Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[CH:21][NH:22]2)=[CH:18][CH:17]=1)[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[CH:21][NH:22]2)=[CH:18][CH:17]=1)[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1c[nH]c2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc2cc[nH]c2c1)c1c[nH]c2ccccc12
Reaction time: 24 h

Procedure:
To a solution of 3-(1H-indol-6-yl)-3-(1H-indol-3-yl)-acrylic acid ethyl ester XXVI in ethanol (15 ml) was added catalytic quantity of Pd(OH)2/C (20%). The reaction mixture was hydrogenated in a Parr apparatus under 55 psi of H2 for 24 hours. The catalyst was removed by filtration through a pad of celite with MeOH. The filtrate was concentrated to afford 3-(1H-indol-6-yl)-3-(1H-indol-3-yl)-propionic acid ethyl ester XXVII (241 mg) as a light brown solid, which was used in the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2]
Reactant: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1csc(C2CCNCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.87 g, 6.40 mmol) in anhydrous dichloromethane (16 ml) was added at 0° C. trifluoroacetic acid (16 ml). After stirring at 0° C. for 30 mins, the mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was concentrated to dryness. The residue was washed with dichloromethane (extracted from solid phase) and the washing solution was concentrated to give 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine (1.176 g, yield 98%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[C:5]([N+:11]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1>C(O)C>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11]
Reactant: Cc1cccc(OC(F)F)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cccc(OC(F)F)c1N
Yield: 95 %

Procedure:
The procedures of Example 2 were repeated except that the starting material was 16.0 g (79 mmol) of 3-difluoromethoxy-2-nitrotoluene as dissolved in 100 ml of ethanol. As a result, 13.0 g of 2-difluoromethoxy-6-methyl aniline was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42])=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](=[O:43])(=[O:42])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:30][CH:31]=1)=[O:35]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccsc4C(=O)OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester. Purity (ELSD, based on MW=625.7)=92%.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([N+:12]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:12][C:8]1[CH:7]=[CH:6][C:5]([O:15][CH3:16])=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[CH2:10][CH3:11]
Reactant: CCc1c([N+](=O)[O-])ccc(OC)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(N)ccc(OC)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A solution of 2,4-dinitro-3-ethylanisole (23.7 mmol) in methanol (200 mL) is treated with stannous chloride (83.0 mmol). A reflux condenser is attached and the mixture is heated with an oil bath to 45° C. for two hours. The mixture is cooled to room temperature and poured over a saturated sodium carbonate solution (300 mL). The mixture is extracted with methylene chloride (400 mL). The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to yield the crude product. This material is purified by chromatography (silica gel, 30% ethyl acetate/hexanes) to afford 4-amino-3-ethyl-2-nitroanisole.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].[OH-].[Na+]>CO.ClCCl.[Pd]>[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=1[NH:1][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-nitroresorcinol (1.0 g, 6.45 mmol) and 10% Pd—C (100 mg) in methanol (15 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. A mixture of the residue, triethylamine (1.8 mL, 12.9 mmol) and acetyl chloride (1.38 mL, 19.35 mmol) in dichloromethane (15 mL) was stirred at ambient temperature for 1 hour, poured into 1N NaOH (20 mL) and methanol (20 mL). After 10 minutes, the mixture was concentrated under reduced pressure and taken up in ethyl acetate and 1N HCl (50 mL, 1:1). The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated to provide titled compound. MS (ESI (−)) m/e 166(M−H)+; 1H NMR (300 MHz, DMSO-d6) 9.31(s, 2H), 6.86 (t, 1H), 6.34 (d, 2H), 2.11(s, 3H).
Reaction SMILES: ON[C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[O:4].C(C1C=C2C(=CC=1)N(S(C)(=O)=[O:47])C=C2C1CCN(S(Cl)(=O)=O)CC1)#N.S(Cl)(Cl)(=O)=O.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.N1CCCC[C@@H]1C(O)=O>>[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=[C:20]2[CH:17]1[CH2:16][CH2:15][N:14]([S:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]2[C:3]([OH:47])=[O:4])(=[O:12])=[O:13])[CH2:19][CH2:18]1)#[N:30]
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)Cl)CC2)c2cc(C#N)ccc21
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)NO)CC2)c2cc(C#N)ccc21
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C(O)[C@H]1CCCCN1
Solvent: O=S(=O)(Cl)Cl
Product: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)O)CC2)c2cc(C#N)ccc21
Yield: 86 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]#[C:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([CH2:20][CH2:21][P:22]([O:25][CH2:26][CH3:27])([CH3:24])=[O:23])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:32][C:30]([CH3:31])([CH3:33])[C:29]#[C:28][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH2:20][CH2:21][P:22]([O:25][CH2:26][CH3:27])([CH3:24])=[O:23])[C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[CH:8]=1
Reactant: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)O
Yield: 68.4 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (251 mg, 0.51 mmol) was dissolved in THF (7.3 mL) and MeOH (7.3 mL). A 1N solution of LiOH in H2O (1.52 mL, 1.52 mmol) was added to the reaction drop-wise at room temperature. The reaction was run at room temperature until complete, as determined by LC/MS. The reaction was cooled in an ice bath and then acidified to pH 3 with 1N HCl. The entire mixture was then evaporated in vacuo and stored under high vacuum overnight. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (168 mg, 69%) was isolated from the residue by reverse phase HPLC. MS (m/z): 481.93 [M+H]+; 31P NMR (161.9 MHz, CDCl3): d 56.771, 55.816.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]([CH2:26][CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:26]([N:9]1[C:8]2[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:27]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 94.8 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (770.0 mg) was prepared by following General Procedure E starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (840.0 mg) and sodium hydroxide (2.0 N solution, 2.0 mL) MeOH (1.0 mL) and THF (2.0 mL).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20][Cl:21])[C:12]=2[N+:22]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C.[Pd]>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20][Cl:21])[C:12]=2[NH2:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Temperature: 60 °C

