Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B.[ClH:11]>C1COCC1>[ClH:11].[Br:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Br
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ncccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 132.2 %

Procedure:
To a cooled (0° C.) solution of 3-bromo-2-cyanopyridine (975.0 mg, 5.328 mmol) in THF (30 mL) was added borane (1.0 M in THF, 27.0 mL, 27.0 mmol) slowly via addition funnel over the course of 15 min. The reaction was stirred at 0° C. for 45 min and then warmed to RT for 17 h. After cooling to 0° C., the reaction was quenched with methanol (35 mL) and concentrated. The residue was dissolved in dichloromethane (6 mL) and charged with hydrochloric acid (4.0 M in 1,4-dioxane, 5 mL, 20 mmol) and then concentrated to afford 1.574 g (>100%) of the title compound as a yellow solid. The crude material thus obtained was used without further purification. MS (ESI): 187.09, 189.12 [M+H]+; HPLC tR=0.67 & 0.97 min (ZQ3: polar—5 min).
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.C(Cl)Cl.[CH3:14][OH:15]>[Ti](Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14](=[O:15])[CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CO
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c2ccc(Br)cc12

Procedure:
To 5-bromoindole (160 g), 1-phenylacetyl-1H-1,2,3-benzotriazole (193.62 g) and methylene chloride (2120 ml) were added, the mixture was stirred under ice cooling while adding a solution of titanium(IV) chloride (179 ml) in a methylene chloride solution (450 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, methanol (220 ml) and water (1126 ml) were added, the mixture was stirred at room temperature for 21 hours and in an ice water bath for 3 hours, then the precipitated crystals were obtained by filtration to afford the above-identified compound (163.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[OH:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cnn(CCO)c2)c1
Temperature: 95 °C

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (193 mg, 0.600 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 95° C. 7 h. The RM was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 25 g, EtOAc). The purified intermediate was treated with 5 M HCl in MeOH (5 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from Et2O/EtOAc afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.92 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.78 (q, J=5.47 Hz, 2H) 4.19 (t, J=5.47 Hz, 2H) 4.96 (t, J=5.08 Hz, 1H) 7.40 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (s, 1H) 8.38 (s, 1H) 8.43 (d, J=1.17 Hz, 1H) 8.88 (s, 1H) 9.03 (s, 1H) 10.63 (s, 1H).
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH:14]([OH:16])[C:13]2[C:8](=[C:9]([CH2:37][CH2:38][CH3:39])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[O:7]1)([O:3]CC)=[O:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:34]([C:25]1[C:26]([OH:33])=[C:27]([C:30](=[O:32])[CH3:31])[CH:28]=[CH:29][C:24]=1[O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:10]1[C:9]([CH2:37][CH2:38][CH3:39])=[C:8]2[C:13]([CH:14]([OH:16])[CH2:15][CH:6]([C:1]([OH:3])=[O:2])[O:7]2)=[CH:12][CH:11]=1)[CH2:35][CH3:36]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OCC)CC3O)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3O)ccc(C(C)=O)c1O

Procedure:
1.2 g (2.2 mmole) of the compound of Example 28 dissolved in 20 ml ethanol and 35 ml tetrahydrofuran was saponified with 0.3 g NaOH, the reaction mixture acidified with dilute HCl to pH 3 and extracted with ethyl acetate. The organic phase was washed with water until neutral, then with brine and dried with magnesium sulfate. The crude residue after evaporation of the solvent was triturated with benzene and 0.18 (16%) of the title compound as a white solid, mp 95.5°-97.5° C., separated by filtration. Calc: C, 67.68; H, 7.44; Found: C, 67.56; H, 7.34.
Reaction SMILES: [O:1]1[CH2:4][CH2:3][C@@H:2]1[CH2:5][CH2:6][OH:7].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][CH2:4][O:1]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC[C@H]1CCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2CCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mixture of (S)-2-(oxetan-2-yl)ethanol (408 mg, 4 mmol), TsCl (1.15 g, 6 mmol), TEA (0.85 g, 6 mmol) and DMAP (92 mg, 0.8 mmol) in DCM (20 mL) was stirred at RT for 18 h. Then the mixture was concentrated, the residue was dissolved into EtOAc (15 mL), washed with sat. NaHCO3 aqueous solution, water and brine, then the EtOAc layers was dried with Na2SO4, then the solvent was removed under the reduced pressure. The crude product was purified with Combiflash (PE/EtOAc=5/1, silica gel) to give the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[S:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].ClS([N:27]=[C:28]=[O:29])(=O)=O>C1(C)C=CC=CC=1>[C:28]([N:11]1[C:10](=[O:14])[C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[S:13][CH2:12]1)(=[O:29])[NH2:27]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2SCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 69.3 %

