Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+]=[N-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[CH2:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Take up the mixture of 4-[4-(2-aminoethyl)phenoxy]benzenesulfonyl azide (0.210 g, 0.661 mmol) in methanol (9.9 mL). Add benzaldehyde (0.20 mL, 1.98 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.075 g, 1.98 mmol) and stir for 1.5 hours. Filter the reaction mixture and purify by flash 40 chromatography, eluting with 3% (2.0 M NH3 in methanol), 30% hexanes and 67% ethyl acetate to give the title compound (0.0696 g, 25.8%): TOF MS ES+383.1 (M+H)+, HRMS calcd for C21H23N2O3S 383.1429 (M+H)+. found 383.1436, time 0.33 min; TLC [silica gel 60 F254, 10% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.31.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(Cl)([Cl:24])=O.C(N(CC)C=O)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:24])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: CCN(C=O)CC
Solvent: ClC(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of diethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-8 for the 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[CH:14]2.ClC1C=CC=C(Cl)C=1[CH2:33][O:34]C1C=C2C(=CC=1)N(C(C)CC#N)C=C2.[OH-].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[C:14]2[CH:33]=[O:34]
Reactant: N#CCCCn1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: CC(CC#N)n1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCCCn1cc(C=O)c2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 70 %

Procedure:
A flame dried flask under argon was charged with DMF (0.43 mL, 5.57 mmol) and cooled to 0° C. Phosphorus oxychloride (0.16 mL, 1.67 mmol) was slowly added to the cooled DMF. The solution was stirred at 0° C. for 1 min and to this was added a DMF (1.5 mL) solution of a mixture of 4-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (85%) and 3-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (15%) (0.5 g, 1.4 mmol). The reaction mixture was stirred at room temprature for 1 h and heated at 50° C. for 4 h. The reaction solution was poured into ice water. A light yellow colored sticky solid precipated immediately. The mixture was neutralized by adding 1N NaOH until a pH of 7 was obtained. The product was extracted into ethyl acetate (3×) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude yellow oil was purified by flash column chromatography (silica gel, ethyl acetate/hexane) to yield the desired aldehyde as a white solid (0.38 g, 70%) and the undesired aldehyde (0.099 g, 18%).MS(ES) m/e 387.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:22]>C(O)C.Cl>[ClH:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:18][C:4]=2[CH:3]=1
Reactant: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Reaction time: 16 h
Yield: 72.7 %

Procedure:
Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile (1.747 g, 6.44 mmol) in ethanol (35 ml) to 60° C. and add a solution of tin (II) chloride (6.06 g, 31.96 mmol) in 5.0 N hydrochloric acid (35 ml). Reflux the resulting mixture to reflux for 40 hours. Cool the reaction to room temperature and place in a freezer for 16 hours. The product precipitates from the solution and is collected by filtration to obtain 1.3 g of the title compound (4.68 mmol, 73% yield) as a yellow-green amorphous solid: Mass Spectrum (m/e): 241 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[NH:18][C:19]4[C:20]([N:25]=3)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[O:26]1[CH2:27][CH:28]=[C:29]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([C:17]4[NH:18][C:19]5[C:20]([N:25]=4)=[N:21][CH:22]=[CH:23][CH:24]=5)=[O:16])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:30][CH2:31]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ncccc2[nH]1
Temperature: 120 °C

Procedure:
To a glass microwave vial was added (4-(3-bromopyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone (1.1099 g, 2.81 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.180 g, 5.62 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.158 g, 0.225 mmol), and sodium carbonate (0.893 g, 8.43 mmol) in DMF (7.02 mL) and water (2.340 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 120° C. for 20 min. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone. MS (ESI, pos. ion) m/z: 398.9 (M+1).
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][O:26][CH:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:30])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1CCl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 122 %

Procedure:
Solid magnesium turnings (9.5 g, 28 equiv.) under nitrogen atmosphere at room temperature were stirred vigorously with a magnetic stirring bar overnight. The magnesium was then covered with dry diethyl ether and to the suspension was added 1,2-dibromoethane (50 μL). A cold bath was then applied followed by dropwise addition of 1-chloromethyl-2-methoxy-benzene (18.18 g, 5 equiv. available from Aldrich Chemical Company) in diethyl ether (71 mL) which maintained the temperature at up to 15° C. The resulting black suspension was stirred at room temperature for 30 minutes and cooled down at −20° C. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (4 g, 1 equiv.) in diethyl ether (50 mL) was then added dropwise via canula. The reaction mixture was left to warm to room temperature over two hours and then quenched by addition of aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 7 g of a yellow amorphous solid. The compound was taken without further purification in the next step. FIA [M+H]+=404.
Reaction SMILES: [CH2:1]=O.[NH2:3][CH2:4][C@@:5]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1C=CC=CC=1>[Si:9]([O:8][CH2:7][CH2:6][C@:5]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:16][CH2:1][NH:3][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(CN)c1ccc(F)cc1
Reactant: C=O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CNCO1
Yield: 104.2 %

