Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.[CH3:39][Mg]Br.[Cl-].[NH4+].O.[CH2:45]1[CH2:49][O:48][CH2:47][CH2:46]1>CCOCC>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:46]3[C:10](=[CH:11][CH:12]=[C:49]([O:48][CH3:47])[CH:45]=3)[CH:9]=2)([OH:14])[CH3:39])[N:16]=[CH:17]1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C(C)(O)c3c[nH]cn3)ccc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (2.50 g) was dissolved in THF (20 ml), and the solution was cooled to 0° C. To the solution was slowly added dropwise a solution of methylmagnesium bromide in ether (3.0M, 3.4 ml), and the mixture was stirred for 20 min at 0° C. To the reaction mixture was added saturated aqueous solution of ammonium chloride and water. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried and concentrated to give the titled compound (2.51 g) as a colorless powder.
Reaction SMILES: [NH:1]([CH:6]([CH3:11])C(NN)=O)[NH:2][C:3]([NH2:5])=[O:4]>O.CN(C)C=O.[N-]=C=O>[NH:1]([CH2:6][CH2:11][C:3]([NH:2][NH2:1])=[O:4])[NH:2][C:3]([NH2:5])=[O:4]
Reactant: CC(NNC(N)=O)C(=O)NN
Agent: [N-]=C=O
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)CCNNC(N)=O

Procedure:
11.8 parts of semicarbazido-propionic acid hydrazide were dissolved in 23.0 parts of water and 580 parts of dimethylformamide, and 268.75 parts of isocyanate prepolymer solution (a) were added. The clear, colourless elastomeric solution was pigmented with 4% TiO2.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2].[OH-].[Na+]>Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C(=O)c2ccc(N)cc2C(=O)O)c2ccccc21
Temperature: 55 °C

Procedure:
To a solution of 7.04 g (0.02 mole) of 2-[(1-ethyl-2-methyl-3-indoly)carbonyl]-5-nitrobenzoic acid, prepared as described in part A of this example, in 70 ml of concentrated hydrochloric acid, there was added 13.5 g (0.06 mole) of stannous chloride dihydrate at such a rate as to allow the reaction to exotherm to 55° C. The temperature was maintained at 55° C. for an additional one-half hour. The reaction was then cooled to room temperature and the pH adjusted to six by the addition of 10 percent aqueous sodium hydroxide solution. The red precipitate thus formed was filtered off and extracted into acetone. The acetone solution was evaporated and the paste-like residue was slurried in diethylether and then the solid was collected by filtration to obtain 3.5 of 2-[(1-ethyl-2-methyl-3-indolyl)-carbonyl]-5-aminobenzoic acid (Formula VIII: R3 =R2 =R°=Y1 =H; R1 =NH2 ; R5 =CH3 ; R 6 =CH2CH3), a red solid which melted at 187°-189° C. E. A mixture of 3.22 g (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-aminobenzoic acid, 118 g (0.01 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 10.0 ml of acetic anhydride was heated to 50° C. for one-half hour. After cooling to ambient temperature, 50 ml of water was added and the reaction mixture was filtered. The filtrate was rendered alkaline with dilute aqueous sodium hydroxide in the presence of 100 ml of toluene. The toluene layer was separated, dried and evaporated to obtain as tan crystals 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-acetamidophthalide (Formula III: R°=R1 =R3 =Y1 =H; R2 =NHCOCH3 ; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3) having a melting point of 204°-206° C. Infrared analyses showed maxima at 1733 cm-1 (C=O; s) and 1695 cm-1 (C=O; s). Nuclear magnetic resonance analysis was consistent with the structure. An acetone solution of the above compound developed an intense grape color when spotted on silica gel.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]3[CH2:18][CH2:17][CH2:16][CH:15]4[CH:13]3[O:14]4)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[CH:24]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.O1CCOCC1.C1(C)C=CC=CC=1.BrC1CC2C(C2)OC1>C1COCC1>[CH:30]1[C:26]2[CH2:27][CH2:28][C:29]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH:24]([N:34]3[CH2:35][CH2:36][N:37]([CH:15]4[CH2:16][CH2:17][CH2:18][CH:12]([O:11][C:10]5[C:4]6[S:3][C:2]([CH3:1])=[N:6][C:5]=6[CH:7]=[CH:8][CH:9]=5)[CH:13]4[OH:14])[CH2:38][CH2:39]3)[C:25]=2[CH:33]=[CH:32][CH:31]=1.[CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]3[CH2:18][CH2:17][CH2:16][CH:15]4[CH:13]3[O:14]4)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Agent: BrC1COC2CC2C1
Agent: Cc1nc2cccc(OC3CCCC4OC34)c2s1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2cccc(OC3CCCC(N4CCN(C5c6ccccc6CCc6ccccc65)CC4)C3O)c2s1

