Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.CC([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: CC(=O)Nc1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1ccc(Nc2ccc(Cl)cc2)cc1

Procedure:
Methyl 2-(4-iodophenyl)propionate (2 g.), acet-p-chloroanilide (1.17 g.), potassium carbonate (0.62 g.) and copper powder (0.1 g.) were heated at 165°C. for 7.5 hours. The cooled solid was triturated with methylene chloride, filtered, and the filtrate evaporated to dryness. The residue was refluxed for 1.5 hours with ethanol (7 ml.) and 2.5N sodium hydroxide (14 ml.); ethanol was distilled in vacuo and the residue diluted with water, washed with ether and acidified with dilute hydrochloric acid. The resulting oil was isolated in ether and evaporated to dryness. The resulting gum was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68°C. and eluting with ethyl acetate; recrystallization from benzene/petroleum ether b.p. 62°-68°C. and from petroleum ether b.p. 80°-100°C. gave 2-[4-(4-chloroanilino)-phenyl]propionic acid, m.p. 106-109°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([CH2:5][NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[NH:1][CH:22]=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Solvent: O=CO
Product: O=CNc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
0.90 g (2.82 mmol) of the 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline prepared in Example 151 was dissolved in 15 ml of formic acid, followed by the addition of 1 ml of acetic anhydride. The obtained mixture was stirred at room temperature for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 0.64 g of the title compound as a pale yellow crystal.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[CH:23]=[C:22](I)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=[CH2:29]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[CH:23]=[C:22]([CH:29]=[CH:28][CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=CCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.30 g, allylbenzene 0.16 mL and triethylamine 0.11 mL was added palladium acetate 9 mg, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added to it, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added, and it was heated and refluxed under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, palladium acetate 18 mg was added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-(3-phenyl-1-propenyl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[C:18]([C:17]([NH2:16])=[O:24])=[N:20][CH:19]=[CH:15][CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ncccc1-c1c[nH]nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4-(3-[4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl-2-pyridinecarboxamide as a white solid (67% yield), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1>O1CCCC1>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:8](=[O:12])[C:9]#[C:10][CH3:11])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and butyryl chloride (0.380 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. The residue was washed with boiling methanol and dried in vacuo to give 0.773 g of brown powder; mp 276-277° C.(dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH:21]1([CH2:24][O:25][C:26]2[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=2)[CH2:23][CH2:22]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH2:24][CH:21]4[CH2:23][CH2:22]4)=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=464.3 [M+H]+.
Reaction SMILES: F[C:2]1[C:3]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1.[Cl:22]C1C=CC(C)=CC=1O>>[Cl:22][C:2]1[C:3]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: Cc1cc(S(C)(=O)=O)c(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)c(O)c1
Product: Cc1cc(S(C)(=O)=O)c(Cl)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared by a method analogous to that described for 2-(5-fluoro-2-methyl-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Steps 1-5 of Example 223), using 2-chloro-5-methylphenol as the starting material. MS (ESI, pos. ion) m/z: 353.0 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C:30]([NH:29][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(N)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-amino-2-methylpropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=447.3 [M+H]+.
Reaction SMILES: [C:1]1([C@@:11]23[CH2:16][CH:15]2[CH2:14][O:13][C:12]3=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl>O1CCCC1>[C:1]1([C@@:11]2([CH2:12][OH:17])[CH2:16][CH:15]2[CH2:14][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC2C[C@@]12c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1C[C@]1(CO)c1cccc2ccccc12
Yield: 167 %

