Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(N3CCOCC3)ccc21
Yield: 41.5 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (100 mg, 0.3 mmol), morpholine (0.052 ml, 0.6 mmol) and NMP (2 ml) gave title compound (50 mg, 41%) after purification by column chromatography using chloroform/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH2:31](O)[CH2:32][CH3:33].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH2:31][CH2:32][CH3:33])=[O:28])[CH:17]=1
Reactant: CCCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and n-PrOH (1.13 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×50 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2% EtOAc/hexanes) to furnish 1.33 g of propyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (yellow-coloured oil, yield: 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[CH:26])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: C#Cc1cccc(O)c1
Product: C#Cc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 91.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-ethynyl-phenol (31 mg, 0.26 mmol) to give the title compound (55 mg, 91%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][S:6][CH2:7][C:8]1[NH:9][C:10]([CH3:32])=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(C=CC(O)=CC=1)O.C(O)(=O)C(O)=O>C1COCC1>[CH:4]([CH2:5][S:6][CH2:7][C:8]1[NH:9][C:10]([CH3:32])=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:3]
Reactant: CCOC(=O)C1=C(CSCC(OCC)OCC)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(CSCC=O)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
A THF solution (25 ml) of 2-[(2,2-diethoxyethyl)-thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (5 g), hydroquinone (0.5 g), and oxalic acid (1N water solution, 10 ml) is heated to the reflux temperature, under N2 atmosphere, for one hour, then the THF is evaporated in vacuum and the water layer is extracted with AcOEt (3×20 ml). The organic phases are washed with water (2×5 ml), a satured solution of NaHCO3 (2×5 ml) and water (3×5 ml), dried on Na2SO4 and evaporated to dryness. The residue, after purification by column chromatography (SiO2 120 g; eluent: hexane/isopropyl ether 70/30), yields 3.8 g of pure 2-[(formylmethyl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, oil.
Reaction SMILES: C(S)C.[H-].[Na+].[H][H].[S:8]([CH2:18][C@@H:19]1[C@@H:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:24][C@H:23]2[N:34]([CH3:35])[C@@H:20]1[CH2:21][CH2:22]2)([C:11]1C=CC(C)=C[CH:12]=1)(=O)=O>CN(C)C=O.CCOCC.O>[CH2:11]([S:8][CH2:18][C@@H:19]1[C@@H:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:24][C@H:23]2[N:34]([CH3:35])[C@@H:20]1[CH2:21][CH2:22]2)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2[C@@H](c3ccc(Cl)c(Cl)c3)C[C@@H]3CC[C@H]2N3C)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCSC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 39.6 %

Procedure:
To a cold (0° C.) solution of ethanethiol (0.5 ml) in dimethylformamide (30 mL) was added sodium hydride (60%, 0.27 g). When the evolution of hydrogen had ceased (1R,2R,3S)-2-tosylmethyl-3-(3,4-dichlorophenyl)tropane (2.0 g, 4.4 mmol) in dimethylformamide (20 ml) was added. The mixture was stirred at 0° C. for 25 min. The reaction mixture was heated at 100° C. for 5 days. The reaction was cooled to ambient temperature and poured into a mixture of water (500 ml) and ether (100 ml). The phases were separated and the aqueous phase was extracted once more with ether (100 ml). The ether phase was evaporated and the residue was dissolved in ether (75 ml) and washed with water (2×400 ml), dried over MgSO4 and evaporated to dryness. Yield: 1.4 g. of the title compound. The crude product was purified by column chromatography on silica gel using a mixture of CH2Cl2MeOH NH3(aq)(9:1)+1% NH3 (aq). 0.6 g of the title compound was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](=O)[CH2:14][C:15]#[N:16].[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:14]=[C:15]([NH2:16])[NH:18][N:19]=1
Reactant: NN
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CC#N
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cc(N)[nH]n1

