Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:38]C1C=CC=CC=1B(O)O>>[Cl:38][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]([CH3:36])[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)[N:24]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2Cl)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-chlorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=2[CH:36]=1)=[O:23]>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=4[CH:36]=3)=[O:23])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(C(=O)CBr)ccc2o1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc2cc(C(=O)CN3CCN(c4ccncc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-pyridyl)piperazine (262 mg) and triethylamine (0.1 ml) in acetonitrile (10 ml) was added dropwise over 40 minutes a solution of methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate in acetonitrile (5 ml). The resulting mixture was stirred for 2 hours, concentrated and purified by flash column chromatography on grade III alumina, eluting with methanol/dichloromethane (1:99 to 4:96 v/v) to give the title compound as a solid (138 mg); m.p. 173°-177° C., NMR 2.66(4H,m), 3.8(4H,m), 3.91(3H,s), 4.00(2H,s), 6.82(2H,m), 7.8°-8.5(6H,m); m/e 380 (M+H+); calculated for C21H21N3O4. 0.5H2O: C, 64.9; H, 5.7; N, 10.8. Found: C, 65.2; H, 5.7; N, 10.9%.
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([O:42]CC)=O)[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([NH:7][CH3:6])=[O:42])[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(3,4-dichlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 15).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:13](=[N:1]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc2cccc(/N=C/c3ccccc3)c2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 8-amino-2-naphthol 1 (8.2 g, 52 mmol), benzaldehyde (16 mL, 156 mmol) and sodium sulfate (41.3 g, 291 mmol) in THF (100 mL) was stirred at reflux over night. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane/ethyl acetate/triethyl amine 75/23/2) to give 12.65 g of impure (E)-8-(benzylideneamino)naphthalen-2-ol (2) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2F)[CH3:11])=[O:8])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.C(OCC)(=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[C:13]3[C:12]([CH:10]([CH3:11])[N:9]([C:7]([C:6]4[CH:27]=[CH:28][C:3]([OH:2])=[CH:4][CH:5]=4)=[O:8])[C:24]=2[CH:23]=1)=[CH:17][C:16]([F:18])=[CH:15][CH:14]=3
Reactant: COc1ccc(C(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 70 °C
Yield: 40.2 %

Procedure:
3,8-Difluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—A stirred solution of 4-methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzamide (0.95 g, 2.46 mmol) in tetrahydrofuran was treated under nitrogen with a 1.0 M solution of lithium bis(trimethylsilyl) amide in tetrahydrofuran (5 mL, 5.0 mmol) and heated at 70° C. for fifteen hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo to afford a residue. The residue was dissolved in ethyl acetate and washed sequentially with a 1 N hydrochloric acid solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to afford a crude solid. The crude solid was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 3% and 15% methyl tert-butyl ether in hexane to afford, after crystallization from ethyl acetate-hexane, the title compound (0.36 g, 0.99 mmol, 40%) as a homogeneous, colorless, crystalline solid, m.p. 98-100° C.; MS [(+ESI), m/z]: 366 [M+H]+; IR (Solid), vmax: 2920, 1630, 1600, 1580, 1510, 1495, 1385, 1320, 1250, 870, 840, 810 cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 1.22 (d, J=7.0 Hz, 3H), 3.77 (s, 3H), 5.73 (q, J=6.7 Hz, 1H), 6.59 (dd, J=10.3, 2.3 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.07 (td, J=8.6, 2.7 Hz, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.27 (td, J=8.5, 3.2 Hz, 1H), 7.39 (dd, J=9.2, 2.7 Hz, 1H), 7.98 (dd, J=8.9, 6.3 Hz, 1H), 8.02 (dd, J=8.5, 5.4 Hz, 1H); Anal. calcd for C22H17F2NO2: C, 72.32; H, 4.69; N, 3.83. Found: C, 71.82; H, 4.52; N, 3.76.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]OC2C=CC=CC=2)[CH:2]=1.[ClH:15].[CH3:16][OH:17]>O=[Pt]=O>[ClH:15].[CH3:16][O:17][C:3]1[CH:2]=[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]2)[CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(OCc2cccnc2)cc1
Reactant: CO
Agent: O=[Pt]=O
Agent: Cl
Product: COc1cccc(C2CCCNC2)c1