Procedure:
BMS (8.10 mL, 107 mmol) was added to (1R)-1-(1-naphthyl)-3-oxabicyclo[3.1.0]hexan-2-one (12 g, 53.5 mmol) in dry tetrahydrofuran (100 mL) under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 20.4 g (92%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.87 (1H,m), 1.01-1.25 (2H,m,), 1.78-1.83 (2H,m,) 3.4-3.7 (2H,m), 4.12-4.18 (2H,m), 7.36-7.52 (4H,m), 7.57-7.75 (1H,m) 7.83-7.86 (1H,m) 8.25 (1H,brs).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]([CH3:18])[C:6]1=O)=O.Cl.[CH:21]([NH2:23])=[NH:22].CC[O-].[Na+]>CCO>[CH2:11]([N:8]1[CH2:9][CH2:10][C:5]2[C:3](=[O:2])[NH:23][CH:21]=[N:22][C:6]=2[CH:7]1[CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C(C)C1=O
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1c2nc[nH]c(=O)c2CCN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylic acid methyl ester (1.0 g, 3.9 mmol), formamidine hydrochloride (930 mg, 11.6 mmol), and EtOH (6 mL) is treated with NaOEt solution (5.5 mL, 13.57 mmol, 21% w/w in EtOH) and the reaction is stirred at 90° C. for 2 h. Reaction is concentrated in vacuo after adjusting to pH 6. Residue is via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 256.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO.O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCNC2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a stirred solution of 6-methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-3,4-dihydro-isoquinoline (0.077 g, 0.197 mmol) in MeOH (3 ml) cooled to 0° C. was added NaBH4. The reaction mixture was then stirred at RT for 2 hours and diluted with water (5 ml) and sat. NaHCO3 (5 ml). The mixture was extracted with EtOAc (3×10 ml). The combined organics were washed with brine (1×10 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (SiO2, 1 mm, CH2Cl2 to 5% MeOH/CH2Cl2) to give the product as an oil (0.055 g, 0.141 mmol, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.NN>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(CN2CCOCC2)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCOCC3)n1-2

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:6]=O.[CH3:14][N:15]1[CH:19](P(OCC)(=O)OCC)[C:18](=[O:28])[NH:17][C:16]1=[O:29]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:5]([CH:6]=[C:19]2[N:15]([CH3:14])[C:16](=[O:29])[NH:17][C:18]2=[O:28])[CH:4]=1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Product: COc1ccc([N+](=O)[O-])c(C=C2C(=O)NC(=O)N2C)c1
Yield: 93 %

Procedure:
Reaction of 3-methoxy-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Method D provided the title compound as a mixture of geometrical isomers, m.p. 257°-260° C. in 93% yield.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][CH:13]=1.S([CH2:31][N+:32]#[C-:33])(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([C:14]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:31][NH:32][CH:33]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)/C=C/c1cccc(F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a suspension of 38.3 g (341 mmol) of potassium tert-butoxide at 60% in oil in 500 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 55.2 g (284 mmol) of ethyl (E)-3-(3-fluorophenyl)acrylate (CAS 166250-00-6) and 55.5 g (284 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 500 ml of tetrahydrofuran, while maintaining the temperature of the reaction medium at about 25° C. The mixture is then stirred for 1 hour 30 minutes at room temperature. The mixture is then poured into saturated aqueous solution and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown solid, which is chromatographed on a column of silica gel, eluting with dichloromethane, to give 40.7 g of ethyl 4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate, in the form of a white powder after triturating in diisopropyl ether, filtering off and drying.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Temperature: 75 °C
Yield: 54.3 %

