Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH3:17])[S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[C:4]1[C:18](OCC)=[O:19])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:3]1[C:4]([CH:18]=[O:19])=[CH:5][C:6]([N:8]([CH3:17])[S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:11])=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)c1cc(N(C)S(=O)(=O)c2cccs2)cn1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(N(C)S(=O)(=O)c2cccs2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl 1-ethyl-4-[methyl(2-thienylsulfonyl)amino]-1H-pyrrole-2-carboxylate (11.9 g) in tetrahydrofuran (200 mL) was slowly added lithium aluminum hydride (1.46 g) in small portions. The reaction mixture was stirred at room temperature for 1 hr, and water (1.5 mL), 15% aqueous sodium hydroxide solution (1.5 mL) and water (4.5 mL) were successively added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hr, the insoluble material was filtered off, and the filtrate was concentrated. To a solution of the residue in tetrahydrofuran (200 mL) was added manganese dioxide (12 g), and the mixture was stirred at room temperature overnight. The manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give N-(1-ethyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (9.5 g, yield 91%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: O.[NH2:2]N.[N:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:13][CH2:12]2)=[S:10])C=CN=C1>C(O)C>[F:26][C:25]([F:28])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([NH:4][NH2:2])=[S:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(C(=S)n2ccnc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
The mixture of hydrazine hydrate (0.584 mL, 12.03 mmol) and [4-(imidazole-1-carbothioyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (4.03 g, 10.94 mmol) in anhydrous ethanol was refluxed for 3 hours. The reaction mixture was cooled to room temperature and kept in the fridge overnight. The precipitate formed was collected by filtration and washed with ethanol, dried in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide in 60% yield (2.20 g). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.55 (dd, J=7.5, 7.5 Hz 1H), 7.33 (d, J=7.5 Hz, 1H), 3.70-4.00 (m, 8H). MS (ES+) m/z 333 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Temperature: 25 °C

Procedure:
The starting material for the latter is prepared as follows: The mixture of 28.9 g of ethyl 6-fluoro-4-hydroxy-quinolin-3-carboxylate [J.A.C.S., 69, 371 (1947)] and 240 ml of phosphorus oxychloride is refluxed under nitrogen for 3 hours. After cooling to room temperature, the solution is evaporated and the residue treated with ice-water and chloroform. The organic layer is dried and evaporated. The residue is taken up in aqueous sodium bicarbonate and diethyl ether, the ethereal layer is dried and evaporated, to yield the ethyl 4-chloro-6-fluoroquinolin-3-carboxylate melting at 55°-57°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.OO.C(=O)([O-])[O-:13].[Na+].[Na+]>C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N+:6]([O-:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1ccc[n+]([O-])c1
Temperature: 80 °C

Procedure:
A mixture of 7.74 g of 3-methoxymethylpyridine, 60 ml of acetic acid and 7.5 g of 30% hydrogen peroxide solution was stirred while heating at 80° C. for four hours. The reaction mixture was cooled to room temperature, and then sodium carbonate was added in small portions. The reaction mixture was subjected to filtration, and washed with ethyl acetate. The resultant filtrate was washed with a saturated aqueous solution of sodium hydrogensulfite and a saturated sodium chloride solution, and dried over anhydrous sodium carbonate. Activated carbon was added, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give 2.66 g of 3-methoxymethylpyridine N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17](C#N)=[CH:16]3)[C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.[CH:35]([O:38]C1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)([CH3:37])[CH3:36]>CC(O)=O>[Cl:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:38][CH:35]([CH3:37])[CH3:36])[CH:17]=[CH:18][N:19]=3)[N:14]=2)[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc2c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc12
Temperature: 100 °C
Yield: 59.5 %

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (see Example 18), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH(0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 3 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a light brown solid (43.5 mg, 59.5%). HR-ES (+) m/e calcd for C22H18FClN4O2S (M+H)+ 457.0896. found 457.0897.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5]([CH3:12])=[N:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[CH2:9][CH2:10][C:11]2[N:3]([CH3:2])[N:4]=[C:5]([CH3:12])[C:6]=2[CH2:7]1
Reactant: Cc1nn(C)c2c1CNCC2
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(C)c2c1CN(CCCCl)CC2
Yield: 49.8 %

Procedure:
To a mixture of 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride (2.00 g, 13.22 mmol, 1.0 eq) and K2CO3 (5.47 g, 39.66 mmol, 3.0 eq) in 40 mL of acetone was added 1-bromo-3-chloropropane (4.16 g, 26.44 mmol, 2.0 eq) at room temperature. The reaction mixture was heated to reflux for 5.0 h and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 100:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (1.50 g, 51.02%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 228.73 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH:4]1[CH2:7][CH:6]([C:8]2[CH:9]=[C:10]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][CH:13]=2)[CH2:5]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH:52]([F:54])[F:53])=[CH:47][CH:46]=1.C(N(CC)CC)C>C1COCC1.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:53][CH:52]([F:54])[O:51][C:48]1[CH:49]=[CH:50][C:45]([C:15]#[C:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH:6]3[CH2:5][CH:4]([CH2:3][CH2:2][F:1])[CH2:7]3)[CH:9]=2)=[CH:46][CH:47]=1
Reactant: CC(C)[Si](C#Cc1cccc(C2CC(CCF)C2)c1)(C(C)C)C(C)C
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FCCC1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Yield: 53.1 %

