Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]([C:37](OC)=[O:38])=[CH:31]1.Cl>C1COCC1>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:37]([C:32]1[CH:33]=[CH:34][C:35](=[O:36])[N:30]([C:24]2[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[CH:31]=1)=[O:38]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: COC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(NC(=O)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of 3-amino-4-chlorobenzoic acid (3.99 g) in THF (35 mL) was added dropwise an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (46.5 mL) while keeping the internal temperature below −5° C. under a nitrogen atmosphere, and the mixture was stirred for 15 min around −10° C. Powder of methyl 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (3.46 g) was added to the mixture at once, and the resulted mixture was stirred at the same temperature for 3 hr under a nitrogen atmosphere. The reaction mixture was poured into a mixture of ice-water (700 mL) and 1 M HCl (100 mL), and the resulting mixture was extracted with EtOAc (150 mL×3). During the extraction, undissolved materials were produced, which were removed by filtration. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with MeOH, and the precipitates produced were collected by filtration to give 4-chloro-3-({[1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid (1.74 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:23])([F:22])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1>CO>[F:23][C:4]([F:3])([F:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102.5 %

Procedure:
NaBH4 was added to a solution of 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-one (1.0 g, 3.0 mmol) in MeOH (15 ml) at 0° C. and stirred at 0° C. for 45 minutes. The reaction was quenched with water (30 ml) and hydrochloric acid (2 M, 5 ml), extracted with EtOAc, washed with water (×2) and brine, dried (MgSO4) and evaporated under reduced pressure to give 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ol (1.0 g, 100%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][N:24]=1.N=C=N>CN(C=O)C>[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:17]([C:10]3[CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH3:16])=[O:18])[CH:30]=2)[NH:25][N:24]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
The product of Example 5, Step 2 (0.100 g, 0.330 mmol, 1.00 equiv), 3-chloro-1H-indazol-5-amine (84 mg, 0.502 mmol, 1.50 equiv) and PS-carbodiimide resin (456 mg, 0.502 mmol, 1.00 equiv) were suspended in 2.0 mL DMF and stirred overnight at room temperature. The reaction mixture was concentrated to approximately 1 mL DMF and water was added. The resulting precipitate was collected by filtration and washed with 50% CH2Cl2/hexanes. The product was purified by preparative reverse phase HPLC (19×50 Xterra Prep RP 10-90% CH3CN/5 mM NH4HCO3 over 9 min, 25 ml/min) to provide 5.0 mg (3%) of the title compound as a white solid. MS (ES+) m/e 449 [M+H]+
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[F:23].O>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:3][C:4]#[N:5])=[CH:17][C:16]=1[F:23]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
Diethylcyanomethyl phosphonate (3.2 ml, 18.9 mmol) was taken up in dry THF (20 ml) at 0° C. under nitrogen, and stirred as a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added portionwise over ca. 10 min. The resulting grey suspension was then stirred at 0° C. for 1 h, before a solution of 4-chloro-3-fluoro benzaldehyde (Lancaster Synthesis) (3 g, 18.9 mmol) in 5 ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60 h. Water (5 ml) was added, and the mixture extracted with EtOAc (3×50 ml). The combined organics were were dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product as a mixture of geometric isomers (2.4 g, 70%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS+199.1 (M+NH4+).
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:15]2)=[CH:31][CH:32]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
A mixture of methyl 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), 5% palladium-carbon (1.00 g), and tetrahydrofuran (10 ml) was stirred for 18 hours at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (325 mg, yield: 80%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 87–88° C.
Reaction SMILES: [C:1]1([C:7]([N:10]([CH:12]=[C:13](Br)[CH3:14])[CH3:11])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[C:1]1([C:7]([N:10]([C:12]#[C:13][CH3:14])[CH3:11])([CH3:8])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)=CN(C)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC#CN(C)C(C)(C)c1ccccc1
Yield: 98 %

