Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:24]([O:23][C:21](=[O:28])[NH:22][C:14]1[C:13]2=[CH:19][N:10]([C:9]3[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[Cl:20])[N:11]=[C:12]2[CH:17]=[CH:16][N:15]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(N)=O
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1nccc2nn(-c3c(Cl)cc(C#N)cc3Cl)cc12
Temperature: 90 °C
Yield: 123.7 %

Procedure:
A mixture of 3,5-dichloro-4-(4-chloro-pyrazolo[4,3-c]pyridin-2-yl)-benzonitrile (3.23 g, 10 mmol), tert-butyl carbamate (5.85 mg, 50 mmol), Pd2(dba)3 (458 mg, 0.5 mmol), Xantphos (576 mg, 1.0 mmol) and potassium phosphate tribasic (4.24 g, 20 mmol) in toluene (100 mL) and water (20 mL) was degassed with argon then heated at 90° C. for 30 minutes. The reaction was cooled to room temperature and then filtered through Celite® using ethyl acetate to wash the filter pad. The filtrate was washed with water and sodium bicarbonate (sat. aq.), dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as an off-white solid (5.0 g, contaminated with residual tert-butyl carbamate). LCMS (Method D): RT=2.44 min, m/z: 348 [M−C4H7+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[CH:22]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[CH:22]4)=[O:14])=[C:10]([CH3:17])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2c(cnn2C)c1

Procedure:
Using the procedure outlined in Example 15, the title compound was prepared from 6-(4-fluorophenyl)nicotinic acid (D3) (100 mg, 0.43 mmol) and 5-amino-1-methylindazole (58 mg, 0.39 mmol) as a white solid (21 mg). MS (ES): MH+ 361, (M−H)− 359.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[NH:10][N:11]=[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:25])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[C:12]1[CH:13]=[C:9]([CH2:8][NH2:7])[NH:10][N:11]=1
Reactant: Cc1nc(-c2ccccc2)oc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)oc1-c1cc(CN)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of the above-prepared [5-(4-Methyl-2-phenyl-oxazol-5-yl)-2H-pyrazol-3-ylmethyl]-carbamic acid tert-butyl ester (258 mg, 0.728 mmole, 1.0 eq) in dry CH2Cl2 (4 ml) was treated with trifluoroacetic acid (1 ml, excess) and the brown homogeneous mixture stirred under nitrogen at room temperature for one hour. The mixture was partitioned between CH2Cl2 and 1.0N NaOH, the organic phase washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 177 mg (96%) of the title compound as an off-white solid. The crude solid was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 20.8 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.15 mmol), 4-methoxyphenylboronic acid (35 mg, 0.23 mmol), K3PO4 (65 mg, 0.31 mmol), SPhos (3.2 mg, 0.0077 mmol) and Pd(OAc)2 (3.1 mg, 0.0046 mmol) in toluene (3 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added with stirring until pH was about 3, and the aqueous layer extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 13 mg of the title compound. MS: (+) m/z 417.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.0 g (3.3 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of concentrated sulfuric acid, and 0.25 g (4.0 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 1 hour. This reaction solution was poured into.ice water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 96%) of the desired product. Melting point: 139-140° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15]1([C:18](OCC)=[O:19])[CH2:17][CH2:16]1.O.[H-].[Na+].C(Cl)OC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)C.C1(C)C=CC=CC=1>[OH:19][CH2:18][C:15]1([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[OH:11])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(c2c(OCOC)cccc2OCOC)CC1
Agent: COCCl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1cccc(O)c1C1(CO)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of ethyl 1-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)cyclopropanecarboxylate (Reference Intermediate 211, 490 mg) in ethanol (10 ml) HCl 2N in water (0.789 mL, 1.579 mmol) was added and the reaction mixture was stirred overnight at 50° C. Toluene (20 mL) was added and the combined solvents were removed under reduced pressure. The residue was re-suspended in toluene (20 ml) and the solvent evaporated. The obtained residue was dissolved in dry tetrahydrofuran (20 ml), the mixture was cooled to 0° C. and NaH 60% dispersion in mineral oil (126 mg, 3.16 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. MOM-Cl (0.120 mL, 1.579 mmol) was then added and the reaction mixture was stirred for 2 hours at 0° C. LiAlH4 (1 M in THF, 1.579 ml, 1.579 mmol) was added and the reaction mixture was further stirred for 1 hour at the same temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (10 ml) and extracted with ethyl acetate (2×50 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a colourless oil (191 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[C:27]1([CH2:33][OH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>CN(C=O)C>[CH2:33]([O:34][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(OCc4ccccc4)ncn3)CC2)CC1
Temperature: 30 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (100 mg, 0.26 mmol), phenylmethanol (0.031 mL, 0.29 mmol) were added to DMF (2.6 mL), and then sodium hydride (7 mg, 0.29 mmol) was added to the mixture. The reaction was heated to 30° C. for 30 min The reaction crude was cooled down to r.t. and quenched with ice ammonia chloride solution (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% ethylacetate:hexane to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])=[S:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: S=C=Nc1ccccc1Cl
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=S)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-chlorophenyl isothiocyanate according to the procedure of Example 65. MS (ES) m/z 559.8.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=2[N:5]=1)[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[C:11]3[C:10](=[O:13])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])=[CH:24][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOc1nc2c([nH]1)c(=O)n(CCCO)c(=O)n2CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To a solution of 8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg, 0.248 mmol, intermediate 26) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (80 mg, 0.390 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 60° C. for 4 h, then diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (15 mg, 14.9% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.43-7.41(d, 2H), 7.34-7.32(d, 2H), 5.21(s, 2H), 4.53-4.44(m, 3H), 3.99-3.88(m, 4H), 3.45-3.39(m, 2H), 1.71-1.64(m, 2H), 1.37-1.33(t, 3H), 1.23-1.19(t, 3H). LCMS retention time 2.654 min; LCMS MH+ 407.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](N)=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([OH:14])=[O:1])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1(c2ccc(Cl)cc2)CC1