Procedure:
To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) in methanol (250 ml), PtO2 (2 g) and conc. HCl (30 ml) were added and the mixture was hydrogenated at 0.34 MPa in a Parr apparatus. After complete hydrogenation, the catalyst was filtered off. Most of the solvent was evaporated, the residue was made alkaline with 1 M NaOH and extracted with ether. The ether-phase was dried (Na2SO4) and the solvent evaporated giving 18 g of the amine product. The hydrochloride was made and then recrystallized from ethanol/ether yielding 20.9 g (93%), mp. 137°-138.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=O)C(F)(F)F)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C=O.[C:21](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:21][N:12]([CH3:13])[C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
In 3 mL of methanol, 150 mg (0.55 mmol) of N-(3-amino-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide, 0.076 mL (0.9 mmol) of a 37% formaldehyde aqueous solution and 0.05 mL of acetic acid were dissolved, and 47 mg (0.74 mmol) of sodium cyanoborohydride was added thereto, and the mixture solution was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution and concentrated, and the residue was dissolved in 6 mL of tetrahydrofuran. To this solution, 10 mL of a saturated sodium bicarbonate solution was added and the mixture solution was heated at 50° C. for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was dried on anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain 100 mg (89%) of a brownish oily target product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[O:36]1[C:40]2[CH:41]=[CH:42]C(CN)=[CH:44][C:39]=2[O:38][CH2:37]1>>[O:36]1[C:40]2[CH:41]=[CH:42][C:2]([CH2:1][NH:3][C:4]([CH:6]3[CH2:10][CH:9]([N:11]4[C:15]5[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]6[CH2:23][CH:22]6[C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:14]=5[N:13]=[N:12]4)[CH:8]([OH:34])[CH:7]3[OH:35])=[O:5])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4ccc5c(c4)OCO5)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39 step a) using the product of example 1, step c) and 2H-1,3-benzodioxol-5-ylmethylamine.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[OH:14]N1C2C=CC=CC=2N=N1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:14]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=2)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-trifluoromethylpyridin-3-ylamine (1.0 g, 6.17 mmol) and 4-amino-3-nitrobenzoic acid (1.12 g, 6.17 mmol) in DMF (25 mL) was added HATU (3.5 g, 9.23 mmol) followed by NEt3 (1.77 ml, 9.23 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a heptane/EtOAc (1:1 then followed by 100% EtOAc) to give 4-amino-3-nitro-N-(6-trifluoromethylpyridin-3-yl)-benzamide as a red solid.
Reaction SMILES: [Br:1]Br.N[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.N([O-])=O.[Na+]>Br.O>[Br:1][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1
Reactant: BrBr
Reactant: Cc1cc(N)cc(C)n1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(C)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Bromine (4 g) is added, with stirring over 10 minutes, to a mixture of 4-amino-2,6-lutidine (22, 1 g, approximately 6.5 mmol) in 48% HBr (12 ml) at −10° C., followed by cooling to −20° C. A solution of sodium nitrite (1.4 g) in water (4 ml) is added slowly. The mixture is stirred at −20° C. for 1 hour, and then warmed and left at room temperature for 3 hours. The mixture is distilled. The oil fraction of the distillate is extracted with chloroform (3×10 ml). The combined extracts are dried over magnesium sulfate. After filtration, the filtrate is neutralized in an ice-bath using 2M butyl lithium in hexanes until the pH reaches 7. A large amount of salt forms. After filtration, the filtrate is concentrated and dried, yielding 4-bromo-2,6-lutidine (23) oil. 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 6H), 7.5 (s, 2H). MS, m/z 186 and 188 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3OC)cccc2c1O
Product: COc1ccccc1Oc1cccc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c12

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.5.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[CH2:16]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL of methanol under inert atmosphere, 35.2 g (0.592 moles) of glacial acetic acid and 50 mL of methanol was added followed by a solution of 62.83 g (0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture was cooled to approximately 15° C. and a solution of 134.6 g (2.14 moles) of sodium cyanoborohydride in 700 mL of methanol was added in approximately 40 minutes, keeping the temperature between 15° C. and 25° C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and partitioned between 1 L of 2M ammonium hydroxide solution and 2 L of ether. The ether layer was washed with 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500 mL of brine and dried over magnesium sulfate for 1 hour. The ether layer was filtered, concentrated under reduced pressure and the crude solid product was recrystallized from 110 mL of ethyl acetate and 1.3 L of hexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a solution of methyl 2-tert-butylquinoline-6-carboxylate (347 mg, 1.43 mmol) in MeOH (4 ml) and THF (4 ml) was added 2M aqueous sodium hydroxide (2 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours. Then evaporated, diluted with water (5 ml), neutralized to pH 5˜6 by 2M aqueous hydrochloride. The formed precipitate was collected, washed with water to furnish the title compound (282 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.49 (9H, s),7.62 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.31-8.34 (1H, m),8.64-8.66 (1H, m) MS (ESI): m/z 230 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:16]=[CH:15]3)=[O:10])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[N:16]=[CH:15]4)=[O:10])=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(NC(=O)Nc2ccc3c(cnn3CCN3CCCC3)c2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Yield: 45.4 %

