Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][C:12]=2[F:32])=[O:17])[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 27.8 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (101 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (196 mg) described in Preparation Example 116 and by the reaction and treatment in the same manner as in Example 4, the title compound (62 mg) was obtained.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]1)(=O)=O.O[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[F:13][C:10]1([F:14])[CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=[O:20])[CH2:8][CH2:9]1
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1cccc(OCC2CCC(F)(F)CC2)c1
Reaction time: 1 h

Procedure:
Mesylate 142 (0.9 g, 3.94 mmole), 3-hydroxybenzaldehyde (0.577 g, 4.73 mmole), K2CO3 (0.817 g, 5.91 mmole) and NMP (5 ml) were heated at 70° C. overnight. H2O (30 ml) and hexanes (50 ml) was added and stirred for 1 hr. The organic layer was dried over Na2SO4 and evaporated. Purfication by flash chromatography (20% ether/hexanes gradient) gave 3-((4,4-difluorocyclohexyl)methoxy)benzaldehyde (143) as ah oil. Yield (0.559 g, 56%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.51-7.46 (m, 21H), 7.41-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.8 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H), 2.06-1.98 (m, 5H), 1.89-1.73 (m, 5H), 1.37-1.27 (m, 2H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56](Br)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(=O)([O-])[O-].[K+].[K+].C(COC)OC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C:26]3[S:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[CH:6]=[O:5])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)=[CH:28][CH:27]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C=O)[nH]5)cc4)s3)cc2[nH]1
Temperature: 110 °C
Yield: 66.2 %

Procedure:
A mixture of 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh3)4 (0.012 g) in 2.0M potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at 110° C. for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.085 g) as a bis-TFA salt: LCMS-ESI+: calc'd for C38H45N6O4S: 681.86 (M+H+). Found: 681.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[C:5]([CH:8]=[O:9])[S:4][N:3]=1.[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O>O>[C:11]1([S:17]([C:6]2[C:2]([Cl:1])=[N:3][S:4][C:5]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1snc(Cl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1snc(Cl)c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
A mixture of 3,4-dichloroisothiazole-5-carbaldehyde (0.087 g), benzenesulfinic acid sodium salt (0.078 g) and dimethyl sulfoxide (3.0 mL) was stirred at room temperature for 3.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a colourless oil (0.093 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][O:15][Si](C)(C)C.[H-].[Na+].[CH2:29]([N:31]([CH2:45][CH3:46])[C:32](=[O:44])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:32]([N:31]([CH2:45][CH3:46])[CH2:29][CH3:30])=[O:44])=[CH:39][CH:38]=1)(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][OH:15]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)OCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.42 h
Yield: 32.2 %

Procedure:
A solution of 1.084 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(trimethylsilyloxy)ethyl]-amino]indol-2-one in 20 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.111 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 25 minutes, 0.78 g of 4-(N',N'-diethylureido)-benzenesulfonyl chloride is added and the reaction mixture is stirred for 3 hours at RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.505 g of the expected product after crystallization and then recrystallization from a DCM/iso ether mixture. M.p.=192°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCCC(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCCC(C)C
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (ESI+) m/z 342, 344 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:13][CH3:14])([CH2:24][OH:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(CC)C(=O)OC
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
5.2 ml (0.037 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 12.9 ml (0.035 mol) of n-butyllithium (2.7 M in heptane) in 17 ml of THF, and the mixture is stirred at 20° C. for 15 min. Within approx. 10 min, 5 g (0.032 mol) of methyl 2-ethylhexanoate are added dropwise at 20° C., and the mixture is stirred at 20° C. for a further 30 min and subsequently admixed with 2.9 g (0.097 mol) of paraformaldehyde. After stirring at 20° C. for 2 hours, a saturated aqueous solution of ammonium chloride (20 ml) is added and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 20 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 77% (GC).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[C:41]([F:52])([F:51])[F:40])=[CH:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccccc1C(F)(F)F)n2S(=O)(=O)c1ccccc1
Yield: 80.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 31, 350 mg, 0.62 mmol), 4-(trifluoromethyl)phenylboronic acid (293 mg, 1.54 mmol) and dichlorobis(triphenylphosphine)palladium (II) (43 mg, 0.06 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 0.8 mL, 1.6 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (272 mg, 82%) as a light yellow solid: LC/MS m/e calcd for C28H25F3N2O4S [M+H]+ 543.58, observed 543.2.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1.[C:26](OCC)(=[O:28])[CH3:27]>CCCCCC.O1CCCC1>[C:20]1([N:17]2[CH2:18][CH2:19][C:15]([N:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[C:26](=[O:28])[CH3:27])=[N:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
1.7M n-butyl lithium in hexane (7.0 ml) was added dropwise to a solution of 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine (2.67 g) in tetrahydrofuran (150 ml) at -25° under N2. After 40 minutes ethyl acetate was added and the solution was allowed to reach room temperature. After being stirred for 2 hours, the solution was evaporated to dryness and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on trituration with ether. The solid was recrystallised from ether and hexane to give the title compound (0.82 g) mp 83°-5° (dec).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].[O-:31][CH2:32][CH3:33].[Na+].O.Cl>CCO>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:31][CH2:32][CH3:33]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl
Yield: 80.8 %

Procedure:
A solution of 50 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 30 mg sodium ethoxide in 3 ml EtOH containing 5% of water was heated to 120° C. for 2 min using a microwave reactor. The reaction mixture was acidified to pH 4 with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 40 mg 2-{[1-(5-chloro-6-ethoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ncsc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncsc1C(O)C(F)(F)F
Yield: 84.5 %

