Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:25].[Na+]>CC(=O)CC>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][I:25])[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccc(OCCI)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 10 mL of 2-butanone was added sodium iodide (8.73 mmol, 1.31 g). The solution was heated at reflux for 48 hours, cooled to room temperature, and concentrated to afford the crude product, 5-(2-iodo-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester: MS(APCI+): m/z 436.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[Se](=O)=[O:18].[CH2:20]([OH:22])[CH3:21]>>[OH:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:3](=[O:4])[C:2]([O:22][CH2:20][CH3:21])=[O:18])=[CH:6][C:7]=1[O:15][CH3:16]
Reactant: O=[Se]=O
Reactant: CCO
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Product: CCOC(=O)C(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1

Procedure:
ba) A suspension of 580.1 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanol is treated with 443.8 mg of selenium dioxide and heated under reflux for 71 hours. Thereafter, the selenium is removed by filtration and the filtrate is evaporated. The residue is dissolved in methylene chloride, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 165°-167° (from ethanol).
Reaction SMILES: [CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:51])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:51])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(=O)OCCCCCCCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=C(COCCCCCCO)COC(=O)OCCCCCCCCCCCCCCCC

Procedure:
3-Hexadecyloxycarbonyloxy-1-[6-(triphenylmethoxy)hexyloxy]-2-methylenepropane (from Preparation 50) (1.95 g), 4-toluenesulfonic acid monohydrate (60 mg) and water (0.15 ml) were stirred in methylene chloride (30 ml) for 24 hours at 22° C. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500 cartridge with ether/chloroform/pentane 1:1:10 followed by ether/chloroform 1:1 as eluents.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
617 mg (2.82 mmol) of the compound from Example 156A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT overnight, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 155 mg (14% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[NH:8][C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4].Cl[CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH2:33][O:34][CH3:35])[C:7](=[O:14])[C:6]=1[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 4′-[(7-butyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (0.88 g), chloro(methoxy)methane (0.19 mL), potassium carbonate (0.58 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 79%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])=[O:4])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH2:39])[CH3:32]>O1CCCC1>[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH:39][C:16]([C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:7]=1)=[O:18])[CH3:32]
Reactant: CCN1CCCC1CN
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Temperature: 25 °C
Yield: 76.7 %

Procedure:
13 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of tetrahydrofuran and 13 g of carbonyldiimidazole were introduced into a balloon flask provided with an agitator, a thermometer and a condenser. The mixture was agitated at ambient temperature and then 9.5 g of 1-ethyl-2-aminomethylpyrrolidine was added. Agitation was maintained at ambient temperature and then the solvent was evaporated under vacuum. The crystals produced were washed with water and then dried. 14 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 118°-119° C.; yield: 73.8%)
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[N:28]1[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Reactant: C[C@H]1CC[C@H](C)N1
Product: C[C@H]1CC[C@H](C)N1CC1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Yield: 98.1 %

Procedure:
A mixture of intermediate (14) (0.0022 mole) in methanol (100 ml) was hydrogenated at 50° C. with palladium-on-carbon (10%) (0.1 g) as a catalyst in the presence of a 4% thiophene solution (0.1 ml). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in hexane. The precipitate was filtered off and dried, yielding 0.7 g of (±)-methyl 1-(4-aminophenyl)-α-phenyl-4-piperidineacetate (intermediate 15, melting point 125° C.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:33][C:11]2[N:12]=[C:13]([NH2:32])[N:14]=[C:15]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:19]([Cl:30])=[CH:18][C:17]=3[Cl:31])[C:10]=2[CH:9]=1)=[O:7])C.C(O)C>O>[NH2:32][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]([Cl:30])=[CH:18][C:17]=2[Cl:31])[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:33][C:11]=2[N:12]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1

Procedure:
Sodium hydroxide (0.190 g; 4.75 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (step 4 example 235). Ethanol (25 ml) was added followed by water (2.5 ml) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool and solvents were removed in vacuo. The resulting residue was dissolved in water and stirred in ice-water bath and the neutralised by the drop-wise addition of 37% (aq) hydrochloric acid solution. The reaction mixture was freeze dried to afford product as a yellow powder (containing 2 equivalents of NaCl) 1.33 g; 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[O:17]([NH2:19])C.[C:20]([O-])(=O)C.[Na+].O(N)C>C(O)C>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[N:19][OH:17])[CH2:10]1
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Reactant: CC(=O)[O-]
Reactant: CON
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(O)ccc1C1CCCC(=NO)C1
Reaction time: 6 h

