Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[N:10]2[CH2:11][CH2:12]SC3=[C:9]2[C:4](=[CH:5][C:6]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:7]3)[S:3]1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>ClCCl.C(O)C>[CH3:35][S:36]([OH:39])(=[O:38])=[O:37].[NH:1]=[C:2]1[N:10]2[CH2:11][CH2:12][S:36](=[O:39])(=[O:37])[C:35]3=[C:9]2[C:4](=[CH:5][C:6]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:7]3)[S:3]1
Reactant: N=c1sc2cc(OC(F)(F)F)cc3c2n1CCS3
Agent: CS(=O)(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCO
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CCS3(=O)=O
Reaction time: 1 h

Procedure:
3.35 g of 2-imino-8-trifluoromethoxy-4,5-dihydro -2H-thiazolo[3,4,5-de][1,4]benzothiazine are added to a solution, under argon and cooled to 5° C., of 5.3 g of 3-chloroperbenzoic acid (80% purity) in 100 ml of dichloromethane and the stirring is maintained for 16 hours at a temperature close to 20° C. 100 ml of a 1 M aqueous solution of sodium hydrogen carbonate are then added and the mixture is stirred for 1 hour at the same temperature. After separation of the two phases, the aqueous phase is extracted twice with 50 ml of dichloromethane and the combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The yellow oil obtained is chromatographed under nitrogen pressure (150 kPa) on 20 g of 20-45 μm silica gel contained in a column 2 cm in diameter, eluting with ethyl acetate. The product obtained (730 mg) is dissolved in 50 ml of absolute ethanol, and then 100 μl of methanesulphonic acid are added. After stirring for 1 hour 45 minutes, the precipitate is separated by filtration, washed with ethanol and then with ethyl ether and dried under reduced pressure (2 kPa) at 20° C. 750 mg of 2-imino-8-trifluoromethoxy -4,5-dihydro-2H-thiazolo[3,4,5-de]-[1,4]benzothiazine 6,6-dioxide methanesulphonate are thus obtained in the form of a white solid melting at a temperature greater than 260° C. [Analysis C11H11F3N2O6S3, % calculated C, 31.43; H, 2.64; F, 13.56; N, 6.66; S, 22.88; % found C, 31.39; H, 2.29; F, 13.28; N, 6.59; S, 22.60].
Reaction SMILES: N1CCC[C@H]1C(N)=O.C(N(CC)CC)C.ClCC(Cl)=O.[Cl:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]([NH2:32])=O)=[O:24].CN(C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]#[N:32])=[O:24]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)CCl
Agent: NC(=O)[C@@H]1CCCN1
Agent: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1CCCN1C(=O)CCl
Reaction time: 1.5 h
Yield: 82 %

Procedure:
This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 20.5 g (201 mmol) of triethylamine, 23.2 g (203 mmol) of chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding a solution of the Vilsmeier-Reagent at RT that was prepared from 33.8 mL (438 mmol) of DMF, 20 mL of methylenechloride and 25.3 g (201 mmol) of thionylchloride. The resulting mixture was stirred for 90 min, then quenched with water and extracted in an analogous manner as example 1. Crystallization from Isopropanol/n-heptane and drying afforded 24.7 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 82%, assay: 99.9% (m/m) based on HPLC).
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH2:29][CH2:28][S:27][CH2:26][C@H:25]3[C:30](=[O:49])[NH:31][CH2:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:30]([C@@H:25]1[CH2:26][S:27][CH2:28][CH2:29][NH:24]1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Piperidine (0.95 mL, 9.65 mmol) was added dropwise to a stirred solution of (R)-(9H-Fluoren-9-yl)methyl-3-[2-{(tert-butoxycarbonylamino)methyl}-5-chloro benzylcarbamoyl]thiomorpholine-4-carboxylate (1.20 g, 1.93 mmol) in CH2Cl2 (50 mL) and the resulting mixture was stirred at room temperature for 2 h. Volatile solvent was removed under reduced pressure and the residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.64 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([NH:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:7]=1)C.[Li+].[BH4-]>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]([NH:17][N:8]2[N:7]=[C:6]([CH2:5][CH2:4][OH:3])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:16])=[O:27])=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CCO)c2ccccc2c1=O
Reaction time: 6 h

