Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:50][CH2:49][CH2:48]1>>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:50][CH2:49][CH2:48]3)=[O:39])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: C1CCNC1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and pyrrolidine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (33 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[CH3:20][C:13]1[CH:12]=[C:11]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
4-Hydroxybenzaldehyde (945 mg, 7.7 mmol), 4-fluoro-2-methyl-1-nitrobenzene (1.0 g, 6.4 mmol), and K2CO3 (1.77 g, 12.8 mmol) were stirred in 55 mL dimethylformamide at 100 degrees Centigrade for 18 hours. The reaction was cooled to room temperature, diluted with ethylacetate, extracted two times with 1N NaOH, and rinsed with brine. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.72 g crude 4-[(3-methyl-4-nitrophenyl)oxy]benzaldehyde, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17](=O)[C:18]([CH3:24])([CH3:23])[C:19]([NH:21][NH2:22])=[O:20])=[N:9]2)=[N:6][CH:7]=1.O.NN.[CH2:29](O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[C:18]([CH3:24])([CH3:23])[C:19](=[O:20])[N:21]([CH3:29])[N:22]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(C(=O)NN)C(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Agent: NN
Solvent: O
Product: CN1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)C(C)(C)C1=O
Temperature: 80 °C
Yield: 86 %

Procedure:
Step-2: 3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-3-oxopropanehydrazide: A mixture of step-1 intermediate (2.40 g, 5.53 mmol) and hydrazine hydrate (0.87 mL, 27.6 mmol) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and the solvent was then evaporated under vacuum. The residue was triturated with toluene to obtain 2.0 g (86%) of title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H, D2O exchangeable), 8.72 (d, J=2.0 Hz, 1H), 8.38 (dd, J=2.0 & 8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 1.42 (s, 6H); ESI-MS (m/z) 420, 422 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a solution of (R)-6-tert-butoxycarbonylamino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (2.000 g, 5.232 mmol) in 10 mL of dichloromethane, was added trifluoroacetic acid (10 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated under reduced pressure, and the residue dried in vacuum for overnight at room temperature. The crude product (1.200 g, 81% yield) was used directly in the next step without further purification. LC-MS: tR=4.8 min; m/z 283 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>COCCOC>[Cl:1][C:2]1[C:7]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: COCCN
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1Cl

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-methoxyethylamine in DME. ES-MS m/e (%): 271 (M{37Cl}+H+, 43), 269 (M{35Cl}+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1F
Reaction time: 4 h

Procedure:
4′-Bromo-2′-fluorobiphenyl (5 g) was dissolved in chloroform (80 mL) at room temperature. Chlorosulfonic acid (5 g) was added dropwise and a precipitate appeared soon after addition was complete. Stirring was continued for a further 4 hours, after which the solid was collected by filtration. Further crops of crystals were collected from the filtrate. The solid was washed with cold chloroform and the washings also allowed to crystallise.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[Na+].[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:18]([C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CC(=C(Cc2ccccc2)c2ccccc2)C=C1
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 2.45 g (25.7 mmol) of anhydrous magnesium chloride and 20 mL of dry THF were put into a 100-mL Schlenk flask and then stirred. To this mixed solution, 10.6 mL (21.2 mmol) of a solution of 2.0-M sodium cyclopentadienide in THF was added. Then, the product was heated for an hour under reflux, the obtained pink slurry was cooled in an ice bath, and a solution in which 3.5 g (17.8 mmol) of benzyl phenyl ketone had been dissolved in 15 mL of dry THF was subsequently added thereto. Then, the product was stirred at room temperature for 18 hours, and the obtained orange solution was quenched with dilute aqueous hydrochloric acid. Then, 30 mL of diethyl ether was added thereto, the soluble part in diethyl ether was extracted, and the organic layer was neutralized and washed with an aqueous solution of saturated sodium hydrogen carbonate, water, and a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography to obtain an objective that was a reddish orange solid (amount: 2.7 g and yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:14]3[CH:15]=[CH:16][O:12][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccoc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccoc1
Yield: 49.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with 3-furaldehyde (1.04 mL, 11.9 mmol) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-furan-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.45 g, 55%)
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([N:7]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1S2
Temperature: 0 °C