Procedure:
A mixture of 1-(4-amino-phenyl)-3-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-urea (364 mg, 1 mmol), phenylboronic acid (244 mg, 2 mmol), copper(II) acetate (364 mg, 2 mmol), triethylamine (0.2 mL, 2 mmol), in 20 mL of dichloromethane was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (acetonitrile/ethyl acetate/triethylamine, 10/4/1) to provide the title compound as a pale white solid (200 mg, 45%). 1H NMR (300 MHz, DMSO-d6) ppm 1.63 (m, 4H), 2.45 (m, 4H), 2.86 (d, J=6.44, 2H), 4.46 (d, J=6.44, 2H), 6.74 (m, 1H), 6.98 (m, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.33–7.36 (m, 3H), 7.58 (m, 1H), 7.88 (m, 1H), 7.90 (s, 1H), 7.95 (s, 1H), 8.44 (s, 1H), 8.55 (s, 1H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]([NH:33][C@H:34]([CH2:40][S:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][C:51]6[N:52]=[N:53][N:54]([CH:56]([CH2:59][OH:60])[CH2:57][F:58])[CH:55]=6)[CH:44]=5)[C:35]([O:37]CC)=[O:36])=[O:32])[CH:29]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=CC=1.Cl.[Li+].[OH-]>CO.O>[F:58][CH2:57][CH:56]([N:54]1[CH:55]=[C:51]([CH2:50][O:49][C:45]2[CH:44]=[C:43]([CH:48]=[CH:47][CH:46]=2)[CH2:42][S:41][CH2:40][C@@H:34]([NH:33][C:31](=[O:32])[CH2:30][N:28]2[CH:29]=[C:25]([CH2:24][O:23][C:21]3[CH:20]=[CH:19][C:17]4[N:18]=[C:14]([S:11](=[O:12])(=[O:13])[NH2:10])[S:15][C:16]=4[CH:22]=3)[N:26]=[N:27]2)[C:35]([OH:37])=[O:36])[N:52]=[N:53]1)[CH2:59][OH:60]
Reactant: CCOC(=O)[C@@H](CSCc1cccc(OCc2cn(C(CO)CF)nn2)c1)NC(=O)Cn1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N[C@H](CSCc4cccc(OCc5cn(C(CO)CF)nn5)c4)C(=O)O)nn3)cc2s1
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask containing 136 (51 mg, 0.0486 mmol) in MeOH (2 mL) at RT, was added 1M HCl (1 mL) and stirred for 2 h. After the reaction is done, MeOH was removed and the residue was dissolved in THF:H2O (1:1, 0.5 mL). To this LiOH (3 mg, 0.0309 mmol) was added and reaction was stirred at RT for 2 h, sample dilute with water (5 mL) and purified by HPLC using CH3CN:H2O (1:2) as an eluent to afford BD-2-120 (5.9 mg, 27%) as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:41][CH3:42]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:41][CH3:42]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(F)c(OC)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncccc2-c2nc(C)nc(N)n2)ccc1F
Temperature: 25 °C
Yield: 3.6 %

Procedure:
A solution of 4-(2-(4-fluoro-3-methoxyphenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.1196 g, 0.211 mmol) in TFA (8.0 mL) was heated at 80° C. overnight. The solution was cooled to room temperature and the TFA was removed in vacuo. The crude product was treated with a saturated solution of NaHCO3, the aqueous layer was extracted with DCM (3×15 mL), the layers were separated, the combined organic layers were dried and concentrated. The crude brown oil was dissolved in 2.5 mL of DMSO and purified by reversed phase chromatography (Gilson, 10-90% CH3CN in water with NH4OH additive: 0.1% v/v in each solvent). The fractions were concentrated in a Genevac Series II System to give 4-(2-(4-fluoro-3-methoxyphenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0025 g, 7.66 μmol, 3.63% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.94 (s, 1H); 8.77 (dd, J=7.7, 1.9 Hz, 1H); 8.35 (dd, J=4.8, 1.9 Hz, 1H); 7.70-7.77 (m, 1H); 7.34 (s, 1H); 7.14 (dd, J=11.4, 8.9 Hz, 1H); 6.91 (dd, J=7.7, 4.8 Hz, 1H); 3.87 (s, 3H); 2.64-2.70 (m, 1H); 2.44 (s, 3H). m/z (ESI, +ve ion) 327.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C1COCC1>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[C:2]([NH:1][S:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=3)(=[O:26])=[O:25])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccnc1Nc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of EXAMPLE 2 in pyridine (9 mL/g) at 0° C. was treated with a mixture of para-methoxybenzenesulfonyl chloride (1.05 equivalents) in THF (1.4 mL/g) at 0° C. at a rate which kept the reaction temperature below 5° C., warmed to 25° C., stirred for 15 minutes, and concentrated. The concentrate was treated with n-propanol to provide a composition having 9% pyridine in the solvent mixture and to precipitate a solid. The mixture was cooled to 0° C. and filtered. The filtrant and washed with ethyl acetate (5-7 mL/g starting material) and dried at 45° C.