Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H+].[B-](F)(F)(F)F.[CH3:7][N:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[NH:14].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:24]=[O:25]>C1C=CC=CC=1>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[NH:23][C:24]([N:14]=[C:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[N:8]1[CH3:7])=[O:25]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CC1CCC(=N)N1C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: c1ccccc1
Product: Cc1cccc(C)c1NC(=O)N=C1CCC(C)N1C
Reaction time: 2 h

Procedure:
The HBF4 salt of 1,5-dimethyl-2-iminopyrrolidine (6.75 g.; 0.0337 mole) is converted to free base in benzene in the usual manner. Then 4.96 g. (0.0337 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo leaving a oily residue which eventually crystallizes. Recrystallization from ethyl acetate gives the product, 1-(2,6-dimethylphenyl)-3-(1,5-dimethyl-2-pyrrolidylidene)urea, m.p. 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](=[N:17][OH:18])[NH2:16])=[C:10]3[CH2:9][N:8]([CH3:19])[C:7](=[O:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:22][CH2:23][C:24]1[O:18][N:17]=[C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:21][C:6]=4[C:7](=[O:20])[N:8]([CH3:19])[CH2:9][C:10]=23)[N:16]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A suspension of 5.8 g (0.020 mol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime in 60 ml of dimethylformamide was treated with 3.9 g (0.023 mol) of chloroacetic anhydride. The yellow solution obtained was stirred at 100° for 11/2 hr. and then completely freed from solvents. The oily product crystallized from acetonitrile and was filtered off. The mother liquor was concentrated, the residue was chromatographed over silica gel with dichloromethane/methanol 97:3 as the eluent and the additional portion of product obtained was recrystallized from acetonitrile. There were obtained a total of 4.05 g (59%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 245°-247°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)CCC2
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC2

Procedure:
50 g (0.34 mole) of 5-methoxyindane are reacted with 75 ml of chlorosulfonic acid analogously to Example 1 a to give 6-chlorosulfonyl-5-methoxyindane.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrCC(C1C=CC=CC=1C1C=CC(F)=CC=1F)=O.[C-:36]#[N:37].[K+]>>[C:36]([CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)=[O:3])#[N:37]
Reactant: [C-]#N
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=C(CBr)c1ccccc1-c1ccc(F)cc1F
Agent: [K+]
Product: N#CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Grignard reagent obtained from 14.2 g. of methyl iodide and 2.4 g. of magnesium in 100 ml. of THF is added dropwise to a solution of 30.4 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-oxopropionic acid ethyl ester, obtained by brominating 4-acetyl-2',4'-difluorobiphenyl to 4 bromacetyl-2',4'-difluorobiphenyl, reacting this with KCN to give 4-cyanoacetyl-2',4'-difluorobiphenyl, hydrolyzing the latter and esterifying the reaction product, in 200 ml. of THF. When the addition is complete, the mixture is heated and stirred for 2 hours more on a water bath and cooled. The resulting alcoholate is hydrolyzed with ice and saturated NH4Cl solution. The ether phase is dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][OH:59])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:62]I.O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:62])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-hydroxyethyl)benzyl]-1H-indole (0.13 g) in N,N-dimethylformamide (3 mL) was added 55% sodium hydride (9 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added a solution of methyl iodide (0.020 mL) in tetra hydrofuran (1 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-methoxy-ethyl)benzyl]-1H-indole (0.13 g). This material was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (4 mL). To the solution was added 10% palladium-carbon powder (60 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. To the reaction mixture was added sodium hydrogen carbonate (200 mg), and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK C18 ODS, UG80, 5 μm, 20×50 mm, linear gradient water/methanol=90/10-10/90, flow rate 30 mL/min) to give the title compound (39 mg).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=O)C.[Cl:9][C:10]1[C:11](=[O:19])[NH:12][C:13](=[O:18])[NH:14][C:15]=1[CH2:16]Cl>CO>[ClH:9].[Cl:9][C:10]1[C:11](=[O:19])[NH:12][C:13](=[O:18])[NH:14][C:15]=1[CH2:16][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)n1ccnc1
Reactant: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Solvent: CO
Product: Cl
Product: O=c1[nH]c(Cc2ncc[nH]2)c(Cl)c(=O)[nH]1
Yield: 128.1 %

Procedure:
To a solution of 4.3 g of N-acetylimidazole in methanol (100 ml), 5.0 g of 5-chloro-6-chloromethyluracil were added, followed by heating for 2 days under reflux. After the reaction mixture was allowed to cool down, a crystallized matter was collected by filtration and then washed with a 10% solution of hydrochloric acid in methanol, whereby 4.32 g of the title compound were obtained (yield: 64%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25](O)=[O:26])=[CH:9]2.Cl.C[N:30](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([NH2:30])=[O:26])=[CH:9]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.05 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (590 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (750 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated to give the title compound (1.00 g, yield 94%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 214-215° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O.CO>[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: II
Reactant: Cc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a suspension of 1.05 g (9.62 mmol) of 2-methyl-3-hydroxypyridine and 2.04 g (19.24 mmol) of sodium carbonate in 10 mL of H2O and 5 mL of CH3OH was added 2.44 g (9.62 mmol) of iodine in several portions. After stirring at rt for 30 min, the reaction mixture was acidified using 5.0 N HCl until pH=3. The mixture was extracted with EtOAc (3×20 mL). Organic layers were combined, dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 1:9 v/v EtOAc/hexanes as the eluant afforded 1.04 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.28 (s, 3H), 6.76 (d, J=8.2, 1H), 7.34 (d, J=8.7, 1H).
Reaction SMILES: N1C=CN=C1.[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH2:8][CH2:9][OH:10].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[NH2:6][CH:7]([CH2:8][CH2:9][O:10][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(N)C(=O)O
Reaction time: 0.25 h