Procedure:
In a mixed solvent consisting of 14 ml of dioxane and 29 ml of a 1N aqueous sodium hydroxide solution was suspended 1.4 g of 1-(4-chlorophenyl)cyclopropanecarboxamide [this compound can be obtained from 1-(4-chlorophenyl)cyclopropanecarboxylic acid produced according to the method described in Chem. Bet., 119, 3694 (1986)]. To the suspension was dropwise added 4.4 g of a 12% aqueous sodium hypochlorite solution at 5°-10° C. The suspension was subjected to reaction at 20°-25° C. for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. To the thus treated organic layer was added the dioxane solution obtained in (1) above at 20°-25° C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/ethyl acetate=15/1) to obtain 0.37 g of N-[1-(4-chlorophenyl)cyclopropyl]-3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutanamide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:29]1(/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:2]4[N:3]=[CH:4][CH:5]=[N:1]4)=[CH:19][CH:18]=3)[N:23]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1c[nH]nn1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3nccn3)cc2)co1)\c1ccccc1
Yield: 35 %

Procedure:
In substantially the same manner as in Working Example 8, 1,2,3-triazole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The reaction mixture was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-1,2,3-triazole was obtained. The yield was 35%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 103-104° C.
Reaction SMILES: Cl[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:11]1([C:2]2[C:10]3[S:9][CH:8]=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: Clc1cccc2ncsc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(C2CC2)c2scnc2c1
Temperature: 100 °C

Procedure:
Into a solution of 7-chloro-1,3-benzothiazole (390 mg, 2.30 mmol, 1.00 equiv), cyclopropylboronic acid (300 mg, 3.49 mmol, 2.00 equiv) and potassium phosphate (2.2 g, 4.50 equiv) in a mixture toluene (12 mL) and water (1.2 mL) was added Pd(OAc)2 (51.6 mg, 0.23 mmol, 0.10 equiv) and PCy3HBF4 (0.17 g, 0.20 equiv). After degassed under vacuum and flushed with nitrogen, the resulting mixture was heated for 6 h at 100° C. in an oil bath under nitrogen atmosphere, cooled down to room temperature, quenched by the addition of 20.0 mL of water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Upon filtration and concentration under reduced pressure, the residue was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (10:1-5:1) to provide the title compound as purple oil. MS m/z [M+H]+ (ESI): 176.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].BrCCO.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:9]1[C:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[C:6]2[C:4](=[O:5])[O:3][CH2:1][CH2:2][N:7]2[N:8]=1
Reactant: CCOC(=O)c1n[nH]c(-c2ccccn2)c1-c1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1OCCn2nc(-c3ccccn3)c(-c3ccnc4ccccc34)c21
Temperature: 60 °C

Procedure:
A mixture of 3-ethoxycarbonyl-5-pyridin-2-yl-4-quinolin-4-yl-pyrazole (0.35 g, 1.00 mmol), 2-bromoethanol (0.15 g, 1.12 mmol), and cesium carbonate (0.50 g, 1.5 mmol) in N,N-dimethylformamide (20 mL) is heated at 60° C. for 2 h. The mixture is cooled to room temperature and poured into ethyl acetate (60 mL). The organic portion is washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (ethyl acetate/hexane) to yield the title compound, 110 mg (32%).
Reaction SMILES: O[CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[S:21]([CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)C2CC(NC(=O)OC(C)(C)C)C2)cc1