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (22 mg), methoxylamine hydrochloride (18 mg) and sodium acetate (18 mg) were heated under reflux in ethanol. After 6 hr, further methoxylamine (36 mg) and sodium acetate (36 mg) were added and the mixture heated under reflux for a further 1 hr. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a mixture of isomers (18 mg, 72%). δH(CDCl3) 1.5-2.2 (6H, overlapping m), 2.42 (0.5H, bd), 2.69 (0.5H, bd), 2.92 (0.5H, m), 3.06 (0.5H, m), 3.24-3.38 (1H, m), 3.81 (1.5H, s), 3.88 (1.5H, s), 5.42 (0.5H, bs), 5.47 (0.5H, bs), 6.28-6.42 (2H, overlapping m), 6.86 (0.5H, bs), 6.98 (1H, m), 7.06 (0.5H, bs); m/z (ES−) 469 (2M−1)−.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][NH:36][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 44 %

Procedure:
Following the procedure described above in Example 34, 6-Fluoro-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.12 g, 44%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 4 H) 2.6 (t, J=6.8 Hz, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.6 (t, J=5.6 Hz, 1 H) 7.0 (m, 2 H) 7.1 (m, 4 H) 7.4 (m, 3 H) 8.2 (s, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C=CC([N-:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:31]([OH:33])=O)=[CH:29][N:30]=2)=[CH:22][CH:21]=1>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:31]([C:28]1[S:27][C:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)=[N:30][CH:29]=1)=[O:33]
Reactant: O=C(C=Cc1ccc(Cl)cc1Cl)[N-]CCCCO
Reactant: O=C(O)c1cnc(-c2ccc(Cl)cc2)s1
Product: O=C(NCCCCO)c1cnc(-c2ccc(Cl)cc2)s1
Yield: 95 %

Procedure:
2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid (4-hydroxy-butyl)-amide (19A) is prepared as described for 17A starting with 2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:15][CH2:16][CH2:17][CH3:18].ICCCC>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccs1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
N-tert-Butylthiophene-2-sulfonamide (5 g, 0.0228 mol, see Example 1(a) above) was dissolved in THF (43 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 38.5 mL, 0.062 mol) was added via a syringe. The reaction mixture was stirred at −78° C. for 30 min and then at −40° C. for 2 h. Iodo-butane (5.19 mL, 0.046 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature, quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic phase was washed with brine, dried and concentrated in vacuo. The crude product was purified on column chromatography (Hex:EtOAc 10:1) to give the sub-title compound in 46% yield (2.92 g, 0.011 mol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12]CCO1.C([Li])(C)(C)C.[Li]C1C=CC=CC=1C1OCCO1.[S:30]1[CH:34]=[CH:33][C:32]2[CH2:35][CH2:36][C:37](=O)[C:31]1=2>>[S:30]1[CH:34]=[CH:33][C:32]2[CH2:35][CH:36]=[C:37]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH:8]=[O:12])[C:31]1=2
Reactant: O=C1CCc2ccsc21
Reactant: Brc1ccccc1C1OCCO1
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1C1OCCO1
Product: O=Cc1ccccc1C1=CCc2ccsc21

Procedure:
This scheme can be summarized as follows: 2-(2-bromophenyl)-1,3-dioxolane (A) is treated with 2 equivalents of tert-butyl lithium to effect halogen-methyl exchange. The 2-(2-lithiophenyl)-1,3-dioxolane (B) is then reacted in situ with 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one. After aqueous acid workup, 2-(4H-cyclopenta[b]thiophen-6-yl)benzaldehyde (C) is isolated by flash chromatography. This is treated with a Grignard reagent (R4MgBr) to provide the 6-[2-(1-hydroxyalkyl)phenyl]-4H-cyclopenta[b]thiophene (D) which is subsequently oxidized to the 6-[2-(alkylcarbonyl)phenyl]-4H-cyclopenta[b]thiophene (E). Reductive amination of E should then provide compounds of structure III.
Reaction SMILES: [N:1](OCCCC)=[O:2].[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18](C)[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:17]([CH3:27])[C:18](=[N:1][OH:2])[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCON=O
Reactant: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC1C(C(=O)N(c2ccccc2)c2ccccc2)=CC=C(S(C)(=O)=O)C1=NO
Temperature: 0 °C

