Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].NC1C=CC(N2C(=O)C(C)(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C2=O)=CC=1C>>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:4]2[C:3](=[O:42])[C:2]([CH3:1])([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:26])([F:27])[C:22]([F:25])([F:23])[F:24])=[O:17])[C:5]2=[O:28])=[CH:30][C:31]=1[CH3:38]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Agent: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Yield: 56 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 25 replacing the compound of Example 1. A colourless oil is obtained with a yield of 56%.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][OH:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH:20]=[O:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-(1-methoxycycloheptyl)-5-(trifluoromethyl)phenyl)methanol (167 mg; 0.552 mmol) in methylene chloride (3.0 mL) was added Dess-Martin reagent (290 mg; 0.683 mmol). Reaction was stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate and quenched with aqueous 1N sodium hydroxide. After partitioning off the aqueous layer, the organic layer was washed with water and brine. It was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a Bakerbond 1 g silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, N.J.) (eluted with 0-5% heptane) to yield 167 mg of a cloudy oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.91 (s, 1H), 811 (d, J=2.07 Hz, 1H), 7.73 (dd, J=8.71, 8.30 Hz, 1H), 7.48 (d, J=7.88 Hz, 1H), 2.96 (s, 3H), 2.25 (m, 2H), 2.09 (m, 2H), 1.94-1.57 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:9])=[CH:4][C:3]=1[F:21].NN>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][C:3]=1[F:21]
Reactant: CC(c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-[1-(4-Chloro-3-fluoro-phenyl)-ethyl]-isoindole-1,3-dione (4.08 g, 13.4 mmol) was dissolved in THF (100 mL). Hydrazine (4 mL) was added. The reaction was stirred at 80° C. for 1 h. Then, the solvent was evaporated and the crude was chromatograph over silica gel using ethyl acetate as solvent to yield 2.0 g of 1-(4-chloro-3-fluoro-phenyl)-ehtylamine. 1H NMR (400 Hz, Cl3CD) δ 7.34 (t, J=7.97 Hz, 1H), 7.18 (dd, J=1.90, 10.25 Hz, 1H), 7.08 (dd, J=1.90, 7.97 Hz, 1H), 4.12 (m, 1H), 1.36 (d, J=6.64, 3H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)ON(Cc2ccccc2F)C1=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
The procedure of Example III was utilized with 10.2 ml (0.128 mole) pyridine, 10.2 grams (0.060 mole) dimethylmalonyl chloride and 120 ml methylene chloride in solution under argon at -72° C., to which 8.5 grams (0.060 mole) of N-(2-fluorophenylmethyl)hydroxylamine (Intermediate F) in 25 ml methylene chloride was added in a single portion, raising the temperature immediately to -25° C., and stirring was continued at 0° C. for two hours. Gas chromatography on a sample of the reaction mixture showed only one major peak. The reaction mixture was washed with 2 N hydrochloric acid and water, the methylene chloride layer was separated and dried over sodium sulfate, and after removal of sodium sulfate by filtration, the solvent was removed under reduced pressure, leaving 13.0 grams of a yellow viscous liquid (91% yield). The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21]([C:27]3[C:32]4[CH2:33][C:34]([CH3:37])([CH3:36])[O:35][C:31]=4[C:30]([O:38][CH3:39])=[CH:29][CH:28]=3)=[N:20]2)[CH2:15][CH2:14]1)=[O:12])(=O)C.[OH-].[K+].Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[C:21]([C:27]3[C:32]4[CH2:33][C:34]([CH3:36])([CH3:37])[O:35][C:31]=4[C:30]([O:38][CH3:39])=[CH:29][CH:28]=3)=[N:20]2)[CH2:17][CH2:18]1)=[O:12]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(C)=O)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.15 g 2-({4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}carbonyl)phenyl acetate (compound described in example 77) are dissolved in 20 ml of methanol, 0.32 ml 1 M methanolic potassium hydroxide solution are added, and the reaction mixture is stirred at RT for 15 min until the reaction is completed according to TLC analysis. The pH is adjusted to 5.5 with 1 M aqueous hydrochloric acid, the solvents are removed under reduced pressure, and the resulting crude product is purified by column chromatography (silica and DCM/methanol=95:5) to yield the title compound.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([C:17](=[O:38])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH2:36][CH3:37])[CH2:22][CH2:21]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].C(N(CC)CC)C>O1CCCC1>[ClH:5].[CH2:36]([O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=2)=[O:38])[CH2:21][CH2:22]1)[CH3:37]
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NS(C)(=O)=O)c2)CC1
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (0.108 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (291 mg). The free base compound (290 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless amorphous powders.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8](O)[CH2:7]2)[N:3]=[CH:2]1.[H][H]>C(O)C.Cl.[Pd]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH:6]2[C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[C:10]([CH3:18])[C:11]=1[CH3:17]
Reactant: COc1cc2c(c(C)c1C)C(O)CC2c1c[nH]cn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(c(C)c1C)CCC2c1c[nH]cn1

