Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.S1(CCC[CH2:28]1)(=O)=O>C(O)C.CO.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:28])=[O:8]
Reactant: O=S1(=O)CCCC1
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CCO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F

Procedure:
5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl2 in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol and ethanol). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.
Reaction SMILES: C12(C([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[O:20][C:19]([C:24]35C[CH:28]6[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]6)[CH2:25]3)C5)=[CH:18][C:17]4=[O:34])=O)CC3CC(CC(C3)C1)C2.[OH-].[K+]>O1CCOCC1>[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19]([CH:24]=[CH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:32]=1)=[CH:18][C:17]2=[O:34]
Reactant: O=C(Oc1ccc2oc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1)C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cc(C=Cc2ccccc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
330 mg 6-(1-adamantoyloxy)-2-(1-adamantyl)-4H-chromen-4-one is dissolved in dioxane and treated with 5 ml of 10% aqueous potassium hydroxide solution. The mixture is stirred for 3 hours at room temperature and then poured into 2M aqueous pH 7 buffer solution. Extraction with ethyl acetate yields after drying and evaporation a crude product which is purified by chromatogaphy. The title compound is obtained [colourless crystals; mp 230°(from 2-propanol)].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C@H:12]([C@@H:14]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:22])[CH3:21])[OH:13].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12]([C@@H:14]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:21])[CH3:22])=[O:13]
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
The solution of the product of Example 40 (50 mg, 0.16 mmol) in dichloromethane (4 mL) at 0° C. was added sodium bicarbonate (13.4 mg, 0.16 mmol) and Dess-Martin periodinane (132 mg, 0.31 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of 5% hydrochloric acid (5 mL) and then the organics were extracted with ethyl acetate (20 mL×3) and the organic phase was washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid (22.8 mg, Yield: 45%). Mp=35.2-38° C.; Rf=0.6 (10:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3+D2O) δ 2.68 (d, J=11.2 Hz, 1H), 2.13-2.09 (m, 1H), 1.78 (dd, J=2.4 Hz 13.2 Hz, 1H), 1.55-1.50 (m, 2H), 1.39 (d, J=12.8 Hz, 1H), 1.31-1.24 (m, 1H), 1.06-0.98 (m, 1H), 0.94 (s, 3H), 0.89 (d, J=6.4 Hz, 3H), 0.86 (s, 3H) ppm; Mass spectrum (EI+ve) m/z 320 (M+); [α]D25=−88.0° (c=0.20, dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.[BH4-].[Na+].Cl>ClCCl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COc1ccc(Nc2ncc(CNc3ccccn3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 52.2 %

Procedure:
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (121.8 mg, 0.2734 mmol) and 2-aminopyridine (72.0 mg, 0.765 mmol) were suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL) and tetraisopropoxytitanium (0.16 mL, 0.54 mmol) was added. The flask was fit with a reflux condenser and put in a preheated oil bath (70° C.) and stirred under nitrogen. After 5 hours, the reaction was diluted with DCM, and stirring was continued overnight. Then, more 2-aminopyridine (63.6 mg, 0.676 mmol) and Ti(OiPr)4 (0.18 mL, 0.61 mmol), and DCM were added, and stirring was continued at 70° C. for about 6 hours. Then, the reaction was cooled to room temperature, and sodium borohydride (38.9 mg, 1.028 mmol) was added. The reaction was stirred at room temperature for 25 minutes, and then aqueous 5N HCl (0.55 mL) was added. The flask was put in a preheated oil bath (50° C.) and stirring was continued overnight. Then, the reaction was cooled to room temperature, diluted with DCM and MeOH, and filtered through a Celite® (diatomaceous earth) pad, which was washed with a 1:1 mixture of DCM and MeOH. The filtrate was concentrated, treated with water, and filtered. The solid was washed with water, collected, treated with DMSO (about 1 mL), diluted with DCM, and filtered. The solid was washed with DCM, collected, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-2-ylamino)methyl)pyridin-2-amine (62.7 mg, 52% yield). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.60 (br s, 1H), 12.63 (s, 1H), 9.80 (s, 1H), 9.01 (br s, 1H), 8.56 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.15 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.98 (d, J=6.26 Hz, 1H), 7.92 (t, J=7.43 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.90 (t, J=6.46 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].C1COCC1.[CH3:9][C:10]([NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25](S(C3C=CC(C)=CC=3)(=O)=O)[CH:24]=2)[N:18]=1)([CH2:14][CH3:15])[C:11]([O-:13])=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH:25]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:31]2[C:23]([C:19]2[N:18]=[C:17]([NH:16][C:10]([CH3:9])([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH:22]=[CH:21][N:20]=2)=[CH:24]1
Reactant: CCC(C)(Nc1ccnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)n1)C(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Temperature: 25 °C
Yield: 68 %

