Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:26].[K+].[K+].OO.O>CS(C)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]([NH2:24])=[O:26])[CH:19]=[CH:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Reaction time: 72 h
Yield: 70.1 %

Procedure:
To a solution of (3-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (58.3 mg) obtained in Example 128 in DMSO (5 mL) were added potassium carbonate (30.4 mg) and 30% aqueous hydrogen peroxide (0.056 mL), and the mixture was stirred for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (43.2 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1.O>C(#N)C>[C:1]([C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1)#[N:2]
Reactant: [C-]#N
Reactant: Clc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2

Procedure:
To a solution of 200 mg of potassium cyanide and 300 mg of 18-crown-6 in 20 mL of acetonitrile was added 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (220 mg). The mixture was refluxed for 2 hours, cooled and poured into water. The aqueous layer was extracted with dichloromethane, the organic layer separated and dried and the solvent removed in vacuo. The resultant crude reaction mixture was chromatographed using 15% ethyl acetate/hexane as eluent to yield 5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 44), m.p. 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.O>CO>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[N:1][C:2]2[N:6]3[CH:7]=[CH:8][C:9]4[C:14]([C:5]3=[N:4][C:3]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:24][CH:23]=1
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reactant: Cc1ccc(C=O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(C=Nc2c(-c3ccccc3C)nc3c4ccccc4ccn23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.6 %

Procedure:
To a solution of 5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of methanol was added 2.2 g of p-tolualdehyde. After the mixture was stirred at room temperature for 22 hours, it was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, and recrystallization from ethyl acetate/petroleum ether gave 5.4 g of the title compound as yellow crystals.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]I.[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH3:8][O:7][C:5](=[O:6])[C@@H:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Temperature: 140 °C

Procedure:
Boc-3-iodo-L-Ala-OMe (10 g) was dissolved in triethyl phosphite (79.7 mL). The mixture was heated at 140° C. for 15 h and evaporated to dryness to give the desired compound (9.37 g). It was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.O.[OH-].[K+].[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(O)C>[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:7]3[N:8]=[CH:9][NH:10][C:6]=3[CH2:5][CH2:4][NH:3]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Yield: 94.9 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: C(C1N(C)C=C([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16](OCC[Si](C)(C)C)[C:17](C)=[CH:18][C:11]=23)N=1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO.[NH4+].[OH-]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[NH:16]1[C:12]2=[N:13][CH:14]=[CH:15][CH:10]=[C:11]2[CH:18]=[CH:17]1
Reactant: Cc1cc2c(-c3cn(C)c(C(C)(C)C)n3)ccnc2n1OCC[Si](C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1cnc2[nH]ccc2c1
Yield: 149.1 %

Procedure:
A solution of 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 442-tut-butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%). 1H NMR (400 MHz, d6-DMSO): δ 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH:16](O)=[O:17]>>[CH:16]([NH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[C:12]=1[CH3:13])=[O:17]
Reactant: O=CO
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(C)O2
Yield: 93.3 %