Procedure:
The title compound was prepared according to Method A from 2-methyl-7-(7-oxa-bicyclo[4.1.0]hept-2-yloxy)-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)piperazine with dioxane/toluene (2:1) as the solvent. mp 207° C. (decomposition); LSIMS m/z 540. The 2-methyl-7-(7-oxa-bicyclo[4.1.0]hept-2-yloxy)-benzothiazole was prepared according to Method IV using THF as the solvent and 4-bromo-2-oxa-bicyclo[4.1.0]heptane as the alkylating agent.
Reaction SMILES: Cl.F[C:3]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:4]=1[C:5](=[N:12][OH:13])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[K+]>O>[F:18][C:16]1[CH:15]=[CH:14][C:4]2[C:5]([CH:6]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)=[N:12][O:13][C:3]=2[CH:17]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)noc2c1

Procedure:
1 g of the compound obtained in stage E is mixed with 2.3 g of potassium hydroxide and 5 ml of water. The reaction medium is heated to reflux for 4 hours. 20 ml of water are then added and the mixture is extracted 4 times with 50 ml of toluene. The organic phase is dried to obtain, after evaporation of the solvent, 6-fluoro-3-piperid-4-yl-1,2-benzisoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[N:13]=[C:12]([OH:14])[CH:11]=[N+:10]2[O-:15])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[N:13]=[C:12]([O:14][CH3:22])[CH:11]=[N+:10]2[O-:15])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(-n2nc(O)c[n+]2[O-])cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c[n+]([O-])n(-c2ccc(C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 25 %

Procedure:
113 g of 2-(3-chloro-4-methylphenyl)-4-hydroxy-2H-1,2,3-triazole-1-oxide (m.p. 166°-170° with decomp., prepared in accordance with Synthesis 1974 (March), pp. 189-199) are added at room temperature to a solution of 43 g of 85% potassium hydroxide in 750 ml of water. With efficient stirring, 79 g of dimethyl sulphate and simultaneously 55 ml of 30% potassium hydroxide solution are added to the reaction mixture in the course of 15 minutes while maintaining an internal temperature of 25°-35° C. by cooling. The batch is subsequently heated for 1 hour to 45°-50° C., and cooled to room temperature. The solid is then collected with suction, washed with water and dried. One crystallisation from isopropanol yields 30 g of 2-(3-chloro-4-methylphenyl)-4-methoxy-2H-1,2,3-triazole-1-oxide in the form of colourless crystals. Melting point: 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:32])OC2C=CC([N+]([O-])=O)=CC=2)[CH:17]=[CH:18][CH:19]=1.[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH2:47])=[N+:34]=[N-:35]>CN(C=O)C>[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)=[O:32])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 2 h