Procedure:
Imidazole (20.4 g, 300 mmol) is added to a solution of homoserine (11.9 g, 100 mmol) in DMF (100 mL) and the solution is stirred 15 minutes then cooled to 0° C. tert-Butyldimethylsilyl chloride (13.7 g, 91 mmol) added and the mixture is stirred for ten minutes at 0° C. the for 4 hours at room temperature. The reaction mixture is poured into water (3 L) and the resulting solid is collected by filtration. The isolated product is dried and used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH:9]=1)=[O:4].C([Li])(C)(C)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8]([CH3:10])[C:9]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(=O)c1cc(C)c(C)s1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1sc(C)c(C)c1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 10 (0.40 g, 2.37 mmole) in 20 mL dry THF was cooled to −70° C. and stirred during the addition of t-butyllithium (5.21 mmole). After 30 minutes of stirring benzoyl chloride (0.42 g=0.35 mL, 3 mmole) was added and the mixture was warmed to room temperature. Workup consisted of quenching the reaction with saturated aqueous NH4Cl and extraction of product into ethyl acetate. The extract was dried over MgSO4, evaporated and product purified by chromatography on silica gel eluted with hexane-ethyl acetate 1:1. Yield 0.356 g, 55% 1H NMR(CDCl3) δ: 1.83 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.79 (d, 3H, NHCH3), 6.58 (br s, 1H, NH), 7.42–7.78 (m, 5H, ArH).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][N:6]([C:12]2[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]3[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=4)[CH:25]=3)=[O:19])=[N:16][CH:17]=2)[CH2:5]1)[CH3:2]
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CCN(CC)C1CCNC1
Solvent: CO
Solvent: CS(C)=O
Product: CCN(CC)C1CCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 81.6 %