Procedure:
5-Amino-2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran (1.00 g, 4.87 mmol) was dissolved in formic acid (20 ml) and the solution was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol, 97:3) to obtain the desired compound (1.06 g, yield: 93.3%). A part of it was recrystallized from dichloromethan-isopropyl ether to obtain white prisms, m.p. 177°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:23]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:21][CH2:22][C:23]4[S:14][CH:15]=[N:16][C:17]=4[CH2:18][CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ncsc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 27 mg (35% of theory). ESI-MS: m/z=378 (M+H)+; Rt(HPLC): 1.08 min. (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][CH2:11][C:10]3=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][NH:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.Cl[Ti](Cl)(Cl)Cl>[ClH:1].[CH3:16][N:17]([CH3:18])[CH:10]1[CH2:11][CH2:12][CH:13]2[C:9]1([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:14]2
Reactant: CNC
Reactant: O=C1CCC2CC12c1ccc(Cl)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCC2CC21c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-one (170 mg, 0.70 mmol) in dichloromethane (6 mL) was cooled to 0° C. and dimethylamine (2M solution in THF, 1.1 mL, 2.2 mmol) and TiCl4 (66 mg; 0.35 mmol; 0.5 eq) were added sequentially. After stirring at 0° C. for 45 min, the mixture was warmed to reflux and was stirred overnight. The reaction was then treated with sodium triacetoxyborohydride (339 mg, 1.6 mmol) at room temperature. The reaction mixture was stirred for 5 h, and then the reaction mixture was quenched with water (10 mL). The layers were filtered, and the pH was adjusted to 9 using saturated NaHCO3. The layers were then separated, and the aqueous layer was re-extracted with CH2Cl2 (2×), dried over sodium sulfate, filtered and concentrated in vacuo. The oily crude residue was converted to HCl salt using HCl/diethyl ether to provide the title compound as a beige solid (81 mg; 38%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.42 (m, 1 H) 1.51-1.59 (t, 1H) 1.91-2.20 (m, 4H) 2.22-2.34 (m, 1H) 2.62 (d, 3H) 2.74 (d, 3H) 4.03-4.13 (m, 1H) 7.15 (d, 1 H) 7.37-7.46 (m, 2 H) 12.07-12.28 (bs, 1 H). 13C NMR (100 MHz, CHLOROFORM-d) d ppm 12.10 (s, 1 C) 25.73 (s, 1 C) 26.34 (s, 1 C) 31.69 (s, 1 C) 32.70 (s, 1 C) 43.47 (s, 1 C) 44.49 (s, 1 C) 74.93 (s, 1 C) 127.47 (s, 1 C) 130.12 (s, 1 C) 131.31 (s, 1 C) 131.47 (s, 1C) 133.44 (s, 1 C) 142.35 (s, 1 C). MS (M+1) 270.1, HPLC Purity 99% (AUC).
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>O1CCCC1>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:8]
Reactant: O=C(Cl)c1ccoc1I
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)c1ccoc1I
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-iodofuran-3-carbonyl chloride (6.69 g, 26.1 mmol) in anhydrous tetrahydrofuran (120 ml) was added DIPEA (9.11 ml, 52.2 mmol) followed by 2,2,2-trifluoroethanamine (2.08 ml, 26.1 mmol) and the solution stirred for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between 2M hydrochloric acid (aq) solution (100 ml) and dichloromethane (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (4.38 g, 53%). LCMS RT=0.98 min, M+H+=319.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(OC)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 311.6 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([OH:21])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of methanesulfonyl chloride (0.145 ml, 1.87 mMol) in anhydrous CH2Cl2 (2 ml.) is added dropwise over 10 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (0.65 g., 1.44 mMol) and Et3N (0.30 ml, 2.16 mMol) in anhydrous CH2Cl2 (10 ml.). After stirring 15 more min. in the cold, the solution is diluted with ice-cold CH2Cl2 (10 ml.), washed with ice-cold H2O (10 ml.), ice-cold 5% HCl (10 ml.), and ice-cold 5% NaHCO3 (10 ml.), dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](=[S:14])[NH2:13])=[C:5]2[N:4]=[N:3]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=O>CC#N>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:13]=[C:12]([C:11]3[N:10]=[CH:9][N:6]4[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[N:4][C:5]=34)[S:14][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cn1nnc2c(C(N)=S)ncn2c1=O
Solvent: CC#N
Product: Cn1nnc2c(-c3nc(-c4ccc(Br)cc4)cs3)ncn2c1=O
Yield: 81 %