Procedure:
To 4-nitrophenyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate (prepared by the procedure described in example 38) (200 mg, 0.40 mmol, 1.00 equiv, 95%) in DMF (5 mL) was added TEA (170 mg, 1.60 mmol, 4.00 equiv, 95%) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (90 mg, 0.39 mmol, 1.00 equiv, 95%) and the resulting solution was stirred for 2 h. The mixture was then concentrated under vacuum, diluted with 10 mL of water and then extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and then evaporated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜1:1). This resulted in 160 mg (72%) of 1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)urea as pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].[CH3:17][O-:18].[Na+].O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([O:18][CH3:17])=[O:13])=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[O-]
Reactant: Cn1ccc2ccccc21
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(=O)c1cn(C)c2ccccc12
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a 0° C. solution of 1-methylindole (7.58 g, 50 mmoles) in dry ether (75 mL) under argon was added oxalyl chloride (4.36 mL, 50 mmoles) slowly. The resulting suspension was stirred for 30 minutes. After cooling to −65° C, sodium methoxide (22.9 mL, 100 mmoles, 25% in MeOH) was added dropwise at a rate to maintain −60° C. After the addition was complete, the reaction was allowed to warm to room temperature and stir for 2 hours. Water was added (30 mL) and the crude mixture was stirred then filtered. The resultant solid was washed with water, ether and then air dried. Purification of the crude product via flash chromatography (SiO2, 20% to 40% ethyl acetate/Hexane—gradient) provided methyl (1-methyl-1H-indol-3-yl)(oxo)acetate as a solid (9 g, 41.4 mmoles).
Reaction SMILES: C12C3C1C23.[S:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.C([Li:14])CCC.[Cu:15][C:16]#[N:17]>O1CCCC1>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[Cu-:15][C:16]#[N:17].[Li+:14]
Reactant: [Li]CCCC
Reactant: N#C[Cu]
Reactant: c1ccsc1
Agent: C12C3C1C23
Solvent: C1CCOC1
Product: N#C[Cu-]c1cccs1
Product: [Li+]
Temperature: -25 °C
Reaction time: 0.08 h

Procedure:
Lithium thienyl copper(I) cyanide was prepared according to the method of B. Lipshutz, et al., Tetrahedran Letters, 1987, 28, 945. To a cooled (-30° C.) tetrahydrofuran (100 mL) solution of thiophene (freshly distilled, 15.96 g, 15.2 mL, 0.19 mole) was added n-butyllithium (2.4 M in hexane, 79.2 mL, 0.19 mole) dropwise, via syringe, at a rate such that the temperature did not exceed -17° C. The homogenous mixture was was stirred at -25° C. for 5 min, warmed to 0° C. for 30 min and then recooled to -25° C. This solution was then added via cannula to a vigorously stirred suspension of copper(I) cyanide (16.91 g, 0.19 mole) in cooled (-25° C.) tetrahydrofuran (120 mL) at such a rate that the temperature did not exceed -20° C. The initial hsterogenous mixture was stirred at .25° C. for 1.5 h during which time all the solids dissolved resulting in a deep amber colored homogeneous solution of lithium thienyl copper(I) cyanide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:7])[CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)CCl>[CH3:2][C:1]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH2:17][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:10]2)=[O:3]
Reactant: CC(=O)NC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC1Cc2ccc(C(C)=O)cc2C1
Reaction time: 3 h

Procedure:
24.4 g (0.31 mol) of acetyl chloride, followed by 35.5 g (0.20 mol) of 2-acetamido-indane are added, with stirring, to a suspension of 68 g (0.51 mol) of anhydrous aluminium chloride in 350 ml of ethylene chloride. In the course of this the reaction temperature rises to approx. 50° C. Stirring is continued for a further 3 hours, the product is decomposed by means of ice and concentrated hydrochloric acid, and the organic phase is separated off and evaporated.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][N:21](S(C5C=CC=CC=5)(=O)=O)[CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCOCC1>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][NH:21][CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc[nH]c4)C3)cc21
Temperature: 100 °C
Yield: 82.2 %