Procedure:
30 g (0.118 mol) of 2-acetylphenothiazine and 9.28 g (1 eq.) of acetyl chloride are introduced into a 500 ml flask containing 150 ml of toluene. The reaction mixture is heated to reflux for 45 minutes before the introduction of a new portion of 4.6 g (0,5 eq.) of acetyl chloride. Stirring is maintained under heating at reflux for another 2 hours. The reaction medium is then poured onto approximately 200 g of ice. After stirring, the organic phase is decanted and washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness using a rotary evaporator. A yellow solid (33 g; 100%) is obtained which is used in the following stage without additional purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:15]([C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2)=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](O)c1ccc2cnc(Cl)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2cc([C@@H](C)O)ccc2cn1
Temperature: 150 °C
Yield: 50.2 %

Procedure:
1,4-Dioxane (5 mL) was degassed with nitrogen, (R)-1-(3-chloro-isoquinolin-6-yl)-ethanol (208 mg, 1 mmol), tributyl(vinyl)tin (951 mg, 0.9 mL, 3 mmol) and bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.1 mmol) were added and the reaction mixture was heated at 150° C. in a microwave reactor for 1 hour. Additional tributyl(vinyl)tin (0.3 mL, 1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (70 mg, 0.1 mmol) was added and the reaction mixture was heated at 150° C. in a microwave reactor for 1 hour. The reaction mixture was cooled to room temperature and the mixture was filtered thorough filter aid and the filter pad was washed with ethyl acetate. The filtrate was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 2:1 followed by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to afford the title compound (100 mg, 50%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.60 (d, J=6.5 Hz, 3H), 2.11 (brs, 1H), 5.10 (q, J=6.5 Hz, 1H), 5.52 (dd, J=10.6, 1.6 Hz, 1H), 6.40 (dd, J=17.2, 1.6 Hz, 1H), 6.95 (dd, J=17.2, 10.7 Hz, 1H), 7.57 (s, 1H), 7.58 (dd, J=8.5, 1.6 Hz, 1H), 7.78 (brs, 1H), 7.94 (d, J=8.5 Hz, 1H), 9.19 (s, 1H). LCMS (m/z) 200 [M+H], Tr=1.50 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12]C(=O)OCC)=[S:11])[CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:3]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)nc(C)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Cl)cc(NC(N)=S)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2 h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s, 1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.
Reaction SMILES: [Br:1]/[C:2](/[CH:10]([OH:19])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].[CH3:22]I>CS(C)=O>[Br:1]/[C:2](/[CH:10]([O:19][CH3:22])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:3]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CCCCCC#CC(O)/C(Br)=C/c1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C#CCCCCC#CC(OC)/C(Br)=C/c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of Compound 7 (303.0 mg, 0.96 mmol) and KOH (214.1 mg, 3.82 mmol) in DMSO (20 mL) was added MeI (271.3 mg, 1.91 mmol) followed by stirring at room temperature for 5 hours. The reaction was then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 214.3 mg (68 percent) of Compound 8: pale yellow oil; Rf=0.56 (20 percent EtOAc in hexane); IR (neat) 3296, 2940, 2232, 2116, 1446, 1078 cm−1; 1H NMR (300 MHz, CDCl3) δ7.68-7.65 (m, 2H), 7.38-7.25 (m, 3H), 7.29 (s, 1H), 4.76 (s, 1H), 3.42 (s, 3H), 2.36-2.31 (m, 2H), 2.26-2.21 (m, 2H), 1.95 (t, J=2.67 Hz, 1H), 1.74-1.65 (m, 4H); 13C NMR (75 MHz, CDCl3) δ135.4, 131.4, 129.8, 129.1, 128.8, 123.9, 89.2, 84.6, 77.5, 76.8, 69.3, 56.0, 28.1, 27.9, 19.0, 18.5; MS (+CI) m/z (relative intensity) 333 (M+H+, 81Br, 10), 331 (M+H+, 79Br, 12), 251 (100); HRMS (+EI) calcd for C18H19BrO 330.0619 (M+), found 330.0606.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Ba+2].[OH-].Cl>C(O)C>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:2](=[O:3])[CH:1]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1cccc(O)c1
Yield: 93.6 %