Procedure:
A mixture of 1-benzenesulfonylmethyl-3-(2-chloro-ethoxy)-5-fluoro-2-nitrobenzene (1.98 g, 5.3 mmoles) in ethanol (25 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.67 g, 4.87 mmoles).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccccc1
Yield: 62.5 %

Procedure:
Using the procedure of Step A of Example 6, 40.28 g of o-trifluoromethyl aniline and 35.14 g of benzoyl chloride were reacted in the presence of 25.3 g of triethylamine in 400 ml of acetone to obtain 41.45 g of N-(2-trifluoromethylphenyl)-benzamide melting at 146° C which was used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[C@@H:19]1([C:25](O)=[O:26])[CH2:21][C@H:20]1[C:22]([OH:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=1)=[O:18]
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)O
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(NC(=O)[C@@H]2C[C@H]2C(=O)O)c1)c1c(Cl)cccc1Cl
Temperature: 70 °C
Yield: 67 %

Procedure:
To a solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (141 mg, 0.50 mmol), trans-cyclopropane-1,2-dicarboxylic acid (325 mg, 2.5 mmol), and disiopropylethylamine (339 mg, 2.63 mmol) in dry DMF (5 mL) was added HATU (1951 mg, 2.5 mmol). The reaction mixture was heated at 70° C. for 6 hours and then quenched with sat. NH4Cl (100 mL). The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by prep HPLC (10-50% CH3CN/H2O with 0.1% formic acid) to give trans-2-(4-(2,6-dichlorobenzamido)pyridin-2-ylcarbamoyl)cyclopropanecarboxylic acid (132 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.86 (s, 1H), 8.38 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.54-7.45 (m, 2H), 1.90-1.82 (m, 1H), 1.25 (dt, J=8.0, 5.4 Hz, 3H). LCMS (ESI) m/z: 394.0 [M+H+].
Reaction SMILES: C(#N)C.Cl.[CH3:5][N:6](/[C:8](=[CH:12]\[CH3:13])/C(O)=O)[CH3:7].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C=O)C>[CH3:7][N:6]([CH2:8]/[CH:12]=[CH:13]/[C:15]([Cl:17])=[O:16])[CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C/C=C(/C(=O)O)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: NC1C=CC(CC(O)=O)=CC=1.C1C(=O)N(Br)C(=O)C1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][C:22]=1[Br:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57].CCN(CC)CC>CC#N.CC(O)=O.C(Cl)Cl>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])=[O:30])=[CH:23][C:22]=1[Br:31]
Reactant: Nc1ccc(CC(=O)O)cc1Br
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccc(CC(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)CCNC(=O)Cc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of (4-amino-phenyl)-acetic acid (320 mg, 2.10 mmol) in CH3CN (4 mL) and AcOH (2 mL) at 0° C. was added NBS (373 mg, 2.10 mmol) in CH3CN (3 mL). The reaction was allowed to warm to room temperature over 1 h and then concentrated in vacuo to give a mixture of (4-amino-3-bromo-phenyl)-acetic acid and starting material which was used without further purification. The crude (4-amino-3-bromo-phenyl)-acetic acid (490 mg, 2.12 mmol), EDCI (487 mg, 2.54 mmol), HOBt (343 mg, 2.54 mmol), and N′,N′-dimethyl-ethane-1,2-diamine (281 mg, 3.19 mmol) were slurried in DCM (10 mL), treated with NEt3 (910 μL, 6.36 mmol) and stirred overnight. The reaction was diluted with DCM (50 mL), washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative TLC (10% MeOH—CHCl3) to afford 70 mg (11%) of the title compound. 1H-NMR (CDCl3; 400 MHz) δ 7.25 (s, 1H, J=2.0 Hz), 6.93 (dd, 1H, J=8.1, 2.0 Hz), 6.65 (d, 1H, J=8.1 Hz), 6.04 (br s, 1H), 4.03 (br s, 2H), 3.32 (s, 2H), 3.24-3.19 (m, 2H), 2.30-2.27 (m, 2H), 2.11 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[CH2:27][O:26]2)[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[CH2:27][C@@H:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=1)[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(CCNCc2ccccc2)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of N-benzyl-2-(4-bromophenyl)ethanamine (13.5 g) in ethanol (270 ml) was added (2R)-2-(3-chlorophenyl)oxirane (8.63 g) and the solution was refluxed for 48 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent:hexane/ethyl acetate=9/1) to give (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.6 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([C:41]([O:43]C)=[O:42])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[Cl:23])=[CH:7][CH:6]=1.