Procedure:
Lithium hydroxide hydrate (1.9 g, 45 mmol) was added to 50 mL THF and 15 mL water. Then 2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate was added and the mixture was heated to reflux for 18 hours. The reaction was cooled to rt and 50 mL 1M citric acid solution was added. The mixture was extracted with 3×100 mL ethyl acetate where upon a white precipitate formed in the aqueous layer. The product was then filtered from the aqueous layer and dried under vacuum affording 1.6 g (68%) 2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylbutanoic acid as white solid. 1H NMR (300 MHz, MeOD) 8.87 (dd, 1H), 8.32 (m, 2H), 7.94 (d, 1H), 3.31 (m, 3H), 2.80 (q, 1H), 2.29-1.95 (m, 2H), 1.68 (s, 3H), 0.96 (t, 3H). m/e m+1=312.22.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[C:7]([NH2:23])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:11]=1)([O-])=O>C(O)(=O)C.C(O)C.[Pd]>[ClH:1].[ClH:1].[O:21]1[C:15]2[CH:14]=[CH:13][C:12]([C:10]3[CH:11]=[C:6]([NH2:3])[C:7]([NH2:23])=[N:8][CH:9]=3)=[CH:22][C:16]=2[CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2ccc3c(c2)CNCCO3)cnc1N
Reaction time: 1 h
Yield: 199.6 %

Procedure:
To a solution of 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (1.0 g, 2.8 mmol) in acetic acid (20 mL) and ethanol (20 mL) was added Pd/C (10% wt/wt, 0.5 g) and the reaction mixture was stirred under H2 (45 PSI) for 1 hour. The resulting pale yellow solution was filtered through Celite and the filtrate was concentrated to give 5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine dihydrochloride (0.92 g, 100%) as a yellow powder. MS (EI) for C14H16N4O: 257.3 (MH+).
Reaction SMILES: [NH:1]([C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O)[NH2:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[N:24]=[C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[NH:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: N#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(Cl)cc3)n[nH]2)CC1
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A mixture of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (1.0 g), 4-chlorobenzonitrile (1.7 g), potassium carbonate (0.28 g), and butanol (8.0 mL) was heated at 150° C. for 2 hours using a microwave device. After leaving to be cooled, the solvent was evaporated under reduced pressure, and the residue was azeotroped with toluene. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10). To the purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-[3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate (0.62 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][OH:31])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:28]([CH2:29][CH:30]=[O:31])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: CCCCCCCCCCN(CCO)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (12.24 mL) and methylene chloride (50 mL) at −35 to −45° C. was added DMSO (14.75 g) in methylene chloride (25 mL) over 20 minutes. The reaction mixture was stirred for 10 minutes at −35 to −45° C. A solution of N-Fmoc-2-(n-decylamino)ethanol (20.0 g) in methylene chloride (70 mL) was added over 25 minutes and then stirred 40 minutes at −35 to −45° C. Triethylamine (21.49 g) was then added and the mixture stirred for 30 minutes at −10 to −20° C. The reaction mixture was quenched with water (120 mL) followed by concentrated sulfuric acid (20.0 g) while maintaining the internal temperature at 0-5° C. The organic layer was isolated and washed with 2% sulfuric acid (100 mL) followed by water (2×100 mL). The organic solution was distilled under vacuum at 60° C. to about 100 mL. Heptane (100 mL) was added, the temperature of the oil bath raised to 80° C. and the distillation was continued until the residual volume was 100 mL. More heptane (100 mL) was added and the distillation repeated to a volume of 100 mL. The heating bath was replaced with a cold water bath at 15° C. The bath was cooled slowly to 5° C. over 20 minutes to start the precipitation of the product. The slurry was then cooled to −5 to −10° C. and the slurry was stirred for 2 hours. The solid was then collected on a Buchner funnel and washed with cold (−5° C.) heptane (2×15 mL). The wet solid was dried in vacuo to yield the title aldehyde.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Firstly, a mixture of 4-iodo-bromobenzene (2.60 g, 9.19 mmol), t-butylammoniumiodido (3.39 g, 9.18 mmol) and [Rh(cod) (CH3CN)2] (105 mg, 0.277 mmol) was added with DMF (26 mL) and triethylamine (2.56 mL, 18.4 mmol). Triethoxysilane (1.87 mL, 10.1 mmol) was added dropwise to the resultant mixture at 0° C., and then the mixture thus newly produced was stirred under a nitrogen atmosphere at 80° C. for 1 hour to obtain a reaction mixture. Subsequently, the solvent in the reaction mixture was distilled away with a vacuum pump, and then the resultant mixture was subjected to a celite filtration process with ether and a concentration process under a nitrogen atmosphere to obtain a crude product. The obtained crude product was purified with a Kugelrohr distillation apparatus to obtain 4-bromo-triethoxysilylbenzene (2.38 g, 81% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-phenylpiperazine (193 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.19 (m, 4H) 4.05 (s, 2H) 6.78 (t, J=7.29 Hz, 1H) 6.95 (d, J=7.80 Hz, 2H) 7.22 (m, 2H) 7.56 (dd, J=8.15, 4.75 Hz, 1H) 8.33 (dd, J=8.15, 1.70 Hz, 1H) (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)N.N[C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=1OC)[C:16]([NH:18]C1C=CC(F)=C(F)C=1)=[O:17]>>[C:16]([NH2:18])(=[O:17])[C:15]1[CH:27]=[CH:28][CH:29]=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Nc1cccc(C(F)(F)F)c1
Product: NC(=O)c1ccccc1
Yield: 15 %

