Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[C:25]=1[F:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[C:25]=2[F:33])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)c(F)c1F
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1F

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 1-bromomethyl-2,3-difluoro-4-methoxy-benzene analogous to Example 1 to afford 4-chloro-N-(2,3-difluoro-4-methoxy-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide:
Reaction SMILES: [H-].[Na+].[CH:3](OC)=[O:4].[CH3:7][C@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[CH2:9]1.Cl>O1CCCC1>[CH3:14][C@H:12]1[CH2:13][C@H:8]([CH3:7])[CH2:9][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH2:26][CH:3]=[O:4])=[CH:21][CH:20]=2)[CH2:11]1
Reactant: CC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1
Reactant: COC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(=O)CC=O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (82 mg, 60% in paraffin) are added methyl formate (150 μL) and a solution of trans-3,5-dimethyl-1-[3-(4-acetylphenoxy)propyl]piperidine (610 mg) in tetrahydrofuran (0.4 mL). The mixture is stirred for two hours at room temperature then hydrolysed with a 1N aqueous hydrochloric acid solution keeping the pH alkaline. The solution is extracted twice with ethyl acetate. The extracts are pooled, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 100/0 to 95/5. Fractions containing the expected product are pooled, concentrated under reduced pressure to give 100 mg of trans-3,5-dimethyl-1-{3-[4-(3-oxopropanoyl)phenoxy]propyl}piperidine as a pale yellow oil that is used rapidly, without further purification in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:14]1>>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCN1CCCC(N)C1
Reactant: Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCN1CCCC(NC(=O)c2ccc(N)cc2)C1

Procedure:
4-Aminobenzoyl chloride hydrochloride is reacted with 3-amino-1-ethylpiperidine to afford 4-amino-N-(1-ethyl-3-piperidyl)benzamide which is reacted with 4-chloro-8-trifluoromethylquinoline to afford the title compound, melting point 177°-178° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]=O.Cl>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2/[CH:22]=[C:7]1\[O:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccc(Br)cc23)Oc2cc(O)ccc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.50 g, 3.3 mmol) and 5-bromo-1H-indole-3-carboxaldehyde (0.90 g, 4.0 mmol) in ethanol (10 mL) was added with concentrated hydrochloric acid (1.0 mL), and the mixture was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain (Z)-2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (1.1 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]1)=[O:25]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(NC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.620 g, 3.60 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.732 g, 50.9% yield).
Reaction SMILES: [N:1]([CH:4]1[CH:7](Cl)[N:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])[C:5]1=[O:20])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>C(Cl)Cl>[N:1]([CH:4]1[CH:7]([S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[N:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])[C:5]1=[O:20])=[N+:2]=[N-:3]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1Cl
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1Sc1nnc(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 2-(3-azido-4-chloro-2-oxo-1-azetidinyl)-2-phenylacetate (two trans and two cis isomers) (4.0 g.) was dissolved in dried methylene chloride (50 ml.), and to the solution were added anhydrous potassium carbonate (1.13 g.) and 5-methyl-1,3,4-thiadiazole-2-thiol (2.10 g.). The mixture was stirred at room temperature for 8 hrs, poured into icewater and then extracted with ether. The extract was washed with 1% aqueous potassium carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution under reduced pressure, and the residue (4.05 g.) was subjected to column chromatography on silica gel (160 g.). The elution was conducted with chloroform and the fractions containing the object compound were collected. The solvent was distilled off from the solution under reduced pressure to give methyl 2-[3-azido-4-(5-methyl-1,3,4-thiadiazol-2-ylthio)-2-oxo-1-azetidinyl]-2-phenylacetate (two trans and two cis isomers) (2.81 g.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[C:25]([F:37])=[C:26]([NH:30]C(=O)OCC=C)[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:26]1[C:25]([F:37])=[C:24]([C:9]2[N:10]=[C:11]([C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 2-propen-1-yl (3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.28 g, 2.336 mmol). tri-n-butyltin hydride (0.624 mL, 2.336 mmol) in dichloromethane (DCM) (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.135 g, 0.117 mmol) followed by water (0.2 mL). After 30 min, the reaction was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([Cl:20])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Yield: 103.4 %