Procedure:
21.92 g of N-1-phenylisopropyl-N-methyl-2-bromo-propenyl amine are dissolved in 320 ml of alcohol and 40 ml of a 50% aqueous potassium hydroxide solution are added. The mixture is refluxed for 216 hours. The alcohol is distilled off and to the residue water is added and the mixture is extracted with benzene. The benzene solution is dried over potassium carbonate and evaporated. The residue is distilled off in vacuo. At 104°-110° C., 5 Hgmm 15 g of N-1-phenylisopropyl-N-methyl-propynylamine are obtained as a main fraction. nD20.4 =1.5229.
Reaction SMILES: [OH:1][C@@H:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][C@@H:5]1[C@H:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:18])[C:16]=3[CH2:17][C@H:8]2[CH2:7][C@H:6]1[OH:19].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][C:33]#[N:34]>CC(C)=O>[OH:19][C@H:6]1[C@H:5]([CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:9]2[CH2:10][C:11]3[C:16]([CH2:17][C@H:8]2[CH2:7]1)=[C:15]([O:18][CH2:32][C:33]#[N:34])[CH:14]=[CH:13][CH:12]=3
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC#N)c3C[C@H]2C[C@H]1O
Temperature: 30 °C
Yield: 82 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalene-2,5-diol (2 g, 0.005 mol) in dry acetone (20 ml) was treated with K2CO3 (2.07 g, 0.015 mol), chloroacetonitrile (0.64 ml, 0.010 mol) and tetrabutylbromide (0.32 g, 0.001 mmol). The mixture was heated at 30° C. overnight. Then, the reaction mixture was filtered with celite pad. The filtrate was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 82%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14]Cl)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH:29][CH2:28][CH2:27][CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: Fc1cc2c(c(OCCCl)c1)OCCC2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1cc2c(c(OCCNCCCc3c[nH]c4ccc(F)cc34)c1)OCCC2
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A solution 2-(6-fluorochroman-8-yloxy)ethylchloride (0.25 g, 7.1 mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (0.42 g, 2.2 mmol) and triethylamine (0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene choride plus ammonium hydroxide) afforded 0.25 g (60%) as a white solid: mp 137-138.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(C)C=CC(S(O[CH:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)(=O)=O)=CC=1.[OH-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:21]1[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]1)[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc2c(ccn2C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromoindole (8.472 g, 43.216 mmol), [CAS: 10075-50-0]), toluene-4-sulfonic acid, 1,4-dioxa-spiro[4.5]dec-8-yl ester (13.5 g, 43.216 mmol) [C.A.S. 23551-05-9]; (prepared according to the procedure described in J. Chem. Soc., Perkin Trans. 1 2002, 20, 2251-2255) and powdered potassium hydroxide (13.239 g, 235.958 mmol) in DMSO (300 ml) was stirred at 80° C. for 6 h. Subsequently, the mixture was cooled to room temperature and poured into ice water. The resulting aqueous mixture was extracted with Et2O, dried (Na2SO4), and the volatiles were evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM/heptane 1:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D11 (2.897 g, 19.93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([C:30](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[C:28]=1[CH3:29])[CH2:5][N:6]([CH:23]1[CH2:25][CH2:24]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[OH:38])[C:28]=1[CH3:29])[CH2:5][N:6]([CH:23]1[CH2:25][CH2:24]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8]
Reactant: Cc1c(Br)cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc1C(=O)c1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Br)cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc1C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a MeOH (0.09 M) solution of trans-N-[3-bromo-5-(3-fluorobenzoyl)-4-methylbenzyl]-N-cyclopropyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-3-piperidine-carboxamide (1 eq., Example 106) was added sodium borohydride (1.4 eq.). The resulting solution was stirred at RT for 15 h before the volatiles were removed in vacuo. The resulting residue carefully added 10% aq. HCl, followed by 1 N aq. NaOH so that the pH of the final solution is ˜10. After extraction with EtOAc, the combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (SiO2, 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH) afforded the title compound as a mixture of diastereomers. MS (ESI+, M+H): 584.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.COC1C=C(C=CC=1)CCO.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C1CNCCN1
Reactant: COc1cccc(CCOc2cncc(Cl)n2)c1
Agent: COc1cccc(CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CCOc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(3-methoxyphenyl)ethoxy]pyrazine (1.12 g, 4.23 mmol; obtained according to the procedure of example 50, step 1, starting from 3-methoxyphenethyl alcohol), piperazine (1.06 g, 12.3 mmol) and K2CO3 (0.585 g, 4.23 mmol). The yield of the title compound was 0.91 g (69%) which was obtained as light beige oil. HRMS m/z calcd for C17H22N4O2 (M)+ 314.1743, found 314.1759. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[O:10][CH2:11][CH3:12])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[CH:17][CH:16]=1>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:3]=[C:4]([C:31]2[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:23]3[O:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[C:25]([C:26]([NH:28][CH3:29])=[O:27])[C:24]=3[CH:30]=2)[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[O:10][CH2:11][CH3:12]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CCO/C=C/c1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a degassed solution of (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (500 mg, 2.29 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (1.15 g, 2.29 mmol) in 1,4-dioxane (8 mL) and water (200 μL) was added CS2CO3 (1.49 g, 4.59 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (120 mg, 0.18 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide (E)-5-(6-chloro-5-(2-ethoxyvinyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, yield: 16%). MS (M+H)+: 558.
Reaction SMILES: [CH2:1]([C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([C:16]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CN(N)C(=O)NCC(=O)OCC)cc1
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCCCCCCCc1ccc(CN(N)C(=O)NCC(=O)O)cc1
Yield: 78 %

Procedure:
When the product of Step D is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 78% yield, as a colourless solid. 1H-NMR (CDCl3) 7.15 (m, 4H); 6.91 (t, 1H, J=5.7 Hz); 4.66 (s, 2H); 4.02 (d, 2H, J=5.7 Hz); 3.56 (bs, 3H); 2.57 (t, 2H, J=7.9 Hz); 1.58 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]([C:4]1[N:8](CC2C=CC(OC)=CC=2)[C:7]([SH:18])=[N:6][N:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]([C:4]1[N:8]=[C:7]([SH:18])[NH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(Cn2c(S)nnc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)c1n[nH]c(S)n1
Yield: 99.1 %