Procedure:
3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.48 mmol) and 2,4′-dibromoacetophenone (0.48 mmol) were stirred in MeCN overnight at room temperature. A slight yellow solid persisted which was filtered off before the remaining mixture was purified by preparative thin layer chromatography, eluting with 10% MeCN/DCM, to give the title compound. Yield=81%. δH (DMSO-d6): 8.92 (1H, s), 8.39 (1H, s), 8.04 (2H, d, J=8.8), 7. (2H, d, J=8.8), 3.89 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][N:31]([S:37]([NH:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1)(=[O:39])=[O:38])[CH2:32]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=2[C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][N:31]([S:37]([NH:40][C:41]2[S:42][CH:43]=[CH:44][N:45]=2)(=[O:39])=[O:38])[CH2:32]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1nccs1)N1CCc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1nccs1)C2
Yield: 31.8 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.023 g, 0.032 mmol), 1-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-1H-pyrazole (Intermediate O, 0.169 g, 0.481 mmol), 5-bromo-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.120 g, 0.321 mmol), and potassium phosphate (0.272 g, 1.282 mmol) in 2.5 mL dioxane, 1.0 mL water was heated to 100° C. 4 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.053 g, 0.102 mmol). [M+H]+=519.8 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.88 (dd, J=8.0, 1.4 Hz, 1H), 7.81 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.09-7.17 (m, 3H), 6.98-7.01 (m, 1H), 6.71 (d, J=4.7 Hz, 1H), 6.00 (d, J=2.0 Hz, 1H), 4.31 (d, J=15.7 Hz, 1H), 4.24 (d, J=15.7 Hz, 1H), 3.30-3.38 (m, 1H), 3.12 (m, 1H), 2.63-2.74 (m, 1H), 2.36-2.46 (m, 1H)
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7](I)[C:6]=1[OH:14])([CH3:3])[CH3:2].C([Mg]Br)#CC.[CH3:20][O:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:37][C:36]1[O:14][C:6]2[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][C:7]=2[C:35]=1[C:34](=[O:33])[C:24]1[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=1
Reactant: C1CCOC1
Reactant: COc1cc(I)cc(OC)c1OC
Reactant: COc1ccc(I)c(O)c1OC(C)C
Agent: CC#C[Mg]Br
Product: COc1cc(C(=O)c2c(C)oc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 2-isopropoxy-3-methoxy-6-iodophenol (308 mg, 1.00 mmol) in dry tetrahydrofuran (2 mL) was added dropwise a solution of 1-propynyl magnesium bromide (5, 6 mL, 3 mmol, 0.5 M solution in THF) at 0° C. under nitrogen. Dichloro-bis-triphenylphosphine palladium catalyst (40 mg, 0.06 mmol) was added and the reaction mixture was heated to 70° C. for 3 hours (tlc). The solvent was removed under vacuum and the residue was dried under vacuum. Dry dimethylsulfoxide (8 mL) was added and the nitrogen atmosphere was replaced with carbon monoxide. 3,4,5-Trimethoxyiodobenzene 6 (310 mg 1.05 mmol) was added and the reaction mixture was stirred at 90° C. for 17 hours and then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water and dried over magnesium sulphate. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 8:2-7:3) to afford the title compound as a creamy white solid. The product was crystallized from methanol. Yield −290 mg, 70%; 1H NMR (300 MHz, CDCl3) δ−7.10 (s, 2H, benzoyl Hs), 7.07 (d, 1H), 6.85 (d, 1H, J=8.57), 4.74-4.68 (m, 1H), 3.93 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.83 (s, 6H, 2×OMe), 2.52 (s, 3H, Me), 1.37 (d, 6H, J=6.18 Hz).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[S:30][C:29]([CH3:31])=[N:28][C:27]=2[CH3:32])(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li][CH2:36][CH2:37]CC.[CH2:40](I)[CH3:41].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCCCCC>[CH2:36]([N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([OH:8])([C:2]([F:34])([F:1])[F:33])[C:4]([F:5])([F:6])[F:7])[CH2:21][CH2:20]1)[S:23]([C:26]1[S:30][C:29]([CH2:31][CH2:40][CH3:41])=[N:28][C:27]=1[CH3:32])(=[O:25])=[O:24])[CH3:37]
Reactant: [Li]CCCC
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2sc(C)nc2C)CC1)(C(F)(F)F)C(F)(F)F
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1nc(C)c(S(=O)(=O)N(CC)[C@H]2CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC2)s1
Temperature: -30 °C

Procedure:
A solution of 200 mg (0.36 mmol) of trans 2,4-dimethyl-thiazole-5-sulfonic acid [4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide in 5 mL of THF was cooled to −78° C. and treated dropwise with 0.25 mL of a 1.6 M solution of nBuLi in hexane. The solution was warmed to −30° C., treated with 1 mL (1.2 mmol) of ethyliodide, allowed to reach RT and then refluxed for 2 hrs. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave a residue that was redissolved in THF and treated with an excess of TBAF. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation of the solvent and chromatography on silicagel with heptane/EtOAc 2:1 yielded 20 mg (11%) of trans 4-methyl-2-propyl-thiazole-5-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a yellow oil, MS: 497 (M+H)+.
Reaction SMILES: [Li]C.[Br:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1C=[CH:10][C:9]([C:17]#[N:18])=[CH:8][C:7]2=1.C1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[C:21]([C:32]#[N:33])[CH:20]=1.[CH2:34]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:35]1[O:37][CH2:36]1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:36][CH:35]([OH:37])[CH2:34][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:12]1[N:18]=[CH:17][C:9]([C:10]#[N:30])=[CH:8][C:7]2=1.[OH:37][CH:35]([CH2:34][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][N:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[CH:22]=[C:21]([C:20]#[N:13])[CH:32]=[N:33][C:31]1=2
Reactant: N#Cc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: N#Cc1ccc2[nH]c3ccccc3c2c1
Agent: [Li]C
Solvent: C1CCOC1
Product: N#Cc1cnc2c(c1)c1cc(Br)ccc1n2CC(O)COc1ccccc1
Product: N#Cc1cnc2c(c1)c1ccccc1n2CC(O)COc1ccccc1
Reaction time: 0.67 h

Procedure:
MeLi (1.6 M in Et2O, 108 μl, 0.17 mmol) was added to a solution of the mixture of 6-bromo-9H-carbazole-3-carbonitrile and 9H-carbazole-3-carbonitrile (24.1 mg) in THF (1.0 mL) at −78° C. and stirred for 40 min. Phenyl glycidyl ether (24.1 mg, 0.16 mmol) was added at −78° C. and the reaction was stirred at 45° C. overnight. Upon completion, the solution was quenched with H2O. Ethyl acetate was added and the mixture was washed with H2O, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. A small fraction was purified by reverse HPLC to afford the title products P7C3-S154 and P7C3-S155.