Procedure:
Paraformaldehyde (18.50 g, 0.617 mol) was added to a solution of (2R)-1-amino-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)butan-2-ol (128.92 g, 0.411 mol) in benzene (1000 mL), a water separator was mounted, and the mixture was stirred at reflux temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 139.43 g of crude (5R)-5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine as a brown oily substance.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1)[CH3:2].[CH3:13]I>CC#N>[CH2:1]([C:3]1[C:8]([CH2:9][O:10][CH3:13])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1)[CH3:2]
Reactant: CI
Reactant: CCc1nc(SC)ncc1CO
Solvent: CC#N
Product: CCc1nc(SC)ncc1COC
Yield: 98 %

Procedure:
A solution of 4-ethyl-5-hydroxymethyl-2-methylthiopyrimidine (0.63 g, 3.42 mmol), Ag2O (1.6 g, 6.9 mmol) and MeI (1.1 mL, 17.1 mmol) in CH3CN (10 mL) was stirred overnight, filtered and concentrated to give 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine in 98% yield (0.66 g); GC/MS calcd. for C9H14N2OS (M+) 198, found 198. The title compound was then prepared by (a) oxidation of 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine (0.66 g, 3.35 mmol) with mCPBA (1.18 g, 6.85 mmol) as described for Example 67, and (b) reaction with methyl hydrazine (0.36 mL, 6.85 mmol) followed by citraconic anhydride (0.77 g, 6.85 mmol) also described in Example 67; resulting in a yield of 41% (0.40 g) from 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine; 1H NMR (CDCl3) δ 8.14 (s, 1H), 6.43 (s, 1H), 4.29 (s, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 2.68 (m, 2H), 2.14 (s, 3H), 1.13 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CN.C[CH2:15][N:16](C(C)C)C(C)C>CS(C)=O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH3:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-fluoro-2-nitrobenzene (832 mg, 4.7 mmol) in DMSO (10 mL) is added a 2M solution of methylamine (3.56 mL, 7.1 mmol) in tetrahydrofuran, followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature and poured over ice water. The resulting solid is isolated by filtration to afford the title compound (713 mg, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.[CH3:19][S:20]C.O>CCOCC>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: CSC
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Reaction time: 1 h

Procedure:
A solution of 5,6,7 or 8-bromo-2-(di-n-propylamino)tetralin (1.4 g; 4.5 mmol) in dry ether (20 ml) was cooled to -78° C. under nitrogen atmosphere. S-BuLi (7 ml, 10 mmol) was added and the mixture was stirred for 1 hr. Methylsulphide (0.31 g; 5 mmol) was added and the mixture was stirred for 3 hr. When the temperature reached -10° C., water was added. Workup afforded the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
DCM (20.0 mL) was added to a flask containing ethyl 3-amino-7-bromoquinoline-2-carboxylate (from commercial source, 1.38 g, 4.68 mmol) and pyridine (1.0 mL, 12 mmol). The reaction mixture was cooled to −10° C. Benzyl chloroformate (0.843 mL, 5.61 mmol) was added slowly. The mixture was then allowed to warm gradually to room temperature and stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with MeOH (10 mL) to form a precipitate that was collected by vacuum filtration and washed with cold MeOH to give the sub-title compound (1.73 g, 86%) as a white powder. LCMS calc. for C20H18BrN2O4(M+H)+: m/z=429.2. Found: 429.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([F:25])[CH:27]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(F)c1
Reactant: Fc1cnc(Cl)nc1-c1c(-c2cccc(Br)c2)nn2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cccc(Nc2ncc(F)c(-c3c(-c4cccc(Br)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 76.9 %

Procedure:
A solution 2-(3-bromophenyl)-3-(2-chloro-5-fluoro-4-pyrimidinyl)pyrazolo[1,5-a]pyridine (100 mg, 0.25 mmol, obtained from composite batches) in 2-propanol (5 mL) was added 3-fluoroaniline (166 mg, 1.4 mmol) followed by 4M HCl/dioxane (0.4 ml, 1.6 mmol). The reaction mixture was heated at 180° C. in the microwave for 1 h. The solvent was removed under reduced pressure and the solids were recrystallized from EtOAc/hexanes to afford the desired product (92 mg, 77%) as a brown solid. ESIMS (M+H)+=478.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCCl)CC1)c1ccccc1

