Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[CH2:12]([CH:16]1[C:25](=[O:26])[CH2:24][CH:23]2[N:18]([CH2:19][CH2:20][C:21]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:22]=32)[CH2:17]1)[CH:13]([CH3:15])[CH3:14]>C1COCC1>[OH:26][C:25]1([C:5]#[CH:6])[CH2:24][CH:23]2[N:18]([CH2:19][CH2:20][C:21]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:22]=32)[CH2:17][CH:16]1[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1(O)CC2c3cc(OC)c(OC)cc3CCN2CC1CC(C)C
Temperature: 20 °C
Yield: 53.7 %

Procedure:
Trimethylsilylacetylene (2 eqs.; 20.4 mmol; 2.88 mL) was dissolved in 80 mL of dry THF and stirred under a nitrogen atmosphere at -5° to 0° C. n-Butyl lithium (20.4 mmol, 12.72 mL) was added dropwise with stirring followed by dropwise addition of a solution of 3-isobutyl-9-,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one (TBZ) in 30 mL dry THF. The reaction mixture was stirred at -5° to 0° C. for 1 h, allowed to warm slowly to 20° C., and stirred for 2 h at 20° C. The reaction was quenched while cold with saturated NH4Cl. The solvent was evaporated under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The organic phase was washed with water (2×50 mL) and brine (50 mL) and concentrated. The residue was dissolved in 30 mL MeOH and 5 mL 5N KOH, and heated to 65° C. with stirring for 30 min. The reaction was cooled and quenched with NH4Cl. The methanol was evaporated and the aqueous phase extracted with ethyl acetate (3×75 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to yield the product (53.7%) as slightly brown solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]=[C:13]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:14]=1
Reactant: Clc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CC(=O)NCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
N-Acetylethylenediamine (1.02 g) was dissolved in ethanol (250 ml) and 4,6-dichloro-2-(4-chlorophenyl)pyrimidine (2.5 g) then triethylamine (1.35 ml) added. The mixture was heated to 85° C. with stirring for 48 hrs. The solvent was then removed in vacuo and purified by column chromatography on silica gel eluting first with ethyl acetate then a mixture of ethyl acetate and methanol (9:1 v/v) to furnish the title compound (1.29 g).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:22]/[C:21]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: Nc1c(F)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (7.1 mL, 51 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (2.52 g, 17 mmol) and 2-chloro-6-fluoroaniline (2.47 g, 17 mmol) in DCM (60 mL) under nitrogen. Titanium tetrachloride (1 M, 10.2 mL, 10.2 mmol) was then added and the resulting mixture was stirred for 1 hour at 0° C. before warming to room temperature and stirring for a further 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][S:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][S:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCNC(=O)CSC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CSCCNCCSC

Procedure:
5.18 g of S-methyl-thioglycolic acid-N-(2-methylthioethyl)-amide (Example 8a) is dissolved in 350 ml of tetrahydrofuran and added in drops to a suspension of 5.48 g of lithium aluminum hydride in 350 ml of tetrahydrofuran under a cover-gas atmosphere. Then, it is refluxed for 18 hours. While being cooled in an ice bath, the excess lithium aluminum hydride is carefully hydrolyzed by adding 100 ml of water in drops, it is stirred for 1 more hour, and then another 700 ml of water is added. The solution is extracted three times with methylene chloride/methanol 10/1, and the combined organic phases are washed with water one time. After concentration by evaporation, the residue is purified by chromatography with the mobile solvent system of methylene chloride/methanol: yield 1.5 g=32% of theory.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][N:19]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:52]>>[CH2:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][N:19]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:52])[C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1Cc1cc(-c2cccnc2)on1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2cccnc2)on1

Procedure:
The methods described in Part I of Example 35 were used to treat 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline (0.920 g, 3.00 mmol) with mCPBA (0.808 g of 77% pure material, 3.6 mmol) followed by p-toluenesulfonyl chloride (0.629 g, 3.30 mmol) and concentrated ammonium hydroxide (15 mL) and purify the final product to provide 0.46 g of 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 206-207° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]([OH:19])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].C(N(CC)CC)C.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1>[OH:19][CH:7]([C@@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:42])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.9 %