Procedure:
3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid (32.0 grams) was stirred in 400 ml of methylene chloride under nitrogen. To this was added N,N-dimethylformamide (12 ml) and thionyl chloride (22.6 grams). The resulting solution was heated at reflux temperature for about 1.5 hours. The solvent was then removed in vacuo leaving about 36 grams of the desired 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxoyl chloride, which was confirmed by IR and NMR spectroscopy.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: Cc1nc(C)c(C=O)s1
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 134; 120 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 36 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. After the volatiles were removed in vacuo, ethyl acetate (10 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution (5 μL) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (3:2 ethyl acetate/hexanes). The appropriate fractions were combined, evaporated and the residue triturated with diethyl ether to yield rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (88 mg, 75% yield) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[Na].[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCO
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Product: CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
2.30 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine (prepared in example 1) in ethanol (5 mL) was added dropwise to 0.16 g of sodium metal in 10 mL of anhydrous ethanol, the reaction mixture stirred at the room temperature for 2 to 6 hours, then treated according to example 1 to obtain 0.68 g of 6-ethoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, at 98.0% purity, as a yellow viscous liquid, yield of 28.2%. GC-MS (M+) (EI, 70 eV, m/z) calc: 342. found: 342. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.100 (t, J=6.9 Hz, 3H, CH3), 1.322 (t, J=6.9 Hz, 3H, CH3), 3.189 (q, J=6.9 Hz, 2H, CH2), 4.295 (q, J=6.9 Hz, 2H, CH2), 4.754 (s, 2H, CH2), 6.108 (d, J=9.0 Hz, 1H, Py H), 7.397 (s, 1H, Thiazole H), 8.084 (d, J=9.0 Hz, 1H, Py H).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH3:35]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:35][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)c1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(C)c3c2C(=O)NC3)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To an oven dry flask was added tert-butyl (1S,2R)-2-(7-bromo-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40 mg, 0.075 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (20.99 μL, 0.151 mmol), and potassium carbonate (31.3 mg, 0.226 mmol) in dioxane (1959 μL) and water (196 μL). The resulting tan solution was degassed with nitrogen for 5 min. Palladium chloride (dppf) (5.52 mg, 7.54 μmol) was added and the mixture was degassed for an additional 2 min. The vessel was capped and the reaction mixture was heated at 100° C. with stirring overnight. The reaction mixture was cooled to RT, diluted with EtOAc (5 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was collected, dried over Na2SO4 and concentrated to give the title compound as a brown viscous oil, which was used without purification (45 mg). [M+H] calc'd for C26H35N5O3, 466. found, 466.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(O)cc1
Yield: 70.2 %

