Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1>>[CH3:30][C:25]1[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:23]=2)=[C:28]([CH3:29])[O:27][N:26]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.44 (s, 2H), 2.71 (s, 3H), 2.66 (s, 3H), 2.49 (s, 3H); MS (ES) m/z 402 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:60][O:61][C:62](=[O:65])[CH2:63]Br>CCOCC.C(Cl)Cl>[C:62]([CH2:63][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1)([O:61][CH3:60])=[O:65]
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.126 g (0.258 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 6 mL of ether was added 0.082 g (0.31 mmol) of 18-crown-6 and 0.31 mL (0.31 mmol) of potassium t-butoxide (1M in t-BuOH). After stirring the reaction mixture at rt for 15 min, the reaction mixture was cooled to 0° C. and to it was added 0.034 mL (0.36 mmol) of methyl-2-bromoacetate. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with sat. NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated and purified by chromatography (silica, hexanes: acetone, 3:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:5]=1.O=P(Cl)(Cl)[Cl:23]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16]([Cl:23])[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(/C=C/c2nc(C)cc(O)n2)c1
Product: COC(=O)c1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Yield: 45.4 %

Procedure:
In analogy to example 12c), by heating (E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzoic acid methyl ester (2 g, 7.4 mmol) in POCl3 (13.6 ml, 0.15 mol) at 130° C. for 4.5 h there was obtained (E)-3-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzoic acid methyl ester (0.97 g, 45%) as a light-yellow solid. EI mass spectrum, m/e: 288.1 (M calculated for C15H13ClN2O2: 288).
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH3:11])[CH:7]=[CH:6]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[H-].[Na+].[CH2:45]([C:49]1[NH:50][C:51]2[C:52]([N:57]=1)=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:46][CH2:47][CH3:48]>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[CH2:45]([C:49]1[N:57]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:2]([Br:1])[N:3]([C:12]4[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=4[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=3)[CH:9]=2)[C:52]2=[N:53][CH:54]=[CH:55][CH:56]=[C:51]2[N:50]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCc1nc2ncccc2[nH]1
Reactant: CCOC(=O)c1ccccc1-n1nc2ccc(C)cc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCc1nc2cccnc2n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Yield: 40.5 %

Procedure:
Carbon tetrachloride (4 ml) was added to ethyl 2-(3-bromo-5-methyl-2H-indazol-2-yl)benzoate (0.300 g, 0.835 mmol) as obtained in Reference Example 4, and the mixture was stirred. Thereto were added N-bromosuccinimide (0.149 g, 0.835 mmol) and azobisisobutyronitrile (14 mg, 0.0835 mmol), and the mixture was refluxed under heating for 3.5 hours. After cooling, the mixture was filtered, and the cake was washed with carbon tetrachloride (1 ml) and the filtrate was concentrated. The residue was then dissolved in DMF (dimethylformamide, 1 ml) and added to a solution obtained by adding sodium hydride (27 mg, 0.668 mmol) to 2-butyl-1H-imidazo[4,5-b]pyridine (0.117 g, 0.668 mmol) in DMF (2 ml) and stirring the solution for 30 minutes. The mixture was stirred at room temperature for 30 minutes, concentrated, and partitioned by ethyl acetate (5 ml) and water (5 ml). The organic layer was washed twice with water (5 ml), dried over magnesium sulfate, and then filtered. The filtrate was concentrated and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (1:2), whereby 0.144 g of 2-butyl-3-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-3H-imidazo[4,5-b]pyridine was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCCl
Reactant: Oc1c(Br)cccc1Br
Product: COCOc1c(Br)cccc1Br
Yield: 99.9 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 19.16 g (76.1 mmol) of 2,6-dibromophenol with 7.35 g (91.3 mmol) of chloromethyl methyl ether, 22.50 g (100%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=O.[C:17]([N:34]([NH:36][CH3:37])[CH3:35])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([N:34]([CH3:35])[N:36]([CH2:1][C:3]3[N:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH3:37])=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CNN(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=Cc1cc2ccccc2n1CCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1CCC(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h
Yield: 62 %