[OH-].[Na+]>CCOCC.CCOC(C)=O>[NH2:1][CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=[O:42])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[Cl:23])=[CH:9][CH:10]=1
Reactant: COCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of methyl 4-(2-amino-1-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-benzyl}ethyl)-2′-(3-methoxypropyl)biphenyl-2-carboxylate (1.0 eq.; EXAMPLE 22) in THF/MeOH (1/1; 0.09M) was added aqueous sodium hydroxide (1N; 3 eq.). The mixture was stirred in a microwave (Smith Creator; Personal Chemistry),) at 120° C. for 80 min. The resulting mixture was cooled to room temperature quenched with excess acetic acid and concentrated. The residue was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3; 2M) 5% afforded the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.50 (br s, 0.5H), 7.44 (br s, 0.5H), 7.25-7.11 (m, 6H), 7.11-7.03 (m, 4H), 6.87-6.81 (m, 2H), 4.36-4.27 (m, 4H), 3.30-3.21 (m, 8H), 3.01-2.91 (m, 2H), 2.65-2.53 (m, 2H), 2.30 (s, 3H), 1.77-1.64 (m, 2H) (mixture of rotamers). LRMS ESI [M+H]; 622.2
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+].O.CO>C1COCC1>[N+:19]([C:17]1[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:18]=1)[C:3]([OH:22])=[O:2])([O-:21])=[O:20]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
Dissolve 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (1.000 g, 3.243 mmol) and lithium hydroxide (0.089 g, 3.730 mmol) in a mixture of THF (3.16 mL), water (1.58 mL) and methanol (1.58 mL). Stir the mixture at room temperature until the starting material is consumed. Concentrate and acidify with 1 N HCl. Extract with ethyl acetate, dry (magnesium sulfate) and concentrate to give the title compound (0.874 g, 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11][CH:10]=2)[O:3]1.B.CO>C1COCC1>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)c3ccccc23)OC1(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OB(c2ccc(CO)c3ccccc23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoic acid (2.5 g, 8.39 mmol) was dissolved in anhydrous THF. The solution was cooled down in an ice-water bath. Borane solution (1.00M in THF, 25 ml, 25 mmol) was added dropwise. After addition, the reaction was stirred at room temperature for 4 hours. Methanol (20 ml) was added with ice-water batch to quench the reaction until no gas was produced. The solvent was evaporated, and the residue was extracted with ethyl acetate/water to give the product as a white solid (1.79 g, 75%). 1H NMR (300 MHz, CD2Cl2, δ): 8.80 (m, 1H), 8.10 (m, 1H), 8.04 (m, 1H), 7.57 (m, 3H), 5.18 (s, 2H), 1.43 (s, 12H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C.O>C1COCC1.C(OCC)(=O)C>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: CN(C)c1cccc(N)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1cccc(N(C)C)c1
Yield: 70 %

Procedure:
To a solution of N,N-dimethyl-m-phenylenediamine (120 mmol) in THF (500 mL) was added methyl bromoacetate (132 mmol) and DIPEA (264 mmol). The reaction mixture was refluxed for 16 h. Water (200 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (4×100 mL) and brine (100 mL) and dried over Na2SO4. The solvents were removed in vacuo and the residue was purified by flash-chromatography (ethyl acetate/heptane 1:4) to give 17.5 g (84.0 mmol, 70%) of an oily product which crystallized slowly.