Procedure:
A mixture of 4-benzamidopiperidine (3.2 g; preparation I11), triethylamine (5.67 ml) and 1-bromo-3-chloropropane (2.31 ml) in 150 ml of tetrahydrofuran was refluxed overnight, then concentrated to a small volume and treated with 100 ml of chloroform. The solution was washed with 50 ml of aqueous saturated solution of potassium carbonate, dried over sodium sulfate and concentrated to dryness. The residue (6 g) was purified by silica gel chromatography (eluent chloroform/methanol 9:1) to give, after recrystallization from 20 ml of diethyl ether, 1.63 g of the product, m.p. 145-147° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29](O)[CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:30]=1)[CH3:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(CCCOC)c(O)c1
Solvent: CCN(CC)CC
Product: CCc1ccc(CCCOC)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) followed by triethylamine (0.42 mL, 3 mmol) was added to a cooled 0° C. solution of 5-ethyl-2-(3-methoxy-propyl)-phenol (0.45 g, 2.3 mmol). The reaction was stirred for 1 hour and then warmed to room temperature. The reaction was partitioned between 1 N HCl and EtOAc. The organic extracts were washed with bring, dried over Na2SO4 and concentrated to a black oil. 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J=7.6 Hz, 3 H), 1.89 (m, 2 H), 2.65 (d, J=7.6 Hz, 2 H), 2.75 (t, J=7.6 Hz, 2 H), 3.35 (s, 3 H), 3.40 (t, J=7.6 Hz, 2 H), 7.07 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.23 (d, J=8.0 Hz, 1 H).
Reaction SMILES: N[N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[N:2]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[NH:5][N:4]=1
Reactant: Nn1c(-c2ccccc2Cl)nnc1-c1ccccc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1-c1n[nH]c(-c2ccccc2Cl)n1
Yield: 52.3 %

Procedure:
The product of stage (a) (19.5 g) was dissolved in glacial acetic acid (100 ml) and was treated with sodium nitrite (4.4 g) in water (15 ml) at 10° C. The precipitated solid was filtered off, washed, dried and recrystallised from methanol to yield 9.7 g of desired product, mp 159°-160° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Potassium t-butoxide (1.83 g, 14.9 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (4 g, 14.9 mmol) in 150 ml of THF at 0° C. and the mixture was stirred for 1 hour at the same temperature. To the above mixture was added 10.58 g (74.6 mmol) of methyl iodide, and the reaction mixture was stirred at 0° C. for 0.5 hour, at room temperature for 6 hours, and decomposed with saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride and the organic layer was washed with brine, dried, and concentrated in vacuo to afford 4.19 g (quantitative) of 2-phenylmethyl-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2cc1OC
Yield: 90.4 %

Procedure:
Following the procedure of Example 11, a mixture of 149.4 mg (0.50 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 100–110° C. for 1.0 hour to yield 184.4 mg (83.0%) of the product as a yellow solid, mp>280° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([S:71][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc2cc(SCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A three-neck 2 L flask equipped with an overhead stirrer, a thermocouple and a nitrogen inlet was charged with 6-bromo-1-chloroisoquinoline (60.0 g, 247 mmol), xantphos (7.16 g, 12.4 mmol) and Pd2(dba)3 (5.66 g, 6.19 mmol) in that order. The flask was evacuated. To the reaction flask was charged sparged dioxane (540 mL) and DIPEA (64.8 mL, 371 mmol). The flask was purged with N2 and warmed to 63° C. upon which a solution of phenylmethanethiol (30.5 mL, 260 mmol) in 180 mL of sparged dioxane was charged to the reaction mixture dropwise over 1 hr. The reaction was completed according to LC/MS. The solids were filtered off. The filtrate was concentrated down to a low volume. 500 mL of isopropanol was added into a separate flask. The concentrated product solution was charged slowly to the flask containing isopropanol. The product crystallized out of the solution. The resulting slurry was stirred at RT for 2 hours. The slurry was cooled to 0° C., filtered, washed with 50% IPA/heptanes, and dried under a vacuum with nitrogen sweep. The product was obtained as yellow solids (44.3 g; 63% isolated yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.26-8.10 (m, 2H), 7.63-7.51 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.28 (m, 3H), 4.31 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].ON1C2C=CC=CC=2N=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)O
Agent: CCN=C=NCCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tertbutyl ester (2.77 g, 10 mmol) and 2-amino-1phenyl-ethanone (1.71 g, 10 mmol), and HOBT (1-hydroxybenzo-triazole) (2.70 g, 20 mmol) were dissolved in dichloromethane (100 ml). The solution was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (2.29 g, 12 mmol) was added followed by NMM (N-methyl-morpholine) (1.31 g, 13 mmol).