Procedure:
3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (0.29 g) is dissolved in the mixture of ethanol (30 ml) and concentrated hydrochloric acid (0.2 ml). The solution is hydrogenated at 50-55° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. The mixture is filtered and the filtrate is evaporated to dryness. The residue is crystallized from the mixture of ethyl acetate and ethanol. M.p. of the hydrochloride salt is 174-177° C.
Reaction SMILES: [BH4-].[Na+].CS(O)(=O)=O.[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].OC(CC1C=C(F)C(F)=CC=1F)CC(N1CCN2C(C(F)(F)F)=NN=C2C1)=O>CC(O)C.C1COCC1>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: O=C(CC(O)Cc1cc(F)c(F)cc1F)N1CCn2c(nnc2C(F)(F)F)C1
Agent: [BH4-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 5 h

Procedure:
In a 250 mL round bottom flask THF (225 mL) was taken. It was cooled to less than −5° C. and NaBH4 (5.62 g) was added. After that methanesulfonic acid (17.8 g) was added dropwise at less than −5° C. over a period of 30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (20.0 g) is mixed in a solvent mixture of THF (50 mL) and IPA (22 mL) and added into the reaction mixture, keeping the temperature below 0° C. It was stirred for 4-6 h below 5° C. After usual work-up procedure, product was extracted in a suitable solvent. Extract was washed and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-20.8 g, % Purity by HPLC-80.7% and % of 3-hydroxy-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one by HPLC-15.5%).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([O:27][CH2:28]C)[N:21]=1>C(#N)C>[Cl:26][C:24]1[CH:23]=[C:22]([O:27][CH3:28])[N:21]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:15])=[O:14])=[O:18])[N:25]=1
Reactant: CCOc1cc(Cl)nc(N)n1
Reactant: CCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: CCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-propylsulfonylbenzenesulfonyl isocyanate (1.74 g, 6.00 mmol) in dry acetonitrile (25 ml) was added 2-amino-4-chloro-6-ethoxypyrimidine (1.00 g, 6.00 mmol). After stirring at room temperature overnight, the reaction mixture was filtered to yield the product as a white powder melting at 193°-195° C.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][CH2:14][CH2:13][C:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OC1(CCO)CC1)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of 1-(2-hydroxyethyl)cyclopropyl benzoate (320 mg, 1.55 mmol) and TEA (235 mg, 2.33 mmol, Shantou Xilong chemical factory) in 20 mL of dry CH2Cl2, was added MsCl (213 mg, 1.86 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at rt. After stirring for 2 hrs at rt, the mixture was diluted with icewater and extracted with CH2Cl2 (30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (400 mg, 90%).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(O)(=O)C>[C:1]1([C:7]2[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:10]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(=O)O
Reactant: CCCC1CCC(C(=O)CCC(=O)c2ccccc2)CC1
Solvent: CC(=O)O
Product: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)O)CC1
Yield: 55.9 %