Procedure:
Compound 3 was synthesized from Compound 2 as follows. To a solution of Compound 2 (1.193 g, 5.492 mmol) and FmocN(Me)NHMe (2.147 g, 7.604 mmol, 1.38 equiv) in 1,2-dichloroethane (anhydrous, 25 mL) was added sodium triacetoxyborohydride (1.273 g, 6.006 mmol, 1.09 equiv). The resulting yellow suspension was stirred for 2 h and then quenched with sodium bicarbonate (saturated aqueous solution, 10 mL), followed by addition of hydrogen chloride (1 M aqueous solution) to pH 4. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (5×10 mL). The pooled organic extracts were dried over sodium sulfate, filtered, and concentrated to an orange oil. Purification by C18 silica gel chromatography (20-90% acetonitrile in water) yielded 3 as a waxy pink solid (1.656 g, 3.425 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 2H), 7.70-7.47 (br m, 3H), 7.42-7.16 (br m, 6H), 7.12-7.05 (m, 1H), 6.37 (s, 0.6H), 6.05 (s, 0.4H), 4.75-4.30 (br m, 4H), 4.23 (m, 1H), 4.10 (br s, 1H), 3.55 (br d, 1H), 3.11-2.69 (m, 5H), 2.57 (br s, 2H), 2.09 (br s, 1H). 13C NMR (101 MHz, CDCl3) δ 174.90, 155.65, 143.81, 141.42, 136.98, 134.64, 127.75, 127.48, 127.12, 124.92, 122.00, 120.73, 120.01, 119.75, 109.19, 103.74, 67.33, 66.80, 51.39, 47.30, 39.58, 39.32, 35.23, 32.10. HRMS (ESI) calcd for C29H30N3O4 [M+H]+: 484.2236. found: 484.2222.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3cccc(C(F)(F)F)c3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluoro-3-(trifluoromethyl)phenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=298.1 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>COCCOC.C(OCC)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:23])=[CH:9][C:10]#[N:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(C(C)=CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethylcyanomethylphosphonate (85 g) is added dropwise to a stirred suspension of sodium hydride (19.2 g) in 1,2-dimethoxyethane (400 ml) under nitrogen. The solution is cooled in an ice bath and a solution of paramethoxyacetophenone (48 g) in 1,2-dimethoxyethane (80 ml) is added dropwise. The reaction mixture is stirred at RT for three hours and diluted with diethyl ether, washed, dried, filtered and evaporated in vacuo affording the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[N:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[N:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 2.78 mmol) in DMF (14 mL) was added NaH (60% in mineral oil, 278 mg, 6.95 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Dichloropyridine (1.23 g, 8.34 mmol) was added and the mixture was heated at 70° C. for 3 hours. Standard work-up and purification afforded 4-[(4-bromo-phenyl)-(6-chloro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid (1.28 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[N:6]=1)=[O:4].[F:17][C:18]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:19]=1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:23]2[CH:24]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C:19]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:18]=2[F:17])[N:6]=1)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Reactant: COC(=O)c1cccc(C2=C(Br)CCC2)n1
Product: COC(=O)c1cccc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)n1

Procedure:
Prepared by general procedure 3 but using 6-(2-bromocyclopent-1-enyl) -pyridine-2-carboxylic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-(2,4-difluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([Cl:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Cl:6])[C:8]([Cl:16])=[N:9][CH:10]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 4 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
4.45 mL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 mL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 4° C., neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH:11]=[C:10]([NH:23]C(OC(C)(C)C)=O)[N:9]=1)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:12]2[CH:13]=[C:8]([NH2:7])[N:9]=[C:10]([NH2:23])[CH:11]=2)[CH:19]=1
Reactant: COc1ccc(Cl)cc1-c1cc(NC(=O)OC(C)(C)C)nc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [6-tert-butoxycarbonylamino-4-(5-chloro-2-methoxy-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (220 mg, 0.49 mmol) in dichloromethane (8 ml) was added trifluoroacetic acid (6 ml). After stirring for 1 hour, volatiles were evaporated under reduced pressure. Treatment with toluene (15 ml) and evaporation of volatiles under reduced pressure provided 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt (180 mg, 100% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:31][OH:32])[CH:17]=2)=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:31][OH:32])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Product: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid acid and 4-[5-[4-Bromophenyl]-3-hydroxymethyl-[4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole in step 2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:31][OH:32].C1COCC1>C(#N)C.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4](/[C:1](=[N:31]/[OH:32])/[CH3:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reactant: NO
Agent: [Ti+4]
Agent: CC[O-]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: C/C(=N\O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 60 °C