Procedure:
To a 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser, was charged 2.7 g (0.02 moles) of 3-hydroxyacetophenone, 2.1 g (0.02 moles) of benzaldehyde, 2.0 g (0.011 moles) of barium hydroxide, monohydrate, and 20 ml of absolute ethanol. The reaction mixture was refluxed for a total of 2.5 hours, after which it became thick and difficult to stir. Upon cooling, the resulting solid was dissolved in 100 ml. of 1 N aqueous hydrochloric acid, and another solid was observed to precipitate from this solution. The solid was collected by vacuum filtration, and washed with 100 ml. of water, then 100 ml. of hexane and dried in vacuuo at 40° C. for 24 hours. As a result, 4.2 g (93% yield) of 3'-hydroxychalcone was isolated as a tan solid, MP=143-147° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([S:11][CH3:12])=[C:9]([CH3:13])[NH:8][C:7]=12.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:13][C:9]1[NH:8][C:7]2=[C:2]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14]3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[S:11][CH3:12]
Reactant: CSc1c(C)[nH]c2c(Cl)nccc12
Reactant: c1ccc2c(c1)CCNC2
Product: CSc1c(C)[nH]c2c(N3CCc4ccccc4C3)nccc12
Temperature: 140 °C
Reaction time: 8 h

Procedure:
7-Chloro-2-methyl-3-methyl sulfanyl-1H-pyrrolo[2,3-c]pyridine (418 mg) prepared in Step 1 was added to 1,2,3,4-tetrahydroisoquinoline (3 ml). The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 440 mg of the titled compound as pale yellow oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[C:24](=[O:26])=[O:25]>C1COCC1.CCCCCC>[Br:16][C:17]1[C:18]([F:23])=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Fc1ccccc1Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cccc(Br)c1F
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at −10° C. The mixture was stirred for 1.5 h at −10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at −75° C. The mixture was stirred for 2 h at −75° C., before being poured on excess of CO2 gas. Then the reaction mixture was warmed to room temperature and stirred over night. After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2×50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][C:3]=1[N:14]=[C:15]=[S:16].[NH2:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][C:33]=1[NH:34][CH3:35])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22]>CN(C=O)C>[C:11]([NH:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:14][C:15](=[S:16])[NH:17][C:18]2[CH:19]=[C:20]([CH:31]=[CH:32][C:33]=2[NH:34][CH3:35])[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[O:22])[CH:4]=1)[CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)NC(C)c1ccc(Cl)c(N=C=S)c1
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1cc(C(C)NC(C)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[1-(4-Chloro-3-isothiocyanatophenyl)ethyl]acetamide in DMF (2 mL) was added to a mixture of 3-amino-N-(4-bromophenyl)-4-methylaminobenzamide (87 mg, 0.2 mmol, crude material from the step above) in DMF (2 mL) at rt. The mixture was stirred at rt overnight and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 130 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCN(C)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 133 (0.5 g, 1.31 mmol) in 1,4-dioxane (5 mL) was added slowly a solution of 1-methylpiperizine (0.13 g, 1.31 mmol) in 1,4-dioxane (5 mL) followed by 2.5 N sodium hydroxide solution (0.5 mL, 1.31 mmol) and water (1.2 mL). The mixture was heated to reflux for 2.5-3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. and diluted with water (10 mL). The mixture was then stirred for 10-15 min., the precipitated solid was filtered off and dried under vacuum to afford the title compound E18 as an off-white solid (0.5 g, 86%). mp 120-122° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 65:35 [0.01 M KH2PO4 (0.1% TFA):CH3CN], 223 nm, Rt 10.23 min, 98.50% purity); MS (CI): m/z 446 (M+H, 100), 375 (25).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3]O.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:34]([S:53][CH2:54][C@@H:55]([C:57]([OH:59])=[O:58])[NH2:56])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH:56][C@@H:55]([CH2:54][S:53][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:57]([OH:59])=[O:58]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a −78° C. methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.1 mL, 35.0 mmol) was added triflic anhydride (1.78 mL, 10.5 mmol). After 2.5 h, S-tritylcysteine was added all at once and the reaction mixture was stirred at 0° C. for 80 min. The reaction mixture was stirred at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (3 hexanes/1 ethyl acetate+1% acetic acid) to provide 2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (3.29 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, and the mixture was heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:29][C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1>>[CH3:27][C:26]1[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[C@H:30]([CH3:29])[CH2:34][O:33][C:32]4=[O:35])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]2)=[N:22][CH:23]=[C:24]([CH3:28])[CH:25]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 8.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (234 mg) described in Preparation Example 123 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (20.8 mg) was obtained.