugelrohr distillation apparatus, and 2,5-bis((1-methylethyl)thio)pyridine obtained, b.p. 310° C. (760 mm Hg).