Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.N#N.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1COCC1.O>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)([CH3:17])[CH3:16]
Reactant: c1cc[nH]c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.1 %

Procedure:
A solution n-BuLi in THF (2.5 M, 19.6 mL, 49 mmol) was added to a stirred solution of pyrrole (3 g, 44.7 mmol) in anhydrous THF (20 mL) at −78° C. in an N2 atmosphere. Then the mixture was warmed to room temperature and stirred at this temperature for 10 min. The mixture was cooled again to −78° C., and chlorotriisopropylsilane (10.5 g, 44.7 mmol) was added dropwisely with stirring. Then the mixture was warmed to room temperature and stirred for additional 30 min., diluted with water (200 mL), extracted with ether (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, concentrated to give crude 1-(triisopropylsilyl)-1H-pyrrole (11 g, 100%) as a oil. LCMS: 224 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 0.98 (m, 18H), 1.40 (m 3H), 6.20 (m, 2H), 6.80 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:22].[C:23](OC(=O)C)(=[O:25])C>C(O)=O>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][CH:23]=[O:25])[C:3]2=[O:22])=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Solvent: O=CO
Product: O=CN[C@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 12, the reaction of (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one with a mixture of acetic anhydride and formic acid yields the title compound as a white solid; MS: m/e=329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 30.5 %

Procedure:
Sulfur trioxide-pyridine complex (1.71 g, 10.7 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (610 mg, 1.54 mmol), triethylamine (1.72 mL) in dimethyl sulfoxide (20 mL) at room temperature, and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (185 mg, 0.469 mmol, 30%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)(=[O:25])[CH3:24]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH2:29][CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCCCOc1c(O)c2cc(O)ccc2oc1=O
Product: CCCCCCCCOc1c(O)c2cc(OCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-octyloxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-octyloxy-4-hydroxy-6-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>CN(C)C=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCC(O)CO
Temperature: 0 °C

Procedure:
4.65 g of 3-amino-1,2-propanediol (0.05 mol) were dissolved in 30 ml of dimethylformamide (anhydrous). This solution and 13.8 g of K2CO3 were placed in a 100 ml three-necked flask with dropping funnel and gas inlet and gas outlet tubes. The mixture was cooled to 0° C. in an ice bath. While stirring gently and slowly bubbling nitrogen through, 6.18 ml of methacryloyl chloride (0.06 mol) dissolved in 30 ml of dimethylformamide were added dropwise over the course of 30 minutes. The mixture was stirred, while cooling in ice, for a further hour and then allowed to warm to room temperature and was stirred for a further 30 minutes. The reaction mixture was filtered through a fluted filter, and the residue was discarded. The filtrate was concentrated to a viscous oil in a rotary evaporator. This oil was dissolved in 30 ml of methanol, a second filtration was carried out, and the filtrate was again concentrated in a rotary evaporator. The residues of the solvent were removed under high vacuum. The yield was 8.52 g.
Reaction SMILES: Cl.C(OC(=O)NC[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:32])[NH:17][CH2:18][C:19]2[S:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:22][CH:23]=2)=[CH:12][N:11]=1)(C)(C)C.[NH2:34][C:35]1C(C(O)=O)=NC=C(N)N=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)C>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[O:24][C:21]1[S:20][C:19]([CH2:18][NH:17][C:16](=[O:32])[C:13]2[CH:14]=[CH:15][C:10]([NH:34][CH3:35])=[N:11][CH:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Reactant: Nc1cnc(C(=O)O)c(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 85.5 %

