Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([OH:17])[CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[Cr](O)(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)c1cccc(Oc2ccccc2)c1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCC(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h

Procedure:
A solution of 35 g of 1-(3-phenoxyphenyl)propan-1-ol and 50 ml of ethyl ether is treated with 1.1 equivalants of chromic acid, which is added dropwise over a 30 minute period. The reaction mixture is allowed to warm to 20°-25° C. and stirred for about 2 hours. Then the reaction mixture is added to a mixture of 25 ml of ethyl ether and 50 ml of water, and sodium carbonate is slowly added to neutralize the acid. The phases are separated and the aqueous phase is reextracted twice with ethyl ether. The ethereal extracts are combined and evaporated under reduced pressure to yield 1-(3-phenoxyphenyl)-propan-1-one as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([C:20]4[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=4)[CH2:25][CH2:26]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)OCCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: CC[Mg+].[Br-].C[C:6]([OH:9])(C)C.[CH3:10][C:11]([CH3:13])=[O:12].[Br:14][CH:15]([CH2:23][CH3:24])[C:16]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=[O:17]>C1C=CC=CC=1>[Br:14][CH:15]([CH2:23][CH3:24])[C:16]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=[O:17].[S:20]1[CH:21]=[CH:22][C:18]([CH:16]([CH2:15][CH3:23])[C:6](=[O:9])[CH2:10][C:11](=[O:12])[CH3:13])=[CH:19]1
Reactant: CC(C)(C)O
Reactant: CC(C)=O
Agent: CCC(Br)C(=O)c1ccsc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: c1ccccc1
Product: CCC(C(=O)CC(C)=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
EtMgBr (6.69 ml, 13 mmol, 2 M in ethyl ether) in benzene (10 ml) was cooled to zero degrees C., and tBuOH (1.28 ml, 13 mmol) was slowly added. The reaction mixture was stirred at zero degrees C. for 5 minutes, then acetone (530 ul, 7 mmol) was added, followed by a solution of 2-Bromo-1-thiophen-3-yl-butan-1-one (1.3 g, 6 mmol) in 3 ml benzene via cannula. The reaction mixture was heated to reflux for 1 hour, and acetone (250 ul) was added. The reaction mixture was heated 2 hours more at reflux. The reaction was cooled, quenched with 1 N HCl (10 ml), extracted three times with diethyl ether, washed brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue chromatographed (5% ethyl acetate/hexanes) to give 247 mg of 2-Bromo-1-thiophen-3-yl-butan-1-one starting material and 520 mg of 5-Thiophen-3-yl-heptane-2,4-dione, 44%.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=O.[C:17]([O:21][C:22]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](=[O:1])[N:3]2[CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:30][CH2:29]2)=[CH:8][CH:7]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-oxo-1-(2-oxoethyl)-1,2-dihydro-7-quinolinecarbonitrile (0.60 g, 2.8 mmol) and 4-t-butoxycarbonylaminopiperidine (0.68 g, 2.8 mmol) in chloroform (30 ml) and MeOH (20 ml) was stirred at 60° C. for 1 h. The mixture was then treated with NaBH(OAc)3 (1.8 g, 8.5 mmol), stirred at rt for 1 h, more 4-t-butoxycarbonylaminopiperidine (340 mg, 1.4 mmol) and NaBH(OAc)3 (1.2 g, 5.7 mmol) were then added and the reaction stirred at rt for 1 h. The solvents were then removed and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford the desired compound (1.1 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:25])[N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:15](CC#N)[C:5]=3[C:4]=2[CH:3]=1.[C:26]([OH:29])(=[O:28])[CH3:27]>Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:25])[N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:15]([CH2:27][C:26]([OH:29])=[O:28])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(Cl)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Reactant: CC(=O)O
Agent: Cl
Product: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 10 g (28 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in a mixture of 200 ml of concentrated hydrochloric acid and of 200 ml of acetic acid is heated at 100° C. for 4 h. The solution is concentrated under reduced pressure, the residue is taken up in 250 ml of water and the precipitate is collected by filtration. It is washed with water and dried under reduced pressure. 10.2 g (27 mmol) of solid are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C=CC(=O)C1=O>[CH:24]1([NH:30][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:12]([O:22][CH3:23])[CH:11]=3)[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: CN1C=CC(=O)C1=O
Product: COc1cc(Nc2nc(C)cc(NC3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 81.5 %