Procedure:
{3-[3-(2-Fluoro-ethyl)-cyclobutyl]-phenylethynyl}-triisopropyl-silane (349 mg, 0.973 mmol) was dissolved in THF (2 ml) and treated with a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (2 ml) at room temperature. The crude product obtained from aqueous work-up was placed in a CEM snap top microwave vial and combined with 1-Bromo-4-Difluoromethoxybenzene (300 mg 1.30 mmol), copper iodide (35 mg, 0.131 mmol), tetrakis(triphenylphosphine)palladium (70 mg, 0.060 mmol) and triethylamine (4.3 g, 42.5 mmol). The vial was quickly agitated then irradiated in a CEM Explorer™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (gradient; 0%, then 5% EtOAc in hexanes) afforded an oil 178 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.80 (m, 2H) 1.85-2.11 (m, 2H) 2.17-2.36 (m, 2H) 2.38-2.43 (m, 1H) 3.28-3.65 (m, 1H) 4.24-4.52 (m, 2H) 7.01-7.47 (m, 5H) 7.18 (d, J=8.8 Hz, 2H) 7.58 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].OB(O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.I[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: COc1cccc(-c2cccc(C(=O)O)c2)c1
Reaction time: 4 h
Yield: 54.3 %

Procedure:
Sodium carbonate (11.13 g) was added portionwise to a stirred solution of dihydroxy-(3-methoxyphenyl)borane (5.85 g) and 3-iodobenzoic acid (8.68 g) in water (138 ml) at room temperature, and then palladium(II) acetate (78.6 mg) was added portionwise thereto at the same temperature. The resulting mixture was stirred at the same temperature for 4 hours. The reaction mixture was filtered, then the filtrate was washed twice with diethyl ether and adjusted to pH 2.0 with 6N hydrochloric acid. The precipitated powder was collected by filtration and dissolved in ethyl acetate. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was washed with n-hexane to afford 3'-methoxy-3-biphenylcarboxylic acid (4.34 g) as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17](Cl)[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH2:21]([O:23]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:22].[F-].[Cs+]>O1CCOCC1.C(OCC)(=O)C.O1CCCC1.O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(Cl)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
A solution of 5-chlorothiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (345 mg), (1-ethoxyvinyl)-tributyltin (448 mg), cesium fluoride (346 mg), tris-hydroxymethyl-aminomethanedibenzylidene acetone-dipalladium(16 mg) and trit-butylphosphine (1.3 mg) in 1,4-dioxane (4 ml) was heated at 100° C. for 4 hours. After the reaction solution was cooled to room temperature, the solution was diluted with ethyl acetate, the resulting insoluble matter was removed by filtration, and washed with ethyl acetate. The filtrate was evaporated in vacuo and crude enol ether was obtained. Enol ether was dissolved in tetrahydrofuran (3 mL)-1N hydrochloric acid (3 mL), and the solution was stirred at room temperature for 30 minutes. After the solution was diluted with water, the solution was extracted with ethyl acetate, and washed with saturated sodium chloride water. After drying with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (154 mg) was obtained as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][NH:45][CH2:44]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C(=O)OC(C)(C)C)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCNC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 3-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)pyrrolidine-1-carboxylate (61.3 mg, 0.08015 mmol), 2,2,2-trifluoroacetic acid (182.8 mg, 1.603 mmol) and CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (40.8 mg, 76.58%). LRMS (APCI pos) m/e 665 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([O:29]CC)=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([OH:29])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cc(C(=O)O)c(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product from Step A above (92 mg, 0.161 mmol) in 1.2 mL of 3:2:1 tetrahydrofuran/methanol/water was treated with lithium hydroxide monohydrate (10 mg) and the solution was stirred at room temperature for 18 h. The volatiles were removed under a stream of nitrogen, and the residue was dissolved in 4 mL of water. The solution was acidified by portionwise addition of citric acid monohydrate, and the product was extracted into ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1cnc2[nH]cc(Br)c2c1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Benzyl 3-bromo-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (10.22 g, 29.53 mmol) in dry THF (120 mL) was cooled to 0° C. and treated portionwise with sodium hydride (1.193 g, 29.83 mmol, 1.01 Eq). The mixture was allowed to stir at this temperature for 1 hour and then treated with tosyl chloride (5.744 g, 30.13 mmol, 1.02 Eq) in THF (15 mL) over a period of 10 minutes. The mixture was left to stir at room temperature for a further 4 hours and then quenched with sat. aq. ammonium chloride. The mixture was diluted with EtOAc and the organic layer separated, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by column chromatography (5% MeOH/DCM) to give 11.09 g (75%) of brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH:15]1([CH2:18]O)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:15]1([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: OCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