Procedure:
Product from step 1 (1.2 g, 3.13 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.0 g) over period of 16 h at rt under H2 balloon. Reaction Mixture was filtered through Celite and concentrated under reduced pressure. The crude mixture was purified by silica gel flash chromatography (20% EtOAc/Hexane) to obtain the title product (645 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:21][CH3:22])=[C:4]([F:23])[CH:3]=1.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[H-].[Na+]>CN(C)C=O>[C:24]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:21][CH3:22])[C:4]([F:23])=[CH:3][C:2]=1[Cl:1])(=[O:27])[CH:25]=[CH2:26]
Reactant: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(=O)Oc1cc(-n2c(OC)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and acryloyl chloride with sodium hydride in dimethylformamide there is obtained {2-chloro-4-fluoro-5-[5-fluoro-2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-phenyl} acrylate, 1H-NMR (CDCl3, 400 MHz): 7.42 ppm d,1H), 7.21 ppm (d,1H), 6.68 ppm (q,1H), 6.35 ppm (q,1H), 6.12 ppm (q,1H), 4.00 ppm (s,3H);
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15](C)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:29](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=CC=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:29])[N:16]=[CH:15][CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)acetic acid (3L) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol (3K) was used instead of compound 1L. 1H-NMR 300 MHz, (CDCl3) δ 8.89-8.86 (m, 1H), 7.98 (s, 1H), 7.75-7.65 (m, 2H), 7.58-7.50 (m, 2H), 7.30-7.20 (m, 2H), 5.30 (s, 1H), 2.66 (s, 3H), 1.02 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClNO3: 384.9. Found:384.1, 386.1.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:29][CH2:28]1>C(O)C>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9](=[O:16])[NH:8][C:7]4[CH:17]=[CH:18][CH:19]=[N:20][C:6]3=4)=[O:4])[CH2:39][CH2:40]2)[CH2:31][CH2:32]1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCN3CCOCC3)CC2)c2ccccc21

Procedure:
5,11-Dihydro-11-{[4-(2-morpholino-ethyl)-1-piperazinyl]acetyl}-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one was prepared from 8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one, 3.5 gm of sodium carbonate and 6.1 gm of 1-(2-morpholino-ethyl)piperazine in 100 ml of absolute ethanol in analogy to Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Yield: 99.5 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 119, 347 mg, 0.70 mmol), iron (235 mg, 4.22 mmol) and NH4Cl (26.3 mg, 0.49 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 1 h. The mixture was then purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-5% 7M methanolic ammonia in CH2Cl2 gave the title compound (323 mg, 99%) as a tan solid; 1H NMR: 2.12 (6H, s), 3.06 (1H, p), 3.48 (2H, t), 3.68 (3H, s), 3.92-4.02 (4H, m), 6.28 (1H, s), 6.91 (1H, s), 7.04 (1H, dd), 7.12-7.19 (1H, m), 7.44 (1H, d), 8.14 (1H, s), 8.28 (1H, s), 8.30 (1H, d), 8.46 (1H, s), 11.77 (1H, s); m/z: ES+ MH+ 464.21.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[ClH:43].O1CCOCC1>C(OCC)(=O)C>[NH:31]1[CH2:30][CH2:29][CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:42])[F:41])=[O:6])[CH:13]=[CH:12][CH:11]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)[CH:24]=[N:25]2)[CH2:33][CH2:32]1.[ClH:43]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (130 mg, 0.22 mmol) in ethyl acetate (2 mL) was added 4.0 M hydrogen chloride in dioxane (0.22 mL, 0.89 mmol). The suspension was stirred at r.t. 2 h. and then concentrated under reduced pressure to afford the desired compound as HCl salt. LCMS (M+H)+: m/z=484.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH3:28])[C:22]=1[O:29][CH3:30].N1C=CC=CC=1.Cl.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:12])([F:10])[F:11])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[NH:19][C:20]([C:21]1[C:22]([O:29][CH3:30])=[C:23]([N:27]([CH3:28])[C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[CH:24]=[CH:25][CH:26]=1)=[O:31]
Reactant: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1OC
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1c(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1

Procedure:
A solution of N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-2-methoxy-3-(methylamino)benzamide (0.600 g, 1.03 mmole), 4-dimethylaminopyridine (0.006 g) and pyridine (0.334 ml, 0.327 g, 4 mmole) in THF (11.4 ml) was treated with isonicotinoyl chloride hydrochloride (0.386 g, 2 mmole). The resulting white suspension was heated under reflux for 0.5 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was taken up in aqueous saturated sodium bicarbonate solution. The product was extracted with ethyl acetate and the organic phase was washed with brine and dried over sodium sulfate. The crude product was purified by column chromatography over silica gel using ethyl acetate 50%-cyclohexane 50% to yield the title compound corresponding to compound No. G14 of table G.