Procedure:
The title compound was synthesized as in Example 1 using 3-trifluoromethylaniline (1.32 g, 10.6 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.92 g, 3.3 mmol) to give 0.060 g of benzamide, N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[[3-(trifluoromethyl)phenyl]amino]carbonyl]amino]sulfonyl]amino]-. Microanalysis: C22H17F5N4O5S; calculated: C=48.53; H=3.15; N=10.29. found: C=48.52; H=3.09; N=10.18. MS: M++1=545 Da. Mp 198-200° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[CH3:25][C:26]1([CH3:41])[CH2:31][N:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[C:29](=[O:40])[CH2:28][NH:27]1>C1(C)C=CC=CC=1>[CH3:25][C:26]1([CH3:41])[CH2:31][N:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[C:29](=[O:40])[CH2:28][N:27]1[CH2:11][C@H:9]([NH:10][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]1[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Yield: 100.3 %

Procedure:
A solution of 863 mg of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (2.43 mmol) and 805 mg of 5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one obtained in Example (70d) (3.40 mmol) in toluene (30 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=5/1-3/1) to obtain 1.44 g of the title compound (yield: 99%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:28])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2)#[N:27]
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 7.5 %

Procedure:
A mixture of 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (500 mg, 1.32 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was prepared. The reaction mixture was stirred at 25° C. for 36 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (36 mg, 7%) as a white solid: LC/MS m/e calcd for C22H25N3O2 (M+H)+: 364.46, observed: 364.1.
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].C(N(CC)CC)C.[CH3:20][C:21]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](=[N:34][O:35][CH3:36])[CH:32]=O>[Cl-].[Na+].O.C(O)CCC>[CH3:36][O:35][N:34]=[C:31]([CH:32]1[NH:9][CH2:10][CH2:11][S:12]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:23][C:22]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:21]=1[CH3:20]
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reactant: NCCS
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: CON=C(c1ccccc1COc1cc(C)ccc1C)C1NCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Toluene (3 ml), butanol (3 ml), cysteamine hydrochloride (0.34 g, 3.0 mmol) and triethylamine (0.42 ml, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetoaldehyde (0.45 g, 1.5 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl thiazolidin-2-yl ketone O-methyloxime (0.49 g, yield 91.6%) as a colorless oil.
Reaction SMILES: [Li].[F:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[F:18][C:19]([F:24])([F:23])[C:20]([CH3:22])=O>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:18][C:19]([F:24])([F:23])[C:20]([CH3:22])=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]1[CH:16]=[CH:17][C:3]([F:2])=[CH:4][CH:5]=1
Reactant: CC(=O)C(F)(F)F
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 23.5 %

Procedure:
Lithium (1.94 g, 280 mmol) was added to a suspension of titanium trichloride (12.3 g, 80 mmol) in 250 mL tetrahydrofuran. After the initial exothermic reaction had subsided, the mixture was heated at reflux for 2 hours. After cooling to 25° C. a solution of 4,4'-difluorobenzophenone (2.18 g, 10 mmol) and 1,1,1-trifluoroacetone (4.48 g, 40 mmol) in 30 mL tetrahydrofuran was added and the mixture stirred for 2 hours. The mixture was then refluxed for 20 hours. The mixture was cooled and diluted with 30 mL of hexane and the insolubles removed by filtration through diatomaceous earth. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with hexane to give 0.7 g of the title compound as an oil. MS(CI): m/e =298 for M+ of C16H11F5.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:13]([O:12][C:10]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:17]([OH:22])[OH:18])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.5 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.18 g, 10 mmol) and B(OiPr)3 (2.8 mL, 12.1 mmol) in 10 mL of THF cooled at 0° C. was added a LDA solution (16 mmol, prepared from 2.24 mL of iPr2NH, 15 mL of THF and 6.4 mL of 2.5 M n-BuLi solution in hexane) by a syringe pump over a period of 2 h. The reaction mixture was stirred for additional 1 h at 0° C. before being quenched by addition of 30 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×100 mL of EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give 3 g of the title compounds as a gray solid which was used for the next step without further purification.