Procedure:
A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97% pure) and 2 g (5.3 mmol) of N,N-diphenyl-2,3-dimethyl-4-methylsulfonylbenzamide in 30 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the pH is subsequently adjusted to 5-6 using glacial acetic acid. The reaction mixture is subsequently poured into 100 ml of ice-water, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.0 g of a partially crystalline crude product which is purified by silica gel chromatography using toluene/acetone as mobile phase.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:44][CH3:45])=[C:10]([CH2:19][NH:20][C:21](=[O:43])[CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37](C=O)[CH:36]=4)[C:31]([F:34])=[CH:32][CH:33]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C[C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1[C:53](OC(C)(C)C)=O.[C:60](O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:44][CH3:45])=[C:10]([CH2:19][NH:20][C:21](=[O:43])[CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([C:35]4[CH:36]=[CH:37][CH:38]=[C:39]([CH2:53][N:48]5[CH2:47][CH2:52][NH:51][C@@H:50]([CH3:60])[CH2:49]5)[CH:40]=4)[C:31]([F:34])=[CH:32][CH:33]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(=O)O
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
In an alternate preparation of the above titled compound previously described in Examples 135 and 143, N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]butanediamide (36.9 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and to the filtrate were added MeOH (2.0 mL) and 1 drop of concentrated HCl. This solution was heated at 60 C. ° for 12 h. Purification was completed via reverse phase HPLC using a Gilson (acidic conditions with 0.1% TFA in the solvents). The product after HPLC purification was dissolved in 3 mL of MeOH and passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 16.3 mg of the title compound (38.9%). LC-MS m/z 700 (M+H)+, 0.66 min (ret time).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=O.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[O-:24]CC.[Na+].O>C(OCC)C>[OH:24][CH:18]([C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[CH2:1])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCl
Reactant: CC[O-]
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=C(c1cccc(Oc2ccccc2)c1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 9.7 g of 3-phenoxyacetophenone and 12.2 g of ethyl chloroacetate in 30 ml of ethyl ether was vigorously stirred, and 8.8 g of sodium ethoxide was gradually added thereto in a nitrogen stream at 5°-6° C. over a period of 1 hour. After stirring at 6° C. for 1 hour, at 25° C. for 1 hour and at refluxing temperature for 1 hour, the mixture was cooled and charged with ether and water, thereby effecting ether extraction. The ether layer was washed with water and then dried over anhydrous sodium sulfate. The ether was removed by distillation under reduced pressure. The residue was dissolved in 150 ml of butyl ether, and the solution was charged with 12 g of aluminum chloride and refluxed with stirring at 80° C. for 5 hours. After cooling, the mixture was charged with dilute hydrochloric acid and, after stirring for 20 minutes, the butyl ether layer was separated, and the aqueous layer was extracted with butyl ether. The extract was combined with the separated butyl ether layer, and the combined layer was successively washed with water, aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The butyl ether was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4.5 g of ethyl 2-hydroxy-3-(3-phenoxyphenyl)-3-butenoate. The yield was 46%.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.Br[C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1.Br[C:22]1[CH:23]=[C:24]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>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>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[O:14][C:10]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:23]=2)=[CH:11][CH:12]=1
Reactant: Fc1cc(Br)cc(-n2ccnc2)c1
Reactant: Brc1ccc(-c2ccccn2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Product: Fc1cc(-c2ccc(-c3ccccn3)o2)cc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 19 h
Yield: 65.8 %

Procedure:
Title compound synthesis: Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of hexamethylditin (169 mg, 0.52 mmol) and 5-bromo-2-(2-pyridyl)-furan (90 mg, 88% purity, 0.36 mmol) in toulene (2 mL) under argon. The resulting solution was stirred at 80° C. for 19 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (10 mg, 0.009 mmol) and 1-(3-bromo-5-fluoro-phenyl)-lH-imidazole (86 mg, 0.36 mmol) were added and the resulting solution was stirred at 110° C. for 36 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 0-3% methanol in 1:1 chloroform:ethyl acetate) afforded 72.3 mg (66%) of 2-(2-pyridyl)-5-(5-fluoro-3-(1-imidazolyl)phenyl)-furan. 1H-NMR (CDCl3), δ (ppm): 8.63 (d, 1H), 7.93 (s, 1H), 7.78 (m, 2H), 7.57 (s, 1H), 7.45 (m, 1H), 7.35 (s, 1H), 7.23 (m, 3H), 7.03 (m, 1H), 6.91 (d, 1H).