Procedure:
18.7 g (100 mmol) tert.butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105 mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwise to this solution at 0° C. with stirring. Then the mixture is left to come up to ambient temperature and stirred for 2 h. The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:29])[OH:25])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(B(O)O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirring solution of 4-(triisopropyl)silyloxy-1-bromobenzene (6) (540 mg, 1.64 mmol) in THF (15 ml) at −78° C. was added n-butyl lithium (0.9 ml, 2.18 M in hexanes, 1.96 mmol) dropwise. The reaction mixture was stirred for 30 minutes then triisopropyl borate (0.5 ml, 2.17 mmol) was added in one portion. The reaction was stirred at −78° C. for 1 hour, allowed to warm to ambient temperature over 4 hours, quenched with 3 N HCl (5 ml) and stirred for 30 minutes at 0° C. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over MgSO4. Purification by flash SiO2 chromatography (loaded with DCM, eluted with hexanes/ethyl acetate (10:1) to (3:1) to (1:1)) gave 7 as a white solid (328 mg, 68% yield): 1H-NMR (400 MHz, chloroform-d) δ 8.10 (d, J=8.4 Hz, 2 H), 6.98 (d, J=8.4 Hz, 2 H), 1.30 (septet, J=7.6 Hz, 3 H), 1.13 (d, J=7.6 Hz, 18 H); 13C-NMR (100 MHz, chloroform-d) δ 160.1, 137.4, 119.6, 17.9, 12.7.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6]1)=[C:2]=[S:3].[CH3:17][NH2:18]>C(O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:2]([NH:18][CH3:17])=[S:3])[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: CN
Reactant: S=C=NCC1CC(c2ccc(Cl)cc2)=NO1
Solvent: CCO
Product: CNC(=S)NCC1CC(c2ccc(Cl)cc2)=NO1
Reaction time: 1 h

Procedure:
To 3 g. of the product of Example 1 was added 5 ml. of 40 percent methylamine in aqueous ethanol. The mixture was stirred for 1 hour, and was then allowed to stand overnight. The product separated as a precipitate, which was collected and recrystallized from methanol-water, and recrystallized a second time from chloroform to produce 0.8 g. of product, m.p. 131°-133° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.CON(C)[C:17]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)=[O:18]>O1CCCC1>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([C:17](=[O:18])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=3)=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Reactant: Cc1cccc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a −60° C. solution of 2,6-dimethyl pyridine (48 mL, 457 mmol) in tetrahydrofuran (800 mL) was added n-butyl lithium (183 mL, 2.5 M in hexanes, 457 mmol) over 30 minutes. The resulting red solution was stirred at −60° C. for 1 hour, and then treated with a solution of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide of Step A (415 mmol) in tetrahydrofuran (200 mL) over 1 hour. The resulting reaction mixture was slowly warmed to −20° C. over 3 hours, and then poured over ice (1 kg). The liquid phase was decanted and the ice was washed with methyl tert-butyl ether (1L). The combined organic extracts were washed with saturated aqueous sodium chloride (3×100 mL), dried with magnesium sulfate and concentrated in vacuo to yield the title compound crude (102 g). Recrystallization from toluene yielded the title compound as a yellow solid (57 g, 49% over two steps).
Reaction SMILES: [O:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:13][S:14]([CH2:17][CH2:18][C:19]([NH:22]C(=O)OCC1C=CC=CC=1)([CH3:21])[CH3:20])(=[O:16])=[O:15]>CO.[Pd]>[O:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:13][S:14]([CH2:17][CH2:18][C:19]([CH3:21])([NH2:22])[CH3:20])(=[O:16])=[O:15]
Reactant: CC(C)(CCS(=O)(=O)CC1COCCOCCOCCO1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CC1COCCOCCOCCO1
Reaction time: 3.5 h

Procedure:
A solution of benzyl 4-((1,4,7,10-tetraoxacyclododecan-2-yl)methylsulfonyl)-2-methylbutan-2-ylcarbamate (120.8 mg, 0.255 mmol) in methanol (1 ml) was put under N2, and 10% palladium on carbon (30 mg) was added. The vessel was purged with hydrogen (1.3 atmospheres) and the suspension stirred for 3.5 hours. The suspension was filtered through a polytetrafluoroethylene filter (0.45 um), and the filtrate concentrated in vacuo to give the title compound as a clear oil (quantitative); LRMS (ESI/APCI) m/z 340 [M]+.