Procedure:
A mixture of 299 mg of 1-ethyl-6 -fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid 3 ml of 1N sodium hydroxide and 10 ml of dioxane was heated at 100° C. for 4 hours, then allowed to cool and neutralized to pH 7 with 10% acetic acid. The solvents were evaporated until a solid formed. This solid was collected, washed with water, methanol and ether and dried, giving 180 mg of the desired product, mp 220° C.
Reaction SMILES: [Na].C(O)C=C.[C:6]([S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])(=O)[CH3:7].C([O:22][CH:23]1[NH:26]C(=O)C1)(=O)C>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][CH2:10][S:9][CH:6]1[NH:26][C:23](=[O:22])[CH2:7]1)=[O:14])[CH:17]=[CH2:18]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: C=CCOC(=O)CCCSC(C)=O
Agent: [Na]
Solvent: C=CCO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CCCSC1CC(=O)N1
Reaction time: 1 h
Yield: 48 %

Procedure:
Sodium (1.15 g) was added to allyl alcohol (50 ml) and this solution treated with allyl 4-(acetylthio)butanoate (10.Og) at room temperature for 20 mins. 4-Acetoxyazetidinone (6.5 g) was added and stirring continued at 20° C. for 1 h The resulting mixture was poured into excess ethyl acetate and the layers separated. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (diethyl ether) to give the title compound as a yellow oil, 5.5 g. 48% yield
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].C[Li].CCO[CH2:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]([NH2:18])[CH3:30])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=Cc1cc(Cl)cc2ccccc12
Reactant: CCOCC
Agent: [Li+]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)cc2ccccc12
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-naphthalenecarbaldehyde (1.93 g) in dry THF (12 mL) was added dropwise to lithium bis(trimethylsilyl)-amide 1M solution in THF (10.1 mL) at −30° C. under a Nitrogen atmosphere. The resulting yellow mixture was stirred under a Nitrogen atmosphere from −30° C. to −5° C. for 1 h, then it was cooled down to −60° C. and methyllithium 1.6M solution in Et2O (11 mL) was added keeping the internal temperature of the reaction mixture <−55° C. The resulting dark violet reaction mixture was stirred for 40 minutes at −50° C. under a Nitrogen atmosphere, then it was carefully quenched at −50° C. with aqueous 2M HCl (30 mL) until pH=2. The reaction was concentrated in vacuo and the aqueous residue washed with 1:1 CH/Et2O (50 mL). The separated aqueous phase was then made basic (pH=14) at 0° C. with NaOH pellets. This basic aqueous phase was extracted with Et2O (3×60 mL), the collected organic layers were dried and concentrated in vacuo to give the title compound (1.12 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C.O>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([S:24]([C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)(=[O:25])=[O:26])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: [H][H]
Reactant: Brc1c[nH]c2cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2cc(Br)c3ccncc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil) (217 mg) was added to a stirred solution of 3-bromo-1H-pyrrolo[2,3-c]pyridine (535 mg) in DMF (5 ml) that had been cooled in an ice bath to 0° C. and placed under nitrogen. The mixture was stirred for 30 min, until hydrogen evolution ceased, and then 4-nitrobenzenesulfonyl chloride (662 mg) was added. The mixture was stirred at 0° C. for 1 hour. The mixture was then warmed to RT and stirred for a further 30 min. The solution was poured into stirring water (10 ml) and rapidly stirred for 15 min. The resulting brown solid was collected by filtration, washed with water and dried in a vacuum oven at 50° C. to give a yellow solid. This crude material was purified by FlashMaster II. The residue was dissolved in DCM:methanol (1:1) and pre adsorbed onto silica. This was added to the top of a 20 g silica SPE cartridge that was subsequently eluted with 0-50% ethyl acetate:cyclohyexane over 40 min. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound, 233 mg as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC([O-])=O.[K+].[Br:18]Br>CC(O)=O>[Br:18][C:5]1[CH:6]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(F)c(N)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 2-fluoro-4-methylsulfonyl-aniline (22.76 mmol) and KOAc (22.7 mmol) in AcOH was stirred at room temperature. The mixture was cooled to 0° C. and Br2 (22.7 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C. The mixture was concentrated and the residue was taken up in EtOAc. The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3), dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[CH:5][C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)c(OC)c1OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(OC)c(OC)c1OC
Temperature: 25 °C
Yield: 82.3 %