Procedure:
A mixture of 5-nitroindazole (40.75 g, 250 mmol), picolyl chloride hydrochloride (45.1 g, 275 mmol) and potassium carbonate (72.4 g, 525 mmol) in DMF (400 ml) was heated at 75° C. for 3 hours. Additional picolyl chloride hydrochloride (4.1 g, 25 mmol) and potassium carbonate (3.45 g, 25 mmol) were added and the mixture was heated at 75° C. for 2 additional hours. After cooling, the mixture was diluted with water (800 ml). The precipitate was filtered, washed with water and dried. The resulting solid was purified by chromatography on silica gel (eluant: 50% ethyl acetate in petroleum ether) to give 5-nitro-1-(pyridin-2-ylmethyl)-1H-indazole as a solid (34.5 g, 55%); NMR Spectrum (CDCl3) 5.77 (s, 2H), 7.03 (d, 1H), 7.23 (m, 1H), 7.55 (d, 1H), 7.63 (m, 1H), 8.27-8.23 (m, 2H), 8.58 (m, 1H), 8.74 (d, 1H); Mass spectrum MH+ 255.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Ni].CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A suspension of 1-isopropyl-4-(4-nitro-benzyl)-piperazine (Step 11.2) (5.7 g, 21.65 mmol) and Raney Nickel (2 g) in MeOH (100 mL) was stirred for 6 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 4.9 g of the title compound as a white solid: ESI-MS: 234.2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[N:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: O=C(c1ccc(F)cn1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc(C(=O)N3CCOCC3)nc2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
Intermediate A (150 mg, 0.92 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 147 mg, 3.66 mmol) in DMF (3.0 mL). The reaction was stirred for 20 min, then Intermediate 17a (280 mg) in DMF (3.0 mL) was added and the reaction heated to 60° C. for 90 min. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was diluted with MeOH and loaded onto an SCX-2 cartridge, which was washed sequentially with MeOH and 2M NH3 in MeOH. The basic fractions were evaporated in vacuo then purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (234 mg, 0.66 mmol, 72%). LCMS (Method 4): Rt 1.60 min, m/z 354 [MH+].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:20]3[CH:25]=[CH:24][C:23](C(F)(F)F)=[CH:22][C:21]=3[C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[ClH:47]>CO>[Cl:47][C:23]1[CH:24]=[CH:25][C:20]([C:14]2[C:13]3[C:17](=[CH:18][C:10]([S:7]([NH:6][C:36]4[S:40][N:39]=[CH:38][N:37]=4)(=[O:8])=[O:9])=[CH:11][CH:12]=3)[N:16]([CH3:19])[CH:15]=2)=[C:21]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:22]=1
Reactant: Cl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)c(OC)c1
Solvent: CO
Product: Cn1nccc1-c1cc(Cl)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.75 h
Yield: 44.6 %

Procedure:
A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (35.79 mg, 0.056 mmol) and methanol (1 mL). Hydrogen chloride (4M in 1,4-dioxane) (141 μl, 0.563 mmol) was added, and the resulting solution was stirred for 45 min. The reaction mixture was loaded onto a 500 mg SCX-2 ion exchange column (Silicycle, Quebec City, Canada). The column was eluted with methanol, then with a solution of 2N ammonia in methanol. The basic fractions were combined and concentrated. The residue was purified further by chromatography on silica gel (0 to 10% MeOH/DCM) to give 3-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (12.05 mg, 0.025 mmol, 44.1% yield) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ=8.35 (br. s., 1 H), 7.90 (d, J=1.1 Hz, 1 H), 7.62 (d, J=1.3 Hz, 2 H), 7.56-7.31 (m, 4 H), 7.12 (s, 1 H), 6.27 (d, J=1.9 Hz, 1 H), 3.79 (s, 3 H), 3.23 (s, 3 H). m/z (ESI) 485.1 (M+H)+.
Reaction SMILES: [CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=2)[O:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)=[O:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:35])[N:4]1[CH3:36])[CH3:2].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:32]=[CH:33][CH:34]=[C:14]([C:7]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH:5]([CH3:35])[N:4]([CH3:36])[C:3]2=[CH:1][CH3:2])[CH:15]=1
Reactant: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)NCCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)NCCN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Product of Step 12 (0.13 g) was dissolved in dichloromethane (10 mL). To this, trifluoroacetic acid (2.5 mL) was added and the reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was evaporated under vacuum to obtain Step 13 product (0.1 g), which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
10.7 gm (0.035 mol of 4-hydroxy-2H-naphtho[2,1-e]1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 15.0 gm (0.0875 mol) of freshly distilled benzyl bromide were added to a mixture of 33 ml of water and 120ml of ethanol, and then 38.5 ml of 1 N sodium hydroxide were added dropwise. After stirring for 24 hours at room temperature, the crystals which had formed were suction-filtered off, washed with water and dried. Recrystallization from ethylene chloride/petroleum ether yielded 11.9 gm (86% of theory) of 2-benzyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, m.p. 254°-156° C.