Procedure:
To a 0° C. solution of the product from Example 116 (365 mg, 0.938 mmol) in THF (10 mL) was added LiBH4 in THF (2M, 0.69 mL, 1.4 mmol). The mixture was stirred for 6 hours, quenched with water (10 mL), extracted with EtOAc (4×20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (0-100% of 1/10 MeOH/EtOAc in hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.31 (dd, J=7.9, 1.4, 1H), 8.08 (d, J=8.1, 1H), 8.04-7.94 (m, 1H), 7.94-7.85 (m, 1H), 7.43-7.35 (m, 4H), 4.74 (t, J=5.4, 1H), 3.81-3.71 (m, 2H), 3.68 (s, 2H), 3.08 (t, J=6.7, 2H); MS (ESI+) M/Z 358 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2].[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cccc2c(Cl)c(C(C)=O)cnc12
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(C)=O)cnc12
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of crude 3-acetyl-4-chloro-8-methoxyquinoline (7.9 g) and o-toluidine (2 ml. 19 mmol) in dioxan (150 ml) was heated under reflux with stirring for 2 hours, then cooled and evaporated. Aqueous sodium bicarbonate was added, the mixture extracted with chloroform, and the organic extract dried and evaporated. Recrystallisation from ethyl acetate and then from ethanol gave 3-acetyl-4-(2-methylphenylamino)-8-methoxyquinoline (2.65 g, 44% from 3-acetyl-8-methoxy-4(1H)-quinolone), m.p. 171°-173°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([N+:18]([O-])=O)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.[Cl-].[Ca+2].[Cl-].C>C(O)C.O.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([NH2:18])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Yield: 85.7 %

Procedure:
A slurry of 7-nitro-α-methylfluorene-2-acetic acid methyl ester (13.1 g) in 78% ethanol (400 ml) is treated with a solution of calcium chloride (4.5 g) in water (6.1 ml), zinc dust (127 g) and charcoal (4.6 g) and the mixture refluxed for 2.5 hours. The hot mixture is filtered and the cake washed with hot 78% ethanol. The filtrate is diluted with water (800 ml) and extracted with chloroform. The chloroform extracts are dried (MgSO4) and evaporated to give 10.1 g of 7-amino-α-methylfluorene-2-acetic acid methyl ester.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[CH:12]=[C:11]([CH2:13][N:14]([CH:22]2[CH2:24][CH2:23]2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:9]2[C:5]=1[C:6]([CH3:30])=[N:7][N:8]2[CH2:25][CH2:26][CH2:27][O:28][CH3:29].Cl>O.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].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH:22]1([N:14]([CH2:13][C:11]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:30])=[N:7][N:8]3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[C:4]([OH:1])[CH:12]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:24][CH2:23]1
Reactant: [OH-]
Reactant: COCCCn1nc(C)c2c(Cl)cc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COCCCn1nc(C)c2c(O)cc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A solution of potassium hydroxide (41 mg) in water (1 ml) was added to a mixture of tert-butyl {[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl}cyclopropylcarbamate (100 mg), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (tBu X-Phos) (8.3 mg), tris(dibenzylideneacetone)dipalladium(0) (9.0 mg) in 1,4-dioxane (1 ml) under argon atmosphere and the mixture was stirred at 100° C. for 90 minutes. A 1N solution of HCl (0.8 ml) and water were added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=1/2) to give tert-butyl cyclopropyl{[4-hydroxy-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl}carbamate (91 mg) as a pale brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC1CCc2ccccc2N1
Reactant: COC(=O)c1ccc(CBr)c(OS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2c3ccccc3CCC2C)c(OS(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 23 h
Yield: 73.5 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-[(methylsulfonyl)oxy]benzoate (0.70 g, 2.2 mmol), 2-methyl-1,2,3,4-tetrahydroquinoline (0.39 g, 2.6 mmol), potassium carbonate (0.60 g, 4.3 mmol) and N,N-dimethylformamide (14 mL) was stirred at 70° C. for 23 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (0.63 g, yield 75%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20]>>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1OC
Reactant: COC(=O)CCCC(=O)[O-]
Product: COC(=O)CCCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
75 g of polyphosphoric acid (Acros) was charged in a 250 mL round bottom flask, followed by addition of 1,2,3-trimethoxybenzene (5.0 g, 29.73 mmol), and mono-methylglutarate (6.516 g, 44.60 mmol). The reaction mixture was stirred mechanically for 2.5 h at 45° C. The reaction mixture was then poured into a 1000 mL beaker containing around 250 mL of ice, and stirred well until all the product precipitated out. The tan colored product was then filtered and washed with water and dried under vacuum. No, purification required at this stage. 6.78 g (77%) of product was obtained, which was pure by NMR.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH:18]=[CH2:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.C(OCC)(=O)C>C1COCC1>[CH2:15]([C:14]1[CH:13]=[C:12]([CH:18]=[CH2:19])[CH:11]=[C:10]([CH2:20][CH2:21][CH3:22])[C:9]=1[OH:8])[CH2:16][CH3:17]
Reactant: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=Cc1cc(CCC)c(O)c(CCC)c1