Procedure:
5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (479 mg, 1.5 mmole) described in Kokai 62-42977 was suspended in dried toluene (3 ml), to which chlorosulfonyl isocyanate (144 μl;1.65 mmole) was added with stirring under nitrogen atmosphere, to obtain a transparent solution of orange color. Furthermore, the solution was heated at 90° C. for 10 min., from which toluene was evaporated under reduced pressure, then 3.6 ml of mixed solution of acetic acid and water (2:1) was added thereto. The resulting mixture was heated at 90° C. for 10 min. and poured into ice-water, which was subjected to extraction with dichloromethane. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (chloroform:acetone=20:1), whereby 377 mg of the objective compound was obtained, which was recrystallized from ethanol-ether in 53% yield. The physical constants are described on Table 1.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C1(C)C=CC=CC=1.[CH3:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)(=O)C>[CH3:7][C:6]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH3:16])=[CH:20][CH:21]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)ccc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (11.7 mL, 100 mmol) and toluene (750 mL) was added p-phenetidine (12.9 mL, 100 mmol) and glacial acetic acid (1 mL). The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.13-7.10 (m, 2H), 6.97-6.94 (m, 2H), 5.88 (br s, 2H), 4.08 (q, 2H), 2.02 (s, 6H), 1.46 (t, 3H); MS (ESI) 216 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCC(CF)(CCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(CF)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 6.36 g. of 4-fluoromethyl-4-trimethylsilyloxy-1-octyne, 11.64 g. of (10.6 ml.) of tributylstannane and 40 mg. of azobisisobutyronitrile is heated and stirred at 120° C. under nitrogen for 3 hours. The mixture is cooled, filtered through Celite and washed with hexanes. The hexanes are removed in vacuo and the residual liquid is vacuum distilled through a short path. The product is obtained at b.p. 110°-135° C./0.2-0.25 mm. (The product contains a minor amount of cis isomer.)
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[C:13]3[N:14]([C:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=4)=[CH:19][N:20]=3)[CH:15]=[CH:16][N:17]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:18]2[N:14]3[CH:15]=[CH:16][N:17]=[C:12]([NH:11][CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[C:13]3=[N:20][CH:19]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COC(=O)c1ccc(CNc2nccn3c(-c4ccc(OC)c(OC)c4)cnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3c(NCc4ccc(C(=O)O)cc4)nccn23)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzoic acid methyl ester (0.20 g, 0.48 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (0.72 ml, 0.72 mmol, 1 M aqueous solution). The reaction was stirred at ambient temperature for 24 hours then diluted with water (30 mL) and washed with ethyl acetate (30 ml). The aqueous phase was acidified with 1 M aqueous HCl and extracted with ethyl acetate (3×30 ml), the organic layers were combined and dried with magnesium sulphate, filtered and concentrated in vaccuo. The product, 4-{[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzoic acid, is obtained as an off white solid (50 mg, 26%) (LC-MS m/z 405 [M+H]+).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-]>C1COCC1>[NH2:2][CH2:1][CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5]1
Reactant: N#CCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 86.5 %

Procedure:
5.7 g (21.7 mmol) of 3-cyanomethyl-1-benzhydryl azetidine was added slowly to a suspension of 2.9 g (76.0 mmol) of LiAlH4 in 80 mL of dry THF at roomtemperature. The reaction mixture was refluxed for 4 h. Excess hydride reagent was hydrolyzed by careful addition, with cooling, of NH4 Cl(aq), the gelatinous mixture was filtered and the filter cake was washed repeatedly with THF. The solvent was evaporated, the residue was dissolved in diethyl ether, washed with brine and dried with Na2SO4. Evaporation of the solvent gave 5.0 g (87%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[CH2:11][S:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:7]3=[N:28][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:30]=[C:5]([C:6]=23)[CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[NH2:13][C:8]1[C:7]2[C:6]3[C:5](=[N:30][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:28]=2)[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[C:12]=3[CH2:11][S:10][N:9]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cnc(Cn2nc3cc(CNC(C)=O)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture composed of di-tert-butyl {8-(aminomethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 112 (20 mg), pyridine (8.3 μl), acetic anhydride (5 μl) and dichloromethane (0.5 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (3.7 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[CH3:11])[C:3]=1[OH:12].O[CH:14]([CH:27]=[CH2:28])[CH2:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][CH:14]([O:12][C:3]2[C:4](/[CH:9]=[CH:10]/[CH3:11])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:27]=[CH2:28])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: C=CC(O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/c1cc(F)cc(Br)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CC(COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1/C=C/C
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenol (6.37 g, 0.0276 mol), toluene-4-sulfonic acid 2-hydroxy-but-3-enyl ester (8.8 g, 0.0363 mol) and triphenylphosphine (10.12 g, 0.0386 mol) in anhydrous toluene (200 mL) at 0° C. under nitrogen was added a solution of diethyl azodicarboxylate (6.72 g, 0.0386 mol) in anhydrous toluene (100 mL) over 10 minutes then the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of water (400 mL), stirred vigorously for 5 minutes and the resulting oily suspension extracted with diethyl ether (300 mL). The organic phase was separated, washed with water (2×500 mL), and saturated brine (400 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 2 to 10% ethyl acetate in hexane gave 12.11 g (96%) of 2-{2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenoxy}but-3-enyl 4-methylbenzenesulfonate as a colorless oil. HRMS: calcd for C20H20BrFO4S+NH4+, 472.05879. found (ESI, [M+NH4]+), 472.0581.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.[Na].C(O)(=[O:20])C.N1C=CC=CC=1>O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:20]
Reactant: N#Cc1ccc2c(/C=C/C(=O)O)n[nH]c2c1
Reactant: CC(=O)O
Agent: [Ni]
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccc2c(/C=C/C(=O)O)n[nH]c2c1
Temperature: 55 °C
Yield: 72 %