Procedure:
According to Reference Example 8-2, by use of 4-methylthiazole-5-carbaldehyde (300 mg, 2.36 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (65 mg, 0.47 mmol) and (trifluoromethyl)trimethylsilane (0.419 mL, 2.83 mmol), the mixture was stirred and reacted at room temperature for 2.2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(4-methylthiazol-5-yl)ethanol (Compound DT) (393 mg, yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
1-Hydroxy-cyclopropanecarboxylic acid methyl ester (Acros; 1.00 g, 8.61 mmol) in 24 mL of THF was stirred with 516 mg (12.9 mmol) of NaH (60% in mineral oil) for 10 min. Benzyl bromide (1.13 mL, 9.37 mmol) and Bu4I (0.32 g, 0.85 mmol) were then added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with saturated NH4Cl. The wash was extracted once with EtOAc, and the combined extracts were washed with brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–50% EtOAc in hexanes) to provide 774 mg (3.75 mmol) of 1-benzyloxy-cyclopropanecarboxylic acid methyl ester that was dissolved in 14 mL of 1:1 Is EtOH/THF. Sodium hydroxide (1M, 5.63 mL) was added, and the mixture was stirred for 4 h. After concentrating, 5 mL of water was added and the solution was extracted once with Et2O. The aqueous layer was then adjusted to pH 3 with HCl, and the suspension was extracted twice with EtOAc. The extracts were washed with brine, dried with Na2SO4, filtered, and concentrated to provide 723 mg of 1-Benzyloxy-cyclopropanecarboxylic acid. To the above acid (3.76 mmol) in 10 mL of CH2Cl2 was added 2.82 mL (5.64 mmol) of 2M oxalyl chloride in CH2Cl2 and one drop of DMF. After stirring for 15 min, the mixture was concentrated and redissolved in 4 mL of MTBE and 0.15 mL of CH2Cl2 and chilled to 0° C. Ammonium hydroxide (28% in water; 0.78 mL) was added, and the mixture was stirred for 15 min when 1 mL of saturated NaHCO3 was added. The mixture was extracted twice with EtOAc, and the extracts were combined, washed with brine, dried with Na2SO4, filtered, and concentrated to provide 550 mg of 1-benzyloxy-cyclopropanecarboxylic acid amide as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.O[C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:35])[CH:19]=1>>[CH:1]1([CH2:4][CH2:5][O:6][C:18]2[CH:23]=[CH:22][N:21]([C:24]3[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=3)[C:20](=[O:35])[CH:19]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Product: CCOC(=O)c1sc(-n2ccc(OCCC3CC3)cc2=O)nc1C
Yield: 35 %

Procedure:
Following the procedure as described in Example 15, making variations only as required to use 2-cyclopropylethyl-4-methylbenzenesulfonate in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 35% yield: mp 188-190° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (dd, J=8.1, 1.1 Hz, 1H), 6.17-6.13 (m, 1H), 6.00-5.99 (m, 1H), 4.35-4.27 (m, 2H), 4.04 (t, J=6.6 Hz, 2H), 2.68 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 1.35 (dt, J=7.1, 1.3 Hz, 3H), 0.90-0.68 (m, 1H), 0.52-0.44 (m, 2H), 0.14-0.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.9, 162.2, 156.6, 155.6, 131.3, 119.7, 104.1, 96.7, 69.1, 60.9, 33.6, 17.3, 14.3, 7.5, 4.2; MS (ES+) m/z 349.2 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[O:20][CH3:21]>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH:1]=[O:3])=[C:13]([O:20][CH3:21])[CH:14]=1)#[N:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C#N)ccc1N
Solvent: O=CO
Product: COc1cc(C#N)ccc1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.65 mL, 6.7 mmol) was cooled in an ice bath and formic acid (0.38 mL, 10 mmol) was added with stirring. The ice-bath was removed and the mixture was stirred for a further 60 minutes. The reaction was re-cooled in the ice-bath and 4-amino-3-methoxybenzonitrile (0.25 g, 1.58 mmol) was added. The reaction was stirred at ice-bath temperature for 5 minutes, then at room temperature for 60 minutes. The reaction was concentrated in vacuo, azeotroped with toluene and the title compound was precipitated from ether/hexanes as a white powder (255 mg, 71.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(1-benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.7 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (8.02 g, 21.3 mmol, prepared as described in Example 1), TMS-acetylene (3.80 mL, 26.4 mmol), Pd(PPh3)2Cl2 (1.52 g, 2.12 mmol), CuI (405 mg, 2.12 mmol), and i-Pr2NH (6.00 mL, 42.6 mmol) in THF (120 mL) was stirred for 3 days at room temperature. The reaction mixture was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4, and filtered. The organic layer was concentrated to give the crude material which was purified by silica gel flash column chromatography (100% Hexane to 1% to 2% EtOAc in Hexane) to afford the desired product (7.11 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](C(=O)NCc3nccnc3Cl)CC2)CC1

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (40.7 mmol, 10.9 g) in dichloromethane (145 ml) and acetic acid (1.450 ml) at room temperature was added 1-methylpiperazine (52.9 mmol, 5.87 ml, 5.30 g) and sodium cyanoborohydride (81 mmol, 5.12 g). After 16 hours at room temperature dichloromethane and an aqueous saturated sodium hydrogencarbonate solution (15 mL) were added and the organic layer was separated. This organic layer was washed with brine. The aqueous layers were washed with dichloromethane twice and the combined organic extracts dried (sodium sulfate). Concentration in vacuo gave the crude product (mixture of cis and trans), which was purified using column chromatography (silica gel; dichloromethane/methanol gradient (0 to 20% methanol) to afford the cis isomer (275 mg), the trans isomer (2.5 g) and a mixture of cis and trans isomers (5.5 g).