Procedure:
The title compound was prepared from t-butyldimethyl-silyloxy-2,6-dipropyl-4-vinylbenzene (Step B, Example 14) by treatment with tetrabutylammonium fluoride in THF for a few hours. It was poured into ether/ethyl acetate mixture and washed with brine. After removal of the solvent the crude product was purified by flash column chromatography using ethyl acetate/hexane as eluent.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([O:19][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)s1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a mixture of anhydrous MgSO4 (11.60 g, 96.4 mmol) in 100 mL CH2Cl2 was added concentrated H2SO4 (1.45 mL, 24.1 mmol) and the mixture was stirred for 15 minutes followed by addition of 5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirring for 1 minute, tert-butanol (11.6 g, 20 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4. The organic solution was concentrated to give a clear oil which was purified via medium pressure chromatography (3% EtOAc in hexanes) to afford the title compound (4.97 g). 1H NMR (400 MHz, CDCl3) δ7.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:11]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=2[C:13]#[N:14])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:20].CCOC(C)=O>CO>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:10])[C:12]=1[C:13]#[N:14]
Reactant: N
Reactant: Cc1cc(C)cc(S(=O)c2cccc(F)c2C#N)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(S(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Yield: 59.2 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfinyl]-6-fluorobenzonitrile (Example 19) (0.4 g, 1.5 mmol) was dissolved in 40 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to 150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.24 g (61%) of 2-amino-6-[(3,5-dimethylphenyl)sulfinyl]benzonitrile: mp 190°-191° C.; NMR (Me2SO-d6, 200 MHz) δ 2.32 (s, 6H), 6.48 (br s, 2H), 6.90 (apparent d, 1H), 7.11 (apparent d, 1H), 7.20 (m, 1H), 7.32 (m, 2H), 7.52 (apparent t, 1H); mass spec (CI) M+ +1=271. Anal. Calc. for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S, 11.86. Found: C, 66.71; H, 5.27; N, 10.32; S, 11.84.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[CH:32]=[CH:31][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=2)=[O:16])=[CH:13][N:12]=1>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:31]=[CH:32][C:11]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)=[N:12][CH:13]=2)=[CH:19][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)n1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
21 mg of sodium hydride was added to a solution of 84 mg of 3,5-dimethylpyrazole in 2 mL of DMF. The reaction mixture was stirred for 10 min, and then added 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide. The reaction was heated to 140° C. for 16 h. The mixture was quenched with MeOH and evaporated. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinamide. MS (Q1) 404.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][CH:5]([C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH3:14])[CH2:4][O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:15])[CH2:6][CH:5]([CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH:8]2[CH3:14])[CH2:4][O:3]1
Reactant: CC1=C(C2COC(C)(C)C2)CCC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1C(C2COC(C)(C)C2)CCC1(C)C
Yield: 100 %