Procedure:
A 4 mL vial was charged with 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedures F and G, 100 mg, 0.23 mmol), hydroxylamine hydrochloride (49 mg, 0.70 mmol), and 2 mL THF. The resultant slurry was mixed well, then titanium ethoxide (98 μL, 47 mmol) was added and the mixture heated to 60° C. overnight. The reaction mixture was subsequently diluted with ˜2 mL of acetonitrile/H2O and purified by reversed phase HPLC to afford N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-{1-[(E)-hydroxyimino]-ethyl}benzenesulfonamide: MS (ES) M+H expected 443.0, found 443.0.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[OH:12][C:13]1[CH:14]=[C:15]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:16]=[CH:17][CH:18]=1>>[CH3:26][O:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:10][C:9]#[C:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:14]=2)[CH2:23][CH2:22][O:21][CH:20]1[CH3:24]
Reactant: BrCC#Cc1ccccn1
Reactant: COC1(c2cccc(O)c2)CCOC1C
Agent: Br
Product: COC1(c2cccc(OCC#Cc3ccccn3)c2)CCOC1C
Yield: 90 %

Procedure:
Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with (2RS,3SR)-3-(3-hydroxyphenyl)-3-methoxy-2-methyltetrahydrofuran to give (2RS,3SR)-3-methoxy-2-methyl-3-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]tetrahydrofuran, as an oil in 90% yield.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cnc2ccccc2n1
Yield: 41 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.27 g), 2-quinoxalinylcarbonyl chloride (0.29 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and evaporated. The residue was triturated under ethyl acetate. There was thus obtained the title compound as a solid (0.175 g); NMR Spectrum: (DMSOd6) 2.31 (s, 3H), 2.95 (s, 6H), 3.31 (s, 3H), 6.91 (d, 1H) 7.27 (m, 4H), 7.59 (d, 1H), 8.01 (m, 2H), 8.24 (m, 3H), 9.56 (s, 1H), 10.15 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:33]=[CH:32][C:18]4[NH:19][C:20]([CH2:22][O:23]C(=O)C5C=CC=CC=5)=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:34]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:33]=[CH:32][C:18]4[NH:19][C:20]([CH2:22][OH:23])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OCc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2[nH]1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2[nH]1
Yield: 57 %

Procedure:
To a stirred mixture of 8.8 parts of {5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1H-benzimidazol-2-ylmethyl}benzoate and 120 parts of methanol are added 13.5 parts of sodium hydroxide solution 50% and the whole is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is stirred in water. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 45 parts of methylbenzene. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 4 parts (57%) of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1H-benzimidazole-2-methanol; mp. 137.1° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[C:7]([OH:9])=[O:8].[CH3:21][Si](C=[N+]=[N-])(C)C>>[F:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:6]=1[C:7]([O:9][CH3:21])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[Si](C)(C)CCOCn1c(C(=O)O)c(F)c2sccc21
Product: COC(=O)c1c(F)c2sccc2n1COCC[Si](C)(C)C
Yield: 0.8 %

Procedure:
4-(2-Trimethylsilanyl-ethoxymethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (1.9 g, 6.4 mmol) was dissolved in anhydrous THF (250 mL) and cooled to −78° C. n-BuLi (1.6 M in hexanes, 12 mL, 19.2 mmol, 3 equiv) was added over 5 min and stirred at −78° C. for 60 min. A solution of NFSI (3.1 g, 9.6 mmol, 1.5 equiv) in 15 mL anhydrous THF was added over 15 min and the reaction was stirred at −78° C. for 5 h and then allowed to warm to rt overnight. The reaction was cooled in an ice bath, quenched with 6N HCl, and then extracted with EtOAc and evaporated in vacuo to give 5.5 g of dark residue. The residue was chromatographed over silica gel (DCM in EtOAc) to give a more pure residue. This residue was further purified via prep reverse phase HPLC (RP-HPLC) to give 360 mg of the 2-fluoro isomer (2-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid) and a separate mixture of starting material and 6-fluoro isomer (6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid). This latter mixture was converted to the corresponding methyl ester via TMSCH2N2. The mixture of esters was chromatographed over silica gel (EtOAc in heptane, 5%-20%) to give methyl 6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (16 mg, 0.0485 mmol, 0.8% yield). 1H NMR (400 MHz, (CD3)2CO) δ ppm −0.08 (s, 9H) 0.80-0.87 (m, 2H) 3.49-3.57 (m, 2H) 3.87 (s, 3H) 5.88 (s, 2H) 7.29 (dd, J=5.32, 2.20 Hz, 1H) 7.66 (d, J=5.32 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.[NH2:21][NH2:22]>>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:21][NH:22][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)c1cc(F)ccc1C(=O)c1ccc(F)cc1
Solvent: O
Product: O=c1[nH]nc(-c2ccc(F)cc2)c2ccc(F)cc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-fluoro-2-(4-fluorobenzoyl)benzoic acid with hydrazine hydrate.