Procedure:
3-Carbamoyl-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol (2.0 g., 0.007 mole), trifluoroacetic acid (8 ml.) and anisole (2 ml.) were heated at 70° C. for 3.5 hours. At this point, most of the trifluoroacetic acid present was removed by means of evaporation under reduced pressure and the residue was subsequently triturated with diethyl ether. The resulting solid was then filtered, washed with diethyl ether and subsequently dried in vacuo at 50° C. to give pure 3-carbamoyl-1,2,4-triazole-5-thiol (1.0 g., 91% yield), m.p. 276°-278° C. The infrared absorption spectrum was identical to that of a reference sample prepared as described in Example XVI, Part C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([CH3:10])[OH:9])[CH3:6]>>[C:1]([CH2:2][CH2:3][P:8]([CH3:10])(=[O:9])[O:7][CH2:5][CH3:6])#[N:4]
Reactant: C=CC#N
Reactant: CCOP(C)O
Product: CCOP(C)(=O)CCC#N
Yield: 90.6 %

Procedure:
120 g (2.26 mol) of acrylonitrile are added dropwise over 12 hours at 160° C. to 324 g (3.0 mol) of methanephosphonous monoethylester with vigorous stirring and under an inert-gas atmosphere. The excess monoester is then distilled off at 0.4 mbar. The residue is distilled using a Vigreux column at 142-143° C. at 0.4 mbar, giving 330 g of ethyl 2-cyanoethylmethylphosphinate (refractive index nD22 : 1.4554). This corresponds to a yield of 90% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH:3]=1.BrBr>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: N#CC1CC=C(Cl)CC1
Agent: BrBr
Solvent: Clc1ccccc1
Product: N#Cc1ccc(Cl)cc1

Procedure:
To a 25 ml three-necked flask equipped with an equal pressure additional funnel, a dry-ice condenser with a gas outlet and a stopper, is charged 14.2 g (0.1 mole) of 1-chloro-4-cyanocyclo-hex-1-ene (I) and 3 g of chlorobenzene The mixture is heated to 90°-100° C. with stirring. Bromine, 32 g (0.2 mole), is added dropwise, sub-surface. The reddish-brown color dissipates quickly and a gas evolution occurs. When approximately 24 g of bromine has been added, the pot temperature is raised to 120°-130° C. The remaining bromine is added in the same fashion. The pot temperature may then be raised to 150°-160° C. for 2-4 hours. During this period, an additional amount of bromine, such as about 1-2 g, may be added to complete the conversion of (I). A good yield of 4-chlorobenzonitrile will be obtained by the fractional distillation of the mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6])(=[O:18])[CH3:17]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
3.5 g (17 mmol) of 3-hydroxy-4-trifluoromethyl-benzoic acid (prepared as described in WO 2006/128184) were dissolved in 35 ml of acetic acid anhydride and heated to reflux for 3 h. 60 ml of water were added and heating to reflux was continued for 10 min. After cooling and stirring overnight, the formed precipitate was collected by suction and dried to give 3.0 g of the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH2:40][CH3:41])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1>[CH2:40]([O:39][CH2:38][C@H:27]([OH:26])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])[CH3:41]
Reactant: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (4.27 mL, 4.27 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H2) (1.45 g, 4.27 mmol) in tetrahydrofuran (25 mL). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated and diluted with EtOAc (50 mL) washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with 50% to 100% EtOAc in isohexane to afford (2S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (700 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 2.54 (3H, s), 3.49 (1H, d), 3.61 (2H, q), 3.75-3.83 (2H, m), 4.35-4.39 (1H, m), 8.14 (1H, d), 9.13 (1H, s), 9.43 (1H, d); m/z (ESI+) (M+H)+=226; HPLC tR=1.00 min.
Reaction SMILES: O.Br[C:3]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:16][CH2:17][CH3:18].[C:19]([O:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([O:16][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:3]=1[C:28]1[CH:29]=[N:30][CH:31]=[C:26]([CH:27]=1)[C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1cncc(B(O)O)c1
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cncc(C(=O)OC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
H2O (59.4 mg, 3.30 mmol) was added to a stirred suspension of PdCl2(dppf) (12.1 mg, 0.0330 mmol), methyl 4-bromo-3,5-diethoxybenzoate (200 mg, 0.660 mmol), [5-(tert-butoxycarbonyl)pyridin-3-yl]boronic acid (177 mg, 0.792 mmol) and K3PO4 (420 mg, 1.98 mmol) in DME (4 ml) and the mixture was stirred at 90° C. overnight. The reaction mixture was filtered through celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compounds as a colorless solid.