Procedure:
31.7 g of rac!-2,2-dimethyl-4-(2,3,3-trimethylcyclopent-1-en-1-yl)tetrahydrofuran (from Example 4), at a purity of 92.7% (0.14 mole) were hydrogenated on a Parr shaker using 2.0 g of 5% Pd on carbon in 50 ml of ethanol. The product, 31.6 g, was distilled to afford 30 g (100% yield). BP 52°-54° C./0.2 mmHg; 1H-NMR (300 MHz), δ0.74 (3H, s), 0.85 (3H, d, J=6.9 Hz), 0.94 (3H, s), 1.2 (1H, m), 1.19 (3H, s), 1.28 (3H, s), 1.3-1.6 (5H, m), 1.65-1.95 (2H, m), 2.33 (1H, m), 3.47 (1H, m), 3.94 (1H, m); 13C-NMR (75 MHz), δ13.83, 22.07, 26.75, 28.29, 28.56, 28.82, 40.64, 43.57, 44.72, 45.76, 49.56, 49.69, 71.84, 81.25; IR (Neat), 2980, 1460, 1055 cm-1 ; MS (m/e), 195 (M+ -15), 137, 43 (Base);
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([N:16]([C:70]3[N:75]=[C:74](Cl)[N:73]=[C:72]([NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH:82]4[CH2:87][C:86]([CH3:89])([CH3:88])[N:85]([O:90][CH:91]5[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]5)[C:84]([CH3:98])([CH3:97])[CH2:83]4)[N:71]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:53]3[CH2:58][C:57]([CH3:60])([CH3:59])[N:56]([O:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)[C:55]([CH3:69])([CH3:68])[CH2:54]3)[C:24]3[N:29]=[C:28](Cl)[N:27]=[C:26]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]4[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)[C:38]([CH3:52])([CH3:51])[CH2:37]4)[N:25]=3)[CH2:10][C:9]2([CH3:100])[CH3:99])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:101]([CH2:103][NH2:104])[OH:102]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([N:16]([C:70]3[N:75]=[C:74]([NH:104][CH2:103][CH2:101][OH:102])[N:73]=[C:72]([NH:77][CH2:78][CH2:79][CH2:80][CH2:81][CH:82]4[CH2:87][C:86]([CH3:89])([CH3:88])[N:85]([O:90][CH:91]5[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]5)[C:84]([CH3:98])([CH3:97])[CH2:83]4)[N:71]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:53]3[CH2:58][C:57]([CH3:60])([CH3:59])[N:56]([O:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)[C:55]([CH3:69])([CH3:68])[CH2:54]3)[C:24]3[N:29]=[C:28]([NH:104][CH2:103][CH2:101][OH:102])[N:27]=[C:26]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]4[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]5)[C:38]([CH3:52])([CH3:51])[CH2:37]4)[N:25]=3)[CH2:10][C:9]2([CH3:100])[CH3:99])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)C3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)C3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(NCCO)nc(N(CCCCCCN(c3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)n3)C3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)C3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
5 g of 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H benzimidazole was dissolved in a mixture comprising 100 ml of dichloromethane and 25 ml of diethyl ether to obtain a solution. 2.83 g of 85% m-chloroperbenzoic acid was added to this solution in portions at -45° C. After the completion of the reaction, 2 g of triethylamine was added to the reaction mixture and the obtained mixture was heated to -10° C., followed by the addition of 50 ml of 1N sodium hydroxide. The obtained mixture was stirred at a room temperature for 30 minutes. The obtained aqueous layer was washed with 20 ml of dichloromethane twice and adjusted to pH 11 with a 2M aqueous solution of ammonium acetate. The aqueous layer was extracted with 50 ml of dichloromethane thrice. The obtained dichloromethane layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate twide, dried over magnesium sulfate and distilled to remove the dichloromethane. The obtained oily product was crystallized from dichloromethane/ether to obtain 4.17 g of the title compound as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[OH:24].[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>CC(N(C)C)=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:25](=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Solvent: CC(=O)N(C)C
Product: C=CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 142.2 %

Procedure:
A solution of (4Z)-4-{[(4-amino-3-hydroxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dione (1.1 g, 2.3 mmol) in dimethylacetamide (12 mL) is cooled to 0° C. in an ice water bath. Acryloyl chloride (1.9 mL, 23 mmol) is added and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is then concentrated under reduced pressure and combined with impure material from a previous batch. The material is adsorbed onto flash silica gel, which is then subjected to flash chromatography (methanol/chloroform) to give N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]acrylamide (1.6 g).