1-Nitro-4-hydroxy-2-trifluromethylbenzene (5.0 g, 14 mmol) and cyclopropylcarbinol (1.75 g, 24 mmol) were dissolved in THF (20 mL) under nitrogen. Triphenylphosphine (9.5 g, 36 mmol) was added and diethyl azodicarboxylate (5.7 mL, 36 mmol) dissolved in THF (10 mL) was added over 30 minutes. The reaction mixture was stirred at 20° C. for 16 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL) and heptane (40 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (350 g silica) using heptane and ethyl acetate (9:1) as eluent to give 1.4 g of 4-cyclopropylmethoxy-1-nitro-2-trifluoromethylbenzene.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1(C(O)=O)[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[NH:4]1.S(Cl)(Cl)=O.CC([CH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([C:38]3[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=3)[C:32]=2[S:31](=[O:46])(=[O:45])[N:30]1[C:47]([O-:49])=[O:48])(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>C(#N)C.CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.[Pd]>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[NH2:15][CH2:14][C:10]1[CH:9]=[C:8]([N:5]2[C:6]([C:52]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([C:37]4[C:32]5[S:31](=[O:46])(=[O:45])[N:30]([C:47]([O:49][C:10]([CH3:14])([CH3:11])[CH3:9])=[O:48])[CH2:29][C:33]=5[CH:34]=[CH:35][CH:36]=4)=[CH:43][CH:42]=3)=[O:54])=[CH:7][C:3]([C:2]([F:1])([F:19])[F:20])=[N:4]2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(N2C=CC(C(=O)O)(C(F)(F)F)N2)c1
Reactant: CC(C)(C)C1c2cccc(-c3ccc(N)cc3)c2S(=O)(=O)N1C(=O)[O-]
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cccc(-c3ccc(NC(=O)c4cc(C(F)(F)F)nn4-c4cccc(CN)c4)cc3)c2S1(=O)=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To the solution of 3-(trifluoromethyl)-1-(3-cyanophenyl)-1H-pyrazolecarboxylic acid (0.1 g, 0.3 mmol) in dry acetonitrile (10 mL) was added thionyl chloride (0.15 mL, 1.8 mmol). The reaction mixture was warmed up at 50° C. for 1 h. The solvent and excess of thionyl chloride were removed under reduced pressure and dried on a vacuum pump over 18 h. To this dried resudue was added a mixture of 1,1-dimethylethyl-7-(4-aminophenyl)-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide (0.1 g, 0.3 mmol) and DMAP (0.13 g, 1.8 mmol) in dry methylene chloride (10 mL). The reaction mixture was allowed to stir at ambient temperature for 18 h, then concentrated and purified by flash chromatography (ethyl acetate/hexane, 1:1) to afford the intermediate product. This material was reduced under an atmosphere of hydrogen gas (55 psi) in methanol (5 mL) and trifluoroacetic acid (5 mL) in the presence of 10% palladium on carbon catalyst (15 mg) over a period of 18 h at ambient temperature. The reaction mixture was filtered over a pad of Celite and washed with methanol (5 mL×3). The residue was purified by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% of trifluoroacetic acid on a reverse phase C18 (60 angstrom) column to give 1,1-dimethylethyl 7-[4-[[[1-[3-(aminomethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]phenyl]-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide (32 mg, 15%). LRMS (ES+): 628.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]2[C:7]([CH2:8][CH2:9][CH:10]3[O:12][CH:11]32)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[N+:1]([C:4]1[CH:14]=[C:13]2[C:7]([CH2:8][CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1CC2
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.7 %

Procedure:
6-Nitro-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (1.3 g, 6.8 mmol) was combined with anhydrous zinc iodide powder (1.0 g, 3.1 mmol) in benzene and stirred at rt under nitrogen in a dark vessel for 15 h. The reaction mixture was filtered and the filtrate concentrated under vacuum. The crude residue was purified by silica gel flash column chromatography (10-50% EtOAc/hexanes) to yield 750 mg (58%) of the desired ketone as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=2.1 Hz, 1H), 8.06 (dd, J=8.2, 2.4 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 3.75 (s, 2H), 3.15 (t, J=6.7 Hz, 2H), 2.50-2.43 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][N:9]=[C:11]=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCCc1ccccc1
Temperature: 25 °C

Procedure:
40 grams of phenethyl amine in 300 ml of dry toluene saturated with dry HCl gas was mixed until a heavy white precipitate formed. An additional 200 ml of dry toluene was added with 50 ml of phosgene (12.5% in benzene). The mixture was refluxed (10 min.) and then 450 ml of phosgene was slowly added over 30 minutes and the mixture refluxed for 4 hours. The reaction mixture was allowed to cool to room temperature slowly and the solvent removed in vacuo leaving a yellow oil. Vacuum distillation of the oil at 82° to 83° C./0.1 mm yielded 1.8 g of end product.