Procedure:
3-(5-Methyl-3-phenyl-isoxazol-4-yl)-3-oxo-propionitrile (0.391 g, 1.73 mmol) in Ethanol (3 mL) was treated with hydrazine (0.168 mL, 3.46 mmol) and heated to reflux. Evaporation in vacuum gave 5-(5-Methyl-3-phenyl-isoxazol-4-yl)-2H-pyrazol-3-ylamine used without purification. To the resulting amine (0.039 g, 0.16 mmol) in dioxane was added triethyl amine followed by benzyl chloride (0.019 mL, 0.16 mmol). The reaction was stirred at 10° C. for 1 hr and 2 hr at ambient temperature. The solution was diluted with water extracted with ethyl acetate, washed with saturated NaHCO3, Brine, dried over MgSO4 and concentrated in vacuum. HPLC purification afforded 1.4 mg of title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[OH-].[Na+].[CH3:11][CH:12]([CH3:17])[CH2:13][C:14](Cl)=[O:15]>O.C1COCC1.CCOCC>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:14](=[O:15])[CH2:13][CH:12]([CH3:17])[CH3:11])[CH2:2]1
Reactant: CC(C)CC(=O)Cl
Reactant: OCC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of piperidin-3-ylmethanol (10 g, 86.83 mmol) in water (25 mL), was added a solution of NaOH (13.89 g, 347.31 mmol) in water (25 mL) dropwise at 0° C. The mixture was stirred for 15 minutes, after which time, a solution of 3-methylbutanoyl chloride (20.94 g, 173.66 mmol) in THF (25 mL) was added dropwise with vigorous stirring. The reaction was slowly warmed to room temperature and, upon completion was diluted with Et2O (500 mL) was added with vigouous stirring. After 15 minutes, the phases were separated, and the aqueous phase was extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over Na2SO4, concentrated under reduced pressure and flash chromatographed on silica gel (0-100% EtOAc in hexanes) to give the title compound as a colorless oil (16.27 g, 94%). MS 200 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10](=[O:19])[CH2:11][C:12](=O)[C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10](=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)cc(-c2ccc(Cl)cc2)o1

Procedure:
A solution of ethyl 6-(4-chlorophenyl)-2,4,6-trioxohexanoate (0.30 g) in dioxan (2 ml) and concentrated hydrochloric acid (2 ml) was heated on a steam bath for 2 hours. The pale solid which formed was recrystallised from ethanol to give the title product identical (mp, IR and NMR, and thin-layer chromatography) with the product described in Example 24.
Reaction SMILES: CC(C)([O-])C.[Na+].O1CCCC1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:20][CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:23]1([C:19](=[O:22])[CH:20]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccccc1
Reactant: CCC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)c1ccccc1)c1ccccc1
Yield: 98 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.011 g (0.05 mmol) of palladium (II) acetate, 1.442 g (15 mmol) of sodium-tert-butoxide and 10 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.029 g (0.05 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 30 minutes. 1.570 g (10 mmol) of bromobenzene was added, followed by stirring at 25° C. for 30 minutes. 1.476 g (11 mmol) of propiophenone was added, followed by stirring at 25° C. for 17 hours. After the completion of the reaction, 5 ml of water was added, followed by separation. The organic phase was purified by column chromatography to afford 2.061 g of 1,2-diphenyl-1-propanone (yield: 98 mol % based on bromobenzene). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([OH:36])=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.Cl[CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([O:36][CH2:51][CH2:52][CH2:53][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(OCCCN3CCCCC3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 45 °C
Reaction time: 5 h
Yield: 53.2 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-hydroxyphenyl)urea(254 mg, 0.47 mmol) in DMF (7 ml) are added successively potassium carbonate (193 mg, 1.40 mmol), potassium iodide (39 mg, 0.23 mmol), 1-(3-chloropropyl)piperidine hydrochloride (111 mg, 0.56 mmol) at room temperature, and the mixture is stirred at about 45° C. for 5 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (ethyl acetate:hexane=3:2→3% ethanol/ethyl acetate) to give the title compound (168 mg, 0.25 mmol) as amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>C1COCC1.C(OCC)(=O)C.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]>[OH:19][CH2:18][CH2:17][CH2:16][C:7]1[C:6]2[C:10](=[C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3OC)cccc2c1CCCO

Procedure:
A mixture of EXAMPLE 1B (456 mg) and 2-methoxyphenylboronic acid (182.4 mg) in THF (10 mL), tris(dibenzylideneacetone)dipalladium(0) (46 mg), tri-tert-butylphosphine tetrafluoroborate (15 mg) and CsF (456 mg) was stirred at ambient temperature, diluted with ethyl acetate (200 mL), washed with water and brine, and dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate in hexanes.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1)(=O)C.O>CO.S(=O)(=O)(O)O>[NH2:5][C:6]1[C:7]([F:28])=[CH:8][C:9]2[N:13]=[N:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:10]=2[CH:27]=1
Reactant: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(NC(C)=O)cc32)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(N)cc32)cc1
Temperature: 25 °C