Procedure:
A solution of (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.2 mmol) and cyclohexylamine (60 mg, 0.6 mmol) in N-methylpyrroldione (2 mL) was heated for 30 min to 200° C. in a microwave oven. Additional cyclohexylamine (60 mg, 0.6 mmol) was added and the reaction was heated for 30 min to 200° C. in a microwave oven. The reaction mixture was poured onto water and the precipitate was filtered off, washed with water, dissolved in 1N aqueous sodium hydroxide solution and extracted twice with diethyl ether. The combined organic layers were washed with water, once with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a light brown solid (64 mg, 82%). MS ISP (m/e): 393.4 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (br s, 2H), 7.13 (s, 2H), 6.92 (br s, 1H), 6.86 (s, 1H), 5.75 (s, 1H), 4.61 (m, 1H), 3.85 (s, 3H), 3.69 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.05 (br d, 2H), 1.60-1.82 (m, 4H), 1.18-1.45 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]([OH:9])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C:3]([O:9][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(CC)(CC)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-ethyl-3-hydroxy-5-hexyne (12.6 g) (WO 93/19044), triethylamine (67 ml) and DMAP (0.47 g) in dichloromethane (150 ml) was added, with stirring at 0° C., trimethylchlorosilane (38 ml), during 10 min. Stirring was continued at 0° C. for 15 min. and at 25° C. for 45 min. The reaction mixture was worked up, and the crude product was purified by distillation in vacuo to give the title compound as an oil, b.p. 83-85° C./25 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:8][CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH2:34][NH2:35])[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:19])[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][NH:35][CH2:34][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([I:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC(CN)(c2ccc(I)cc2)CC1
Reactant: CC(C)(C)OC(=O)N(CC=O)c1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CNCCN(C(=O)OC(C)(C)C)c2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a stirred solution of (3,4-difluorophenyl)-(2-oxo-ethyl)-carbamic acid-tert-butyl ester (1.23 g, 4.3 mmol) in MeOH (35 mL) under Ar at room temperature was added a solution of C-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-yl]-methylamine (1.49 g, 4.5 mmol, 1.05 eq.) in MeOH (10 mL). The mixture was stirred at room temperature for 5 h then NaBH4 (0.255 g, 6.75 mmol, 1.5 eq) was added and the resulting mixture was stirred for a further 1 h and then was quenched by the addition of 1N aqueous NaOH (40 mL). The mixture was extracted twice with Et2O (2×50 mL) and the combined organic extracts were washed with saturated brine (100 mL) and dried over Na2SO4. Filtration and concentration of the filtrate by rotary evaporation gave the crude product which was purified by flash column chromatography by eluting with 12% EtOAc/hexanes to give (3,4-difluoro-phenyl)-(2-{[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester (2.03 g, 76%) as a pale oil. MS (ESI): 585.9/587.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][S:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][S:29][CH:28]([C:32]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C1CN(C(=O)OC(C)(C)C)CCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (150 mg), thiomorpholine-2,4-dicarboxylic acid 4-tert-butyl ester (137 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg), and dimethyl aminopyridine (92 mg) in dichloromethane (15 ml) was stirred at room temperature overnight. After the addition of water (10 ml), the mixture was extracted with 10 ml ethyl acetate three times. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography on silica (20-33% ethyl acetate in hexane) to give the desired product as a resin: MS (m+1)=499.4.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:20]([CH3:22])[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.CO.N>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[C:20]([CH3:22])[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2)c(C)c1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)cnc1-c1ccccc1
Temperature: 60 °C
Yield: 29 %

Procedure:
The solid residue obtained in step A was dissolved in ethanol (5 ml) and aqueous solution 2N NaOH (0.67 ml) was added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SCX cartridge eluting with MeOH/NH3 10:1 affording 0.070 g (yield 29%) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][C:29]([Cl:34])([Cl:33])[C:30](Cl)=[O:31]>>[Cl:28][C:29]([Cl:34])([Cl:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(Cl)(Cl)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and trichloroacetyl chloride (27 mg, 150 μmol). Yield 21 mg (84%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([C:21]3[CH:20]=[C:19]([Br:22])[S:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[N:10]=[C:9]1SCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[NH4+:32]>N.CO>[NH2:32][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[C:11]2([C:21]3[CH:20]=[C:19]([Br:22])[S:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[N:10]=1
Reactant: [NH4+]
Reactant: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CCCc1sc(Br)cc12
Agent: N
Agent: [I-]
Solvent: CO
Product: NC1=NC2(CCCc3sc(Br)cc32)C(=O)N1Cc1ccccc1
Temperature: 90 °C
Yield: 41 %

Procedure:
1′-Benzyl-2′-(benzylthio)-2-bromo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one (0.25 g, 0.5 mmol) and ammonium iodide (0.43 g, 3 mmol) were suspended in 7 N NH3/methanol solution (10 mL). The mixture was heated at 90° C. for 18 hr. The solution was concentrated in vacuo and the crude residue partitioned between water and dichloromethane. The product was extracted into dichloromethane (×3), the organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The crude residue was purified on silica gel using 7 N NH3/methanol in dichloromethane (1:9) to afford the title compound as a foam (80 mg, 41%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[S:7]1[C:3]([CH:2]=[O:1])=[CH:4][C:5]2[S:10][CH:9]=[CH:8][C:6]1=2
Reactant: OCc1cc2sccc2s1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc2sccc2s1