Procedure:
Following the procedure by Tremblay et al.,17 17 (3.851 g, 20.9 mmol) was dissolved in dry acetone (90.0 ml), and K2CO3 (9.36 g, 67.7 mmol) was added followed by MeI (9.0 mL, 144 mmol). The reaction was heated under reflux for 26 h and monitored by TLC (1:9 EtOAc:hexanes) for completion. When complete the reaction was cooled to room temperature and filtered. The acetone was removed under reduced pressure and the residue was taken up in CH2Cl2 (50 mL). The suspension was filtered, dried over MgSO4, filtered again, and condensed. The crude product can be purified by flash chromatography (1:4 EtOAc:hexanes), however, recrystallization from Et2O/hexanes was sufficient to provide pure 18 (3.405 g, 17.2 mmol, 82%) as white needles.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH2:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14](O)=[O:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.CCOC(C)=O>[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:13]=1[C:14]([NH:10][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1)=[O:15]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: Nc1nc2cnccc2s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2cnccc2s1)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A mixture of thiazolo[4,5-c]pyridin-2-amine (Milestone Pharm Tech USA Inc.) (1.35 g, 8.93 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (2.23 g, 10.72 mmol) and triethylamine (2.71 g, 26.8 mmol) in THF (30 mL) was treated drop wise with 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (6.82 g, 10.72 mmol). The mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was triturated with Et2O and hexane to afford the title compound (2.2 g, 72%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.66 (t, J=9.46 Hz, 1H) 8.07 (m, 1H) 8.12 (d, J=4.88 Hz, 1H) 8.26 (dd, J=6.10, 2.14 Hz, 1H) 8.44 (d, J=5.49 Hz, 1H) 9.07 (s, 1H); MS (DCI/NH3) m/z 342 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:26])[C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH3:23])[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:32])(=[O:30])=[O:29]>>[ClH:1].[CH:17]1([NH:16][C:14]2[N:13]([CH3:23])[C:12]3[CH:24]=[CH:25][C:9]([N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:36]5[CH:37]=[CH:38][C:33]([CH:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH3:32])=[CH:34][CH:35]=5)[N:7]=4)[CH3:26])=[CH:10][C:11]=3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Cl)n1
Product: CC(c1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NC3CCCCC3)n4C)n2)cc1)S(C)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-N2-cyclohexyl-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (74 mg, 0.20 mmol) and 4-(1-methanesulfonyl-ethyl)-phenylamine (40 mg, 0.20 mmol) as a white solid (104 mg, 91%). 1H NMR (300 MHz, D6-DMSO) δ 9.34 (s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.22-7.26 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 5.76 (d, J=6.0 Hz, 1H), 4.40 (m, 1H), 3.72 (m, 1H), 3.63 (s, 3H), 3.45 (s, 3H), 2.76 (s, 3H), 1.99 (m, 2H), 1.76 (m, 2H), 1.58-1.65 (m, 4H), 1.33-1.43 (m, 4H), 1.15 (m, 1H) ppm. MS (ESI) m/z=534 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10](C(C)(C)C)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[C:17](C1C=C(Br)C=CC=1)([CH3:20])([CH3:19])[CH3:18]>>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: CC(C)(C)c1cccc(Br)c1
Product: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1

Procedure:
Using the same general procedure as described for Compound 21, but using 3-tert-butyl-bromobenzene, (Compound 24) the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.36 (9H, s), 1.40 (9H, s), 7.32 (1H, m), 7.37-7.47 (2H, m), 7.61 (1H, m).