Procedure:
To a solution of (E)-3-(6-cyano-1H-indazol-3-yl)acrylic acid (25 mg, 0.12 mmol) in acetic acid/pyridine (2 mL/4 mL) was added a solution of sodium hypophophite (42 mg, 0.48 mmol) in H2O (2 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.1 mL). The resulting mixture was heated at 55° C. (oil temp.) for 1 h before cooling to rt. H2O (20 mL) was added and the mixture was extracted with EtOAc (30 mL×2). The combined extracts were washed with 2M HCl (10 mL×2), H2O (10 mL×2), brine (10 mL) and dried (Na2SO4). Removal of the solvent gave the title compound (18 mg, 72%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 14.12 (s, 1H, NH), 12.24 (brs, 1H, CO2H), 10.01 (s, 1H, CHO), 8.26 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.87 (d, J=16.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 6.76 (d, J=16.4 Hz, 1H); MS ESI 217.0 [M+H]+, calcd for [C11H8N2O3+H]+ 217.1.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([N:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:16])(=[O:14])=[O:13]>O.C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([N:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:16])(=[O:13])=[O:14]
Reactant: COC(=O)CCCCN(C)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCCC(=O)O)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide (18.2 mg, 0.76 mmol) in water (3 ml) was added to a solution of methyl 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoate (178 mg, 0.45 mmol) in THF (5 ml), and stirring was carried out for 18 h at room temperature. THF was then concentrated in vacuo, water was added to the residue, and extraction with DCM (2×20 ml) was carried out. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Reactant: OB(O)c1ccc(F)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1ccc(F)cc1

Procedure:
By following a procedure analogous to Example 27 starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluorophenylboronic acid, 2-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=64%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CC(C)OC(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
23 ml (0.19 mol) of 2,6-dimethylmorpholine were added dropwise to a solution of 15 g of diketene (0.18 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 26.5 g (0.13 mol, 74% yield) of a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])CCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[C:3]([CH3:9])=[N:4]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn(C)c(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 g, 5.3 mmol) in anhydrous THF (20 mL) cooled to −78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.2 mL, 1.6 M in hexane) and stirred at room temperature for 20 minutes. Then, 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.7 mL, 8.3 mmol) was added dropwise at −78° C. and allowed to warm to ambient temperature overnight. Ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and chromatographed on silica gel eluting with 40% ethyl acetate in hexanes to provide the title compound as white crystals (996 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 12 H), 2.33 (s, 3 H), 2.37 (s, 3 H), 3.69 (s, 3 H); (DCl/NH3) m/z 237 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:24]1>>[CH:9]1([NH:8][C:6]([C:5]2[CH:15]=[C:16]([F:17])[C:2]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24]3)=[N:3][C:4]=2[S:18][CH2:19][CH2:20][CH3:21])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Reactant: COC(=O)C[C@@H]1CCCNC1
Agent: Cl
Product: CCCSc1nc(N2CCC[C@H](CC(=O)O)C2)c(F)cc1C(=O)NC1CCCCC1

Procedure:
Prepared in a similar manner to that described above from 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide using (S)-methyl 2-(piperidin-3-yl)acetate hydrochloride followed by an ester hydrolysis as described above to give the desired compound (190 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([C:18](OC)=[O:19])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1([CH2:18][OH:19])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:6]1
Reactant: COC(=O)C1(Cc2ccccc2F)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CO)(Cc2ccccc2F)C1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
In a flask, 1-tert-butyl 3-methyl 3-(2-fluorobenzyl)piperidine-1,3-dicarboxylate (1.41 g, 4.0 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium aluminum hydride (8.03 mmol) was added to the flask. The reaction was stirred for an hour at room temperature. Upon completion, the reaction was quenched with ethyl acetate (10 ml) drop-wise. Water (30 mL) was added to the reaction. The reaction mixture then was extracted 3 times with ethyl acetate (50 mL). The organic layers were combined, were dried with sodium sulfate, concentrated and purified using flash chromatography (0 60% ethyl acetate in hexane) to give the titled compound (1.29 g).