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[CH:6]=[C:7]([C:10]([CH3:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[NH:8][CH:9]=1)([O-:3])=[O:2].P(Br)(Br)([Br:20])=O.C([O-])(O)=O.[Na+]>ClCCCl>[Br:20][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]([CH3:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: CC(C)(c1cc(=O)c([N+](=O)[O-])c[nH]1)C(F)(F)F
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(c1cc(Br)c([N+](=O)[O-])cn1)C(F)(F)F
Temperature: 85 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a mixture of 5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (100 mg, 0.400 mmol) in DCE (10 mL) was added phosphoryl tribromide (138 mg, 0.480 mmol). The mixture was stirred at 85° C. for 1 h. Then the mixture was added to aqueous NaHCO3 solution. The mixture was extracted with EA (50 mL×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford 4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (60 mg, 0.096 mmol, 24.0% yield). TLC (PE/EA=10:1, Rf=0.6): 1H NMR (400 MHz, CD3OD): δ 8.74 (s, 1H), 6.83 (s, 1H), 1.54 (s, 6H). ES-LCMS m/z 312.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: Clc1ccc2c(I)c[nH]c2c1
Temperature: 0 °C

Procedure:
A mixture of 6-chloro-1H-indole (2.0 g, 13.2 mmol) and NIS (4.45 g, 19.8 mmol) in THF (60 mL) is stirred at 0° C. After completion the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords 6-chloro-3-iodo-1H-indole as a colorless powder. A mixture of 6-chloro-3-iodo-1H-indole (4.14 g, 13.2 mmol), TsCl (3.77 g, 19.8 mmol), TBAHS (672 mg, 1.98 mmol) and NaOH (16.0 g, 400 mmol) in THF (60 mL) and H2O (25 mL) is stirred at RT. After completion the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Re-crystallization from EtOAc of the residue affords the title compound as a colorless powder; ES-MS: M−H=430.0: AtRet=8.66 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]([C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[C:15]([N:16]4[CH2:21][CH2:20][C:19](/[CH:23]=[CH:24]/[CH:25]=[CH2:26])([CH3:22])[CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH:23](/[C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:7]=[CH:6][CH:5]=4)[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]=2[C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:21][CH2:20]1)=[CH:24]\[CH:25]=[CH2:26]
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1cc(Cl)ccc1O
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: C1COCCO1
Solvent: O
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 73.9 %

Procedure:
To a microwave tube was added (S,E)-methyl 2-(2-(3-bromophenyl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.172 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (44.5 mg, 0.258 mmol), and 2.0 M aqueous K2CO3 (0.086 mL, 0.172 mmol) in dioxane (2 mL) and water (0.5 mL). The reaction was sparged with nitrogen for 1 minutes, treated Pd(PPh3)4 (19.87 mg, 0.017 mmol) then sparged for 1 min. The reaction tube was sealed and then heated at 90° C. in a microwave tube for 1 h. LCMS analysis showed 40% completion. Additional 10 mg of Pd(PPh3)4 added and heated at 90° C. for another 2 h. The reaction was concentrated, diluted with water (15 mL) and extracted wtih EtOAc. The EtOAc layer was washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage (0%-40% EtOAc in hexanes) to isolate 80 mg (74%) of the product as off-white foam. 1H NMR (500 MHz, CDCl3) δ 8.09 (br. s., 1H), 8.06 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=16.9, 10.2 Hz, 1H), 6.17 (dd, J=15.4, 10.4 Hz, 1H), 6.07 (s, 1H), 5.88 (d, J=15.3 Hz, 1H), 5.33 (br. s., 1H), 5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=9.6 Hz, 1H), 4.50-2.50 (m, 4 H), 3.75 (s, 3H), 2.64 (s, 3H), 1.93 (d, J=12.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.67 (br. s., 1H), 1.29-1.24 (m, 12H). LCMS (M+1)=629.08.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)(C(C)(C)C)(C)C.O.NN.Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:12][CH2:11][CH:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCC(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: Cl
Agent: NN
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: NCC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A cooled (0° C.) solution of 2-(3 {[tert-butyl(dimethyl)silyl]oxy}-2-phenylpropyl)-1H-isoindole-1,3(2H)-dione (0.900 g, 2.28 mmol) in EtOH (10 mL) was treated with hydrazine hydrate (1.41 mL, 3.42 mmol) and the resultant solution was allowed to warm to room temperature and stirred for 18 h. A solution of 5 N aqueous HCl in EtOH (25 mL) was added and the resulting biphasic mixture was stirred for 3 h. The mixture was treated with sat. NaHCO3, until PH=9 attained and then extracted with EtOAC (3×60 ml). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a white solid. LCMS=152.2 (M+1)+.