Procedure:
N,N-diethylpyrrolidin-3-amine (142 mg, 1.00 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C. The resulting solution was stirred at room temperature for 50 mins. The reaction mixture was diluted with methanol (5.00 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a brown dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (141 mg, 82%) as a white solid.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[C:5]1([CH:11]([CH3:14])[CH:12]=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>CO>[CH3:3][C:2](=[CH:12][CH:11]([CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CC(C=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C=O)=CC(C)c1ccccc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
192 g of propionaldehyde are added dropwise to a solution of 402 g of 2-phenylpropan-1-al and 12 g of sodium hydroxide in 1 l of methanol in the course of 6 hours. Stirring is continued for one hour, after which the mixture is neutralized with glacial acetic acid (pH=6), stirred overnight and evaporated down, the residue is taken up with CH2Cl2 /H2O, and the solution is extracted with CH2Cl2. The organic phase is washed with water, dried over Na2SO4, evaporated down again and distilled to give 178 g of 2,4-dimethyl-4-phenylbut-2-en-1-al of boiling point 108°-120° C./0.5 mbar.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Br[CH2:14][CH2:15][CH3:16]>C1COCC1.O>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: CCCBr
Reactant: Ic1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1nc(I)c2ccccc21
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
NaH (60%, 197 mg, 4.92 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) in THF (20 mL) at 0° C., and the reaction stirred further for 30 min. Bromopropane (605 mg, 4.9 mmol) was added to the reaction at 0° C. The solution was heated to reflux and stirred overnight. It was then cooled, diluted with water, extracted with EtOAc (3×30 mL), and the organics were washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%-30% EtOAc/hexanes) gave 650 mg (56%) of the title compound as a yellow solid. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J=7.2 Hz), 1.93-1.98 (2H, m), 4.35 (2H, t, J=7.2 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36-7.49 (3H, m).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[CH3:34][N:33]1[C:29]([C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=2[C:18]2[C:13]3[C:14](=[N:15][C:10]([S:7]([NH:6][C:35]4[S:39][N:38]=[CH:37][N:36]=4)(=[O:8])=[O:9])=[CH:11][CH:12]=3)[NH:16][CH:17]=2)=[CH:30][CH:31]=[N:32]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1c[nH]c2nc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (Intermediate J) (46.47 mg, 0.071 mmol) and DCM (0.5 mL) to give a clear solution. TFA (0.1 mL) was added dropwise, and the resulting mixture was stirred for 30 min. The mixture was diluted with methanol, then filtered through Celite® (diatomaceous earth). The filtrate was concentrated, and the residue was triturated with diethyl ether to give a white solid. The diethyl ether was decanted, and the solid was put under vacuum again for 10 min. Diethyl ether was added, and the suspension was sonicated for 1 min to give a fine white precipitate. The mixture was filtered on a membrane filter, and the collected solid was washed with diethyl ether (3×), then dried under a stream of N2 to give 3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (18.02 mg, 0.036 mmol, 50.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.49 (d, J=2.4 Hz, 1 H), 8.45 (s, 1 H), 8.01 (s, 1 H), 7.94-7.88 (m, 2 H), 7.79 (s, 1 H), 7.65 (d, J=8.3 Hz, 1 H), 7.40 (s, 1 H), 7.35 (d, J=2.7 Hz, 1 H), 6.37 (d, J=1.9 Hz, 1 H), 3.23 (s, 3 H). m/z (ESI) 506.0 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](Br)=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O:27][B:28](OC)[O:29]C.Cl>CCCCCC.C(OCC)C>[Br:6][C:7]1[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][C:10]([B:28]([OH:29])[OH:27])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1
Reactant: Brc1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-2,5-diphenylbenzeneboronic acid is prepared as follows: A solution of n-butyllithium (1.6M, 15 ml) in hexane is added slowly to a cooled (-40° C.) solution of 1,4-di-bromo-2,5-diphenylbenzene (25 mmol) in diethylether (100 ml). This mixture is allowed to warm to room temperature an is stirred for 2 hours. This solution is transferred into a dropping funnel and added to a cooled (-60° C.) solution of trimethylborate (74 mmol) in ether (200 ml). It is then stirred for 8 hours at room temperature. After hydrolysis with aqueous HCl (2M, 150 ml), the layers are separated and the aqueous layer is extracted with ether (100 ml). The solvent is then removed from the combined organic layers and water (5 ml) and petroleum ether (100) are added. The precipitate is recovered by filtration, and recrystallized from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11](=O)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:21].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:21][C:11]1[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1
Reactant: COc1ccccc1-c1nc2ccsc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2sccc2n1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A solution of 2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.80 g, 3.1 mmol), POCl3 (0.28 mL, 3.1 mmol), and N,N-dimethylaniline (1.6 mL, 4.7 mmol) in benzene (3.5 mL) was heated at 80° C. for 2 h. An additional portion of POCl3 (0.28 mL, 3.1 mmol) was added, and the reaction was heated at 80° C. for 16 h. The reaction was cooled, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.61 g, 71% yield). LC/MS: m/z 277.1 (M+H)+ at 2.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[O:12]2)[CH:5]=1)([O-])=O.O.[NH2:22][NH2:23].[Cl-].[NH4+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:12])[NH:23][N:22]=2)[CH:5]=1
Reactant: O=C1OC(=Cc2cc([N+](=O)[O-])ccn2)c2ccccc21
Reactant: NN
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 90 °C
Yield: 31 %

Procedure:
A suspension of 3-(4-nitro-pyridin-2-ylmethylene)-3H-isobenzofuran-1-one (0.67 g, 2.5 mmol) in hydrazine monohydrate (0.25 g, 5.0 mmol) was heated to 90° C. for 1 hour and then cooled to room temperature. Ethanol (5 mL) added, followed by ammonium chloride (0.16 g, 3.0 mmol) and iron powder (0.28 g, 5.0 mmol), the mixture was then heated to 90° C. for 3 hours. The reaction mixture was filtered hot through celite which was washed with ethyl acetate (20 mL). The filtered was concentrated in vacuo and then diluted with ethyl acetate (10 mL) washed with brine (10 mL), dried over magnesium, sulphate and dried in vacuo to afford the title cpd as a pale yellow powder. Single peak in LC-MS analysis, (0.20 g, 31% yield) requiring no further purification, m/z (LC-MS, ESP), RT=1.58 (M+H) 253;
Reaction SMILES: F[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CN1CCCNCC1>>[F:49][C:30]1[C:29]([N:15]2[CH2:14][CH2:2][CH2:11][N:12]([CH3:13])[CH2:17][CH2:16]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Agent: CN1CCCNCC1
Product: CN1CCCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 1-methylperhydro[1,4]-diazepine. 1H-NMR (DMSO-d6) δ (ppm): 1.98 (2H, brm), 2.27 (3H, s), 2.68 (4H, brm), 3.24 (4H, brm), 7.15 (2H, m), 7.40 (2H, m), 7.76 (1H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 392.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[H][H]>C(O)C.[Rh]>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:4][CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)C1CCC(C(F)(F)F)CC1

Procedure:
Ethyl 4-trifluoromethylbenzoate (4.9 g) was dissolved in ethanol (60 ml) and catalyst (5% rhodium on alumina, 0.5 g) added. Reduction with hydrogen gas was effected at ambient temperature at 50 atmospheres pressure until the theoretical quantity of hydrogen had been absorbed. The catalyst was removed by filtration through "hyflo" filter aid and the solvent was removed by evaporation to provide crude ethyl 4-trifluoromethylcyclohexane-1-carboxylate.