Procedure:
Ethanol (20 mL) and 5N hydrochloric acid (0.8 mL) were added to (5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)carbamoyl)pyridin-2-yl)methyl-carbamic acid tert-butyl ester described in Preparation Example A+-3 (87 mg, 0.19 mmol), and the solution was stirred for 25 minutes at 80° C. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (58 mg, 0.162 mmol, 85.5%) was obtained as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1.[I:20]I>C1COCC1>[I:20][C:11]1[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][O:7][CH3:6]
Reactant: II
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1I
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.22 mL, 0.56 mmol) was added to a solution of 12 (100 mg, 0.50 mmol) in anhydrous THF (790 μL) at 0° C. After 5 minutes, iodine (141 mg, 0.56 mmol) in anhydrous THF (320 μL) was added. After 2 hours at room temperature, the reaction was quenched via dropwise addition of MeOH and the solvent was concentrated. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organics were washed with saturated aqueous Na2S2O3, saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 15 as a brown oil (129 mg, 79%): 1H NMR (CDCl3, 100 MHz) 7.25-7.18 (m, 1H), 6.79-6.71 (m, 2H), 5.27 (s, 2H), 5.18 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H); IR (film) νmax 2953, 2924, 2853, 1458, 1377 cm−1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Temperature: 130 °C
Yield: 91 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.6 g, 2.3 mmol) was dissolved in anhydrous dioxane (2 mL) and 4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed by HI/H2O (0.2 ml, 47%). The mixture was heated at 130° C. in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800 mg, 91%) which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 3 h
Yield: 113.5 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (780 mg, 3.30 mmol), 2-bromo phenyl isocyanate (0.41 ml, 3.30 mmol) in THF (7 ml) was added Et3 N (0.092 ml, 0.66 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-bromophenyl) ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 138–145° C. (dec.); 1H-NMR (CDCl3) δ 1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J=9.0, 1.4 Hz, 1H), 6.98 (br, 1H), 7.18–7.31 (m, 4H), 7.39 (dd, J=8.1, 2.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H); Anal. Calcd for C20H22BrN2O3.0.2H2O: C, 56.80; H, 5.58; N, 6.62. Found: C, 56.85; H, 5.42; N, 6.62.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](Cl)=[C:5]2[S:4][CH:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([NH:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:5]2[S:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(C)csc2c1Cl
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c(C)csc2c1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethyl 3-methyl-7-chlorothieno[3,2-b)pyridine-6-carboxylate (3.0 g, 0.0117 mol) and benzylamine (2.5 g, 0.0234 mol) were heated in an oil-bath with stirring for 30 minutes (oil-bath temperature to 220°). On cooling the residue was dissolved in chloroform, washed with dilute aqueous sodium hydroxide and the aqueous phase back-extracted with more chloroform. The combined chloroform extracts were washed with water, dried and evaporated to give an oil. This oil was purified by flash chromatography on silica (40-60 mesh) with dichloromethane as eluant to give an oil which crystallised on standing. Recrystallisation from methanol gives the title compound as pale yellow crystals, 3.0 g, m.p. 99°-100°.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:12]=[N+:13]=[N-:14].[Na+].S(=O)(=O)(O)O>CS(C)=O.C(OCC)(=O)C>[N:12]([C@@H:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:1])=[N+:13]=[N-:14]
Reactant: c1ccc2c(c1)CC1OC1C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1Cc2ccccc2C[C@H]1O
Reaction time: 60 h
Yield: 38 %

Procedure:
To a stirred solution of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene (prepared in the manner disclosed in U.S. Pat. No. 4,076,843, 1.7 g, 11.6 mmol) in dimethyl sulfoxide (20 mL) at room temperature under nitrogen was added sodium azide (6.7 g, 0.10 mol) and concentrated sulfuric acid (0.2 mL). After 60 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine three times, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane was used) to obtain the title compound (0.43 g, 38%) and recovered starting material. 1H NMR (400 MHz, CDCl3) δ 7.07-7.18 (m, 4H), 3.92 (m, 1H), 3.73 (m, 1H), 3.22 (m, 2H), 2.87 (m, 2H), 2.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(Br)ccc2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(Br)ccc2ccc(Cl)nc12
Yield: 84 %