Procedure:
To a slurry of 1.04 g (2.7 mmol) of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate and 0.38 mL (2.7 mmol) of trietylamine in 45 mL of dioxane was added 0.24 mL (2.7 mmol) of 4-morpholinecarbonyl chloride. The flask was heated with a heat gun until the mixture became homogeneous and was stirred at room temperature for 5 d. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 6:4 acetone:hexanes to afford 1.05 g (78%) of tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 1H), 7.27 (m, 4H), 7.16 (m, 1H), 6.41 (m, 1H), 6.01 (d, J=9 Hz, 1H), 5.47 (d, J=6 Hz, 1H), 4.87 (qnt, J=7 Hz, 1H), 3.80 (dd, J=3 Hz, J=6 Hz, 1H), 3.65 (m, 1H), 3.46 (t, J=5 Hz, 4H), 3.16 (t, J=5 Hz, 4H), 2.93 (q, J=6 Hz, 2H), 1.13-1.44 (m, 18H). ES-LCMS m/z 493 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42](/[S:50](Cl)(=[O:52])=[O:51])=[CH:43]\[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[CH:42](/[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51])=[CH:43]\[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)/C=C/c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 210.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0269 g, 0.0583 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0490 mL, 0.350 mmol) and trans-β-styrenesulfonyl chloride (0.0350 g, 0.175 mmol) to obtain 4-(trans-β-styrenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0770 g, yield 21%).
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1)(O)=[O:2].O>O1CCCC1>[OH:2][CH2:1][CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CC1(SCC(=O)O)CCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC1(SCCO)CCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2 mmol of 26 in 10 mL of anhydrous tetrahydrofuran (kept at 0° C.) 3 mL of BH3. THF complex (1M) is added slowly. The mixture is stirred for 3 hours in a nitrogen atmosphere at 0° C. Approximately 10 mL of water added slowly and the reaction is stirred for 15 min. The mixture is concentrated in vacuo at 40°-45° C. and the aqueous residue is extracted with ethyl acetate. The organic layer is washed with 10% bicarbonate. The ethyl acetate layer is dried and evaporated to give the product, 27 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCN4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 56 %

Procedure:
To a mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 2-piperidin-1-yl-ethyl ester and 1 mL of dimethylformamide was added 0.160 g (0.5 mmole) of cesium carbonate. The reaction mixture was heated at 100 degrees for 3 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.027 g of 4-(3-chloro-phenyl)-2-[6-(2-piperidin-1-yl-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.27) as a white powder. MH+/Z=482
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:20][C:19]([CH:17]=[O:18])=[CH:7][C:6]=2[CH:9]=1
Reactant: C=CC=O
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(Br)ccc2OC1

Procedure:
The starting material is prepared as follows: A mixture of 5-bromosalicylaldehyde (10.3 g, 51.1 mmol) and potassium carbonate (7.0 g, 51.1 mmol) in 30 ml of 1,4-dioxane is treated with acrolein (4.3 g, 76.6 mmol). The mixture is heated at reflux for 2 hours and allowed to cool. This is partitioned between ether and water, and separated. The aqueous layer is extracted once with ether, and the organic phases are combined, dried (MgSO4) and evaporated. Flash chromatography (silica gel, 8% ethyl acetate/hexane) yields 6-bromo-2H-1-benzopyran-3-carboxaldehyde, m.p. 103°-104° C., which is converted to the final product as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:6]([CH3:29])([CH3:28])[CH:5]2O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:6]([CH3:29])([CH3:28])[CH2:5]2
Reactant: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc(C(=O)OCc2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a sealed tube was added benzyl 3-(6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (1.98 g, 4.70 mmol), dichloromethane (25 ml) and triethylsilane (1.10 g, 9.40 mmol, 2.0 eq.), followed by the addition of trifluoroacetic acid (1.61 g, 14.11 mmol, 3.0 eq.). The sealed tube was heated at 60 for 16 h and cooled to room temperature. The reaction mixture was washed with saturated Sodium bicarbonate and separated. The organic layer was dried the residue was purified by column chromatography using petroleum ether/ethyl acetate=20:1 to afford benzyl 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate 914 mg (47.9% yield) as a yellow solid. MS (ESI+APCI) M+1=406.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:17][C:18]([CH3:20])=[CH2:19])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[C:6]([CH3:16])([CH3:15])[CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][CH2:19][C:18]1([CH3:20])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[N:7]([CH:13]=[O:14])[C:6]([CH3:15])([CH3:16])[CH2:5]3)[CH2:17]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CC(C)(C)N2C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CC(C)(C)N2C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,6,7-tetramethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.60 g, 5.85 mmol) in dichloromethane (15 mL) and methanol (5 mL) were added calcium carbonate (0.76 g, 7.6 mmol) and benzyltrimethylammonium dichloroiodate (2.24 g, 6.44 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added a 5% aqueous sodium hydrogen sulfite solution (15 mL), and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain 1.93 g of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:15]([C:18]1[S:22][C:21]([NH2:23])=[N:20][N:19]=1)([CH3:17])[CH3:16]>N1C=CC=CC=1>[CH:15]([C:18]1[S:22][C:21]([NH:23][S:2]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[N:20][N:19]=1)([CH3:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1nnc(N)s1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4.1 g acetic acid 4-chlorosulfonyl-phenyl ester were added to a stirred solution of 2.5 g 5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 ml pyridine. The reaction mixture was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue dissolved in 200 ml dichloromethane and washed with 60 ml water. The organic layer was dried over MgSO4. Then the solvent was removed in vacuo and the resulting residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 4.47 g Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl ester impurified with 40% of the byproduct N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-acetamide. The material was used without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18]([Cl:28])=[CH:17][C:16]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(O)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nn2c(Cl)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A suspension of 1.3 g (3.43 mmol) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 50 ml of POCl3 was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2 and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 1:1) of the residue yielded 1.2 g (88%) of (3-benzenesulphonyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-dimethyl-amine as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH:37][CH3:38])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([N:37]([CH3:38])[S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])[CH2:36][CH2:35]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CNC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C4CC4)c3)n2)n1
Yield: 51.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available N-cyclopropyl-N-methylamine [CAS-no. 5163-20-2] (0.16 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 51%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 157° C.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:21][CH:22]=1)(=[O:1])[NH2:27]
Reactant: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(-n2c3ccccc3c3c(C(=O)O)cccc32)nc1
Temperature: 60 °C