Procedure:
A solution of 1.43 g (5 mmol) 1-phenyl-4-(4-propyl-cyclohexyl)-butane-1,4-dione and 0.75 g (10 mmol) glycine 16 mL of acetic acid was heated to reflux for 100 min. The solution was concentrated and redissolved in 5% aqueous H2SO4. The solution was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated to afford 0.91 g [2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetic acid as a tan solid which was carried on to the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])=[CH:25][CH:26]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-biphenyl-4-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H25NO5 [M+H]+: 420.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (1.0 g, 2.55 mmol) is coupled to bromobenzene (0.32 mL, 3.0 mmol) using Method A to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)=[O:15])=[C:9]([C:25]3[CH:30]=[C:29]([C:31](=[O:44])[NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)[CH:28]=[CH:27][N:26]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH3:57][NH:58][CH2:59][CH2:60][N:61]1[CH2:66][CH2:65][N:64]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:63][CH2:62]1>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:57][N:58]([CH2:59][CH2:60][N:61]1[CH2:66][CH2:65][N:64]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:63][CH2:62]1)[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:25]2[CH:30]=[C:29]([C:31](=[O:44])[NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=3)[CH:28]=[CH:27][N:26]=2)[CH:17]=1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)-benzoic acid (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (48 mg, 0.25 mmol, 1.50 equiv), 4-dimethylaminopyridine (31 mg, 0.25 mmol, 1.50 equiv). The mixture was stirred for 5 min at room temperature. To the above was added tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (53 mg, 0.22 mmol, 1.30 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 5 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (25% CH3CN up to 45% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 33.6 mg product was obtained. This resulted in 33.6 mg (21%) of PH-RDX-002-1129-0 as a light yellow solid. MS (ES, m/z): 828 [M−+H]+. H-NMR (300 MHz, CD3OD, ppm) 8.98 (d, J=5.1 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.18˜8.11 (m, 3H), 7.89˜7.53 (m, 8H), 4.72 (s, 2H), 4.00˜3.11 (m, 16H), 3.08 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=5.7 Hz, 2H), 1.49 (s, 9H)
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].[N:28]1([CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]
Reactant: OCCOCCN1CCNCC1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCOCCN4CCNCC4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of sodium (50 mg, 2.2 mmol) in 1 mL of 2-[2-(1-piperazinyl)ethoxy]ethanol is heated at 120° C. for 2 hours. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.38 mmol) is added and the reaction mixture is heated at 140-145° C. for 2 hours, then cooled to room temperature. The reaction mixture is partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 3% methanol in dichloromethane to 1% ammonium hydroxide and 30% methanol in dichloromethane followed by recrystallization from acetone and hexane to provide 124 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{2-[2-(1-piperazinyl)-ethoxy]ethoxy)-3-quinolinecarbonitrile, mp 88-90° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[C:8]([F:14])([CH3:13])[C:6]=2[N:7]=1.[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])[C:5]4[CH2:10][S:9](=[O:12])(=[O:11])[C:8]([F:14])([CH3:13])[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:24][CH2:23]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)C2(C)F
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CS(=O)(=O)C2(C)F

Procedure:
The title compound was synthesised following the procedure in Example 5 (step viii) using 2-chloro-7-fluoro-7-methyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.Cl.[NH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:3]([CH2:2][N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CN2CCC(=O)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Yield: 50.7 %

Procedure:
Methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 3.98 mmol), 4-piperidone HCl salt (0.648 g, 4.78 mmol), N,N-diisopropylethylamine (1.53 mL, 8.76 mmol) in acetonitrile (13.27 mL) was heated to 50° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with Na2CO3 and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate/hexanes) to afford methyl 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.051 g, 51% yield). MS (m/z) 521.0 (M+H+).
Reaction SMILES: [C:1]([CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)#[N:2].Cl.[F:22][C:23]([F:28])([F:27])[CH2:24][NH:25][NH2:26].C(N(CC)CC)C>C(O)C>[CH2:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4]1[CH:3]=[C:1]([NH2:2])[N:25]([CH2:24][C:23]([F:28])([F:27])[F:22])[N:26]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc([C@H]2CCCN2C(=O)OCc2ccccc2)nn1CC(F)(F)F

Procedure:
To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10 mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11 mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated and the residue was separated by flash chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI): m/z 369 (M+H)+.