Procedure:
Concentrated hydrochloric acid (6.3 mL) is added to a solution of methyl 2-[p-(6-acetamido-5-fluoro-1H-benzotriazol-1-yl)phenoxy]propionate (4.77 g, 0.013 mol) in methanol. The reaction mixture is refluxed for 18 hours, cooled to room temperature and concentrated in vacuo to obtain a solid. 1HNMR spectral analysis of the solid indicates that ester hydrolysis has occurred. A solution of the solid, sulfuric acid (4 drops) and methanol is refluxed for 6 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a brown powder which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), dimethylcarbamic chloride (3.0 mg, 0.028 mmol), and DIPEA (4.9 μL, 0.028 mmol) in DCM (278 μL) was stirred at room temperature overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method to give the title compound as a TFA salt (5 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.82 (t, J=5.8 Hz, 2H), 2.90 (s, 6H), 2.99 (ddd, J=12.4, 8.6, 3.4 Hz, 2H), 3.34-3.41 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.77 (td, J=14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.42-4.49 (m, 1H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 497.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]([NH2:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]([NH:12][C:42]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:33]([CH2:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]5[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:31][CH:30]=3)[C:34]([CH3:46])=[C:35]4[CH3:45])=[O:43])[CH3:11])[C:4]=2[O:3][CH2:2]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc2c1OCO2
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc4c3OCO4)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(benzo[d][1,3]dioxol-4-yl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 547 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:30](=[O:31])[N:29]([CH3:32])[C:13]2[N:14]([CH3:28])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23][N:24](C)C)=[CH:17][CH:16]=3.O.[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:30](=[O:31])[N:29]([CH3:32])[C:13]2[N:14]([CH3:28])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][C:18]([C:21]1[NH:34][N:24]=[CH:23][CH:22]=1)=[CH:17][CH:16]=3
Reactant: COc1ccc(-c2cc3c4cc(C(=O)C=CN(C)C)ccc4n(C)c3n(C)c2=O)c(Cl)c1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2cc3c4cc(-c5ccn[nH]5)ccc4n(C)c3n(C)c2=O)c(Cl)c1

Procedure:
The process is carried out as indicated in Example 60 above, using compound D 3-(2-chloro-4-methoxyphenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>>[NH:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:26])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH:39]=[N:38]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cn[nH]c2)c1

Procedure:
The same procedure as in example 13.0 was employed for this example, replacing tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 13.B with 1-((4-bromo-2-nitrophenoxy)methyl)benzene 33.B and replacing pyridin-4-ylboronic acid with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 33.C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:18])[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10]2)=[CH:5][C:4]=1[CH3:19].C([O-])(=O)C.[Na+].C[O:26][CH:27]1[CH:31]([CH:32]=O)[CH2:30][CH:29](OC)O1>C(O)C>[CH:27]([C:31]1[CH:30]=[CH:29][N:2]([C:3]2[CH:12]=[C:11]3[C:6]([NH:7][C:8](=[O:18])[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10]3)=[CH:5][C:4]=2[CH3:19])[CH:32]=1)=[O:26]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CCOC(=O)C1Nc2cc(N)c(C)cc2NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(C)cc2NC1=O
Yield: 44.3 %

Procedure:
To a suspension of ethyl 7-amino-6-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate hydrochloride (1.00 g, 3.50 mmol) and sodium acetate (345 mg, 4.20 mmol) in ethanol (35 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (596 μl, 4.20 mmol), and the mixture was refluxed for 3 hours. After cooling, the residue obtained by distilling off solvent was submitted to silica gel column chromatography [ethyl acetate-hexane=3:2] to obtain 508 mg of title compound as yellowish white powder. Yield 44%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[C:14]3[CH:37]=[CH:36][N:35](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[CH:22][C:21]=3[O:33][CH3:34])[N:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[CH:22][C:21]=3[O:33][CH3:34])[NH:16][C:15]3=[N:35][CH:36]=[CH:37][C:14]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCOC[C@@H]2C)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(N2CCOC[C@@H]2C)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 120 °C

Procedure:
2,4-difluoro-6-({2-{[4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (200 mg, 0.301 mmol) was suspended in a mixture of dioxane (10 mL) and aqueous 2.0N NaOH (5 mL) and stirred rapidly under microwave heating (120° C.) for 10 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].O>CN(C=O)C>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC(=S)N(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57.5 %

Procedure:
A solution of 4-bromo-3-methylphenol (8.15 g, 43.6 mmol) in DMF (250 mL) at RT was treated with a suspension of NaH (1.25 g, 52.3 mmol) in 10 mL of DMF. After 15 minutes the solution was cooled to 0° C. and dimethylthiocarbamoyl chloride (8.08 g, 65.4 mmol) was added. The reaction mixture was warmed up to 80° C. and stirred for 45 minutes. After cooling to RT, the mixture was poured into water (1 L). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil. The crude yellow oil material was purified by silica gel chromatography (5-50% EtOAc in hexanes) to afford 6.87 g of O-4-bromo-3-methylphenyl dimethylcarbamothioate as a clear, colorless oil. MS+=276.0 (M+H)