Procedure:
1.6 ml of 2M sodium hydroxide are added to a solution of 0.33 g of 9-(5-cyanopyridin-2-yl)-9H-carbazole-4-carboxylic acid methyl ester, obtained according to the preceding stage, in 30 ml of methanol, and then the mixture is heated at 60° C. for 2 hours. After a return to ambient temperature, the reaction mixture is concentrated under reduced pressure, and then 20 ml of water and a 1M aqueous solution of HCl are added in order to bring the pH to around 6. The aqueous phase is extracted with 3×100 ml of ethyl acetate, and the organic phases are then combined, dried over magnesium sulphate and concentrated under reduced pressure. 0.24 g of 9-(5-carbamoylpyridin-2-yl)-9H-carbazole-4-carboxylic acid is thus obtained in the form of a rubbery residue, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Li]CCCC.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:18]([Si:25]([CH3:27])([CH3:26])[CH3:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1c2c(c3ccc(F)cc31)Cc1ccccc1-2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1c2c(c3ccc(F)cc31)C([Si](C)(C)C)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
Compound 31b (as a 2:1.1 mixture of regioisomers, 1.61 g, 6.79 mmol) was dissolved in anhydrous ether (46 mL) and the reaction mixture was immersed in a 25° C. water bath. n-BuLi (1.5M in hexanes, 5.25 mL, 7.87 mmol) was added dropwise via syringe pump over one hour. Following addition of base, the reaction mixture was stirred for one hour at 25° C. and then cooled to −78° C. TMSCl (1.81 mL, 14.25 mmol) was added rapidly via syringe and the resulting mixture was immediately warmed to 25° C. for 1.5 hours. The reaction mixture was diluted with 20 mL ether, filtered, and concentrated in vacuo to yield a dark green solid which was subsequently purified by multiple rounds of flash column chromatography (15:1 hexanes-ethyl acetate; 20:1 hexanes-ethyl acetate) to give the desired regioisomer in pure form and 2% yield. This low yield is a result of the similar polarities of regioisomers, which render separation a challenge. Spectral data are reported for the mixture that remained following purification of a small percentage of the desired regioisomer. As a result, product ratios do not represent those of the original product mixture. 1H NMR (600 MHz, CDCl3): δ 7.74 (d, 1H, J=7.8 Hz), 7.71 (d, 0.5H, J=7.2 Hz), 7.51-7.55 (m, 2.5H), 7.31-7.34 (m, 1.5H), 7.21-7.24 (td, 1H, J=7.2, 1.2 Hz), 7.18-7.21 (td, 0.5H, J=7.2, 1.2 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.12-7.14 (m, 1H), 7.05-7.07 (dd, 0.5H, J=9.9, 2.4 Hz), 6.87-6.91 (m, 0.5H), 6.80-6.83 (ddd, 1H, J=10.2, 8.4, 1.2 Hz), 4.10 (s, 3H), 4.05 (s, 1.5H), 3.93 (s, 1H), 3.75 (s, 0.5H), −0.04 (s, 4.5H), −0.98 (d, 9H, J=0.6 Hz); 13C NMR (150 MHz, CDCl3): δ 159.3 (d, J=237.0 Hz), 156.0 (d, J=246 Hz), 150.4, 149.6, 144.3 (d, J=10.5 Hz), 143.6 (d, J=3.0 Hz), 143.0, 142.0 (d, J=12.0 Hz), 133.4, 132.7, 125.1, 124.9, 124.6, 124.6, 123.8, 123.52, 123.1, 121.3 (d, J=9.0 Hz), 120.6 (d, J=10.5 Hz), 120.3 (d, J=21.0 Hz), 117.6, 117.3, 113.0 (d, J=21.0 Hz), 107.4 (d, J=24.0 Hz), 105.6, 105.5, 104.4 (d, J=19.5 Hz), 96.2 (d, J=27.0 Hz), 37.3, 36.8, 31.5, 31.3, −2.42, −2.52 (d, J=3.0 Hz); 19F NMR (CD3CD, 376 MHz): δ −117.1 (d, J=6.8 Hz), −120.5-−120.1 (td, J=9.4, 3.8 Hz) FTIR: cm−1 3057, 2953, 1621, 1572, 1436, 1360, 1248, 1048, 839, 756, 727.