Procedure:
A mixture of 7-bromo-8-methoxy-2-quinolinol (4c) (2.22 g, 8.7 mmol) and POCl3 (7 mL) was heated under reflux for 1.5 hours. After neutralization with NaHCO3 and extraction with AcOEt, the residue was dissolved in CHCl3 and filtered through silica gel to remove the brown polar impurities. The product (1.99 g, 84% yield) was obtained as white crystals upon recrystallization from AcOEt-Hexanes. mp 130-132° C.; 1H NMR (400 MHz, CDCl3), 8.06 (d, J=8.8 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.17 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Yield: 88 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.500 g, 1.54 mmol) in 15 mL of ethylene glycol dimethyl ether, was added 3-aminophenyl boronic acid (0.358 g, 2.31 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.178 g, 0.098 mmol), and potassium phosphate (1.63 g, 7.7 mmol). The reaction mixture was heated to reflux temperature of the solvent for 18 hours. The solvent was then removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The title compound was purified by column chromatography (SiO2, 6% MeOH in CH2Cl2) (0.457 g, 88% yield): ES-MS (m/z) 337 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-]>O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MEOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and 1N aqueous HCl. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].O>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH:15]=[CH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=O)ccn1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 2-Methoxy-pyridine-4-carbaldehyde (1 g, 7.29 mmol, 1 eq) in 50 ml of dry DCM was added portionwise (methoxycarbonylmethylene)triphenylphosphorane (1.05 eq, 2.56 g). The mixture was stirred at room temperature for 2 hours. The mixture was then poured into 200 ml of water and the organic substances were extracted with DCM (twice, 150 ml of DCM was used in total) The gathered DCM layers were dried and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP coloumn and cyclohexane/EtOAc solvent system (gradient 2-20% of EtOAc in 20 coloumn volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-methoxy-pyridin-4-yl)-acrylic acid methyl ester (1.3 g, yield=87.6%, purity=95%). MS: [M+H]+=194.14 1H NMR (300 MHz; CDCl3) δ/ppm 3.82 (s, 3H), 3.95 (s, 3H), 6.54 (d, J=16.0 Hz, 1H), 6.80 (s, 1H), 6.97 (dd, J=5.38 Hz, J=1.31 Hz, 1H), 7.55 (d, J=16.0 Hz, 1H), 8.18 (d, J=5.38 Hz, 1H)
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:35])[C:30]([CH3:34])([CH3:33])[CH2:31]O.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:31][C:30]([N:29]([CH3:35])[CH3:28])([CH3:34])[CH3:33])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)C(C)(C)CO
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCC(C)(C)N(C)C

Procedure:
2-Dimethylamino-2-Methyl-1-Propyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) bis(tributyltin) oxide and 23.4 gm (0.2 mole) 2-dimethylamino-2-methyl-1-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes water began to collect in the Dean-Starke tube and after 46 hours only 1.6 ml of water (theory 1.8 ml) had collected. Solvent is stripped off on a rotating evaporator to provide 78.3 gm of straw colored liquid. This is fractionated at reduced pressure to collect the desired product, 52.7 gm of water-white liquid (Percent yield - 65), at 132°-137° C. at 0.5 mm. Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](OC(=O)C)=[O:14]>C1(C)C=CC=CC=1>[CH:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])=[O:14]
Reactant: CC(=O)OC=O
Reactant: COc1cc2cc[nH]c2cc1O
Solvent: Cc1ccccc1
Product: COc1cc2cc[nH]c2cc1OC=O
Yield: 30 %

Procedure:
A solution of 12 g (0.0735 mole) of 6-hydroxy-5-methoxyindole and 12.95 g (0.147 mole) of acetic formic anhydride in 100 ml of toluene is brought to reflux for 16 hours under nitrogen. After the mixture is cooled, 30 g of silica 60 are added to the reaction medium, the mixture is filtered and the filtrate concentrated two-fold. The white precipitate obtained is filtered off and then recrystallized again in 30 ml of toluene. After being dried under vacuum, 4.2 g of the derivative 8 (white powder, 30% yield) are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([N:18]1[C:22]([OH:23])=[CH:21][CH:20]=[N:19]1)[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C>[CH2:16]([N:18]1[C:22]([OH:23])=[C:21]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:10]([Cl:11])[C:2]=2[Cl:1])[CH:20]=[N:19]1)[CH3:17]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 500 mg (1.85 mmol) of 2,3-dichloro-4-methylsulfonylbenzoic acid and 240 mg (2.14 mmol) of 1-ethyl-5-hydroxypyrazole in 10 mL of dry acetonitrile was treated with 430 mg (2.08 mmol) of dicyclohexylcarbodiimide with stirring at ambient temperature for 0.5 hr. The precipitate that formed was removed by filtration and the filtrate was treated with 0.5 mL of triethylamine and 1 mL of acetone cyanohydrin. After 1 hr, the reaction mixture was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The organic layer was recovered and extracted with dilute aqueous sodium bicarbonate solution. The basic aqueous solution obtained was acidified with dilute aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 540 mg (81 percent of theory )of the title compound as an orange syrup.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[N:52]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:18]([N:60]2[CH2:61][CH2:62][CH:57]([N:52]3[CH2:56][CH2:55][CH2:54][CH2:53]3)[CH2:58][CH2:59]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 0.42 g (1.5 mmol) of 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (intermediate 1B) in 15 ml of DMF was added 0.60 g (1.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.62 ml=0.45 g (4.5 mmol) of Et3N; after 30 min, 0.24 g (1.6 mmol) of 4-pyrrolidin-1-yl-piperidine was added. 1 hour later, the reaction mixture was poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 95:5 to 4:1) to give 0.56 g (89%) of the title compound as light brown oil. MS: 418.1 (MH+).