Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:29])[O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:21]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)=[O:22])[CH:20]=1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:44]1([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:18]=[C:19]([CH:20]=[C:5]([O:4][C@@H:3]([CH3:29])[CH2:2][OH:1])[CH:6]=3)[C:21]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)=[O:22])=[CH:17][CH:16]=2)=[O:15])[CH2:43][CH2:42][CH2:39]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]phenoxy}benzoic acid (130 mg, 0.327 mmol), HATU (156 mg, 0.41 mmol), azetidine hydrochloride (38 mg, 0.41 mmol) and DIPEA (0.143 mL; 0.82 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 hours. Water was added to the reaction mixture and it was extracted into ethyl acetate (3×30 mL). The organic phases were combined, washed with brine solution and dried (MgSO4). The filtrate was concentrated in vacuo and the residue chromatographed, eluting with 0-50% methanol in DCM, to give a clear oil which gave a foam under high vacuum (65 mg, 46%).
Reaction SMILES: [NH2:1][C:2]([N:9]([CH3:11])[CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH3:10])[CH3:11])[C:3]=1[C:7]#[N:8]
Reactant: CN(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CN(C)c1nsc(N)c1C#N
Reaction time: 0.25 h

Procedure:
A slurry of 5.1 g of 3-amino-2-cyano-3-(dimethylamino)propenethioamide and 25 ml of ethanol was heated to reflux (about 80°) while 3.8 ml of 30% hydrogen peroxide (1.1 g of active H2O2) were added dropwise; the exothermic reaction maintained the mixture at the reflux temperature. After addition of the peroxide was completed, the reaction mixture was heated under reflux for 30 minutes, then filtered hot and allowed to cool. The mixture was diluted with 100 ml of water and stirred for 15 minutes. The resulting precipitate, 5-amino-4-cyano-3-(dimethylamino)isothiazole, was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CC(O)=O.CS(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Br)cc4)nc3n2)CC1
Yield: 67.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.44 g of 4-bromophenyl isocyanate according to the general procedure of Example 37 to give 0.97 g of 1-(4-Bromo-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3 CN+0.1% AcOH+DMSO): M+ +H=645; mp 171°-175° C.
Reaction SMILES: [N+](C1C([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=NC=CC=1)([O-])=O.Cl[C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH2:32][CH2:33][CH2:34][CH3:35])[N:26]=1.N1CCC(NC(=O)OC(C)(C)C)CC1>>[CH2:32]([C:27]1[N:26]=[C:25]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:14][CH2:15]2)[CH:30]=[C:29]([CH3:31])[N:28]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: CCCCc1nc(C)cc(Cl)n1
Agent: CC(C)(C)OC(=O)NC1CCNCC1
Product: CCCCc1nc(C)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1

Procedure:
Prepared in a manner analogous to Intermediate 38 starting from 4-chloro-2-butyl-6-methylpyrimidine (Intermediate 97) and tert-butyl piperidin-4-ylcarbamate.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)=[CH:5][N:4]([CH:13]([CH3:15])[CH3:14])[N:3]=1.[Cl:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[NH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[Cl:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][N:10]=[CH:9][N:8]=4)=[CH:5][N:4]([CH:13]([CH3:15])[CH3:14])[N:3]=3)[CH:24]=2)[NH:19][CH:18]=1
Reactant: CC(C)n1cc(-c2ccncn2)c(I)n1
Reactant: CC1(C)OB(c2cnc3[nH]cc(Cl)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2ccncn2)c(-c2cnc3[nH]cc(Cl)c3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(3-Iodo-1-isopropyl-1H-pyrazol-4-yl)-pyrimidine (0.05 g, 0.2 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.089 g, 0.318 mmol) and 2 M aq Na2CO3 (0.067 g, 0.636 mmol, 0.318 mL 3.0 Eq) in DMF (4 mL) was bubbled with Nitrogen for 15 min and DPPF PdCl2 (0.0140 g, 0.019 mmol, 0.06 Eq) was added and then heated in biotage microwave initiator for 2.0 hour at 100° C. and under a high absorption. The resultant black reaction was cooled to room temperature. The reaction was poured into H2O (100 mL) and extracted (3×50 mL EtOAC). The combined organics were dried over Na2SO4 and concentrated in vacuo to a black oil which was purified by Biotage column (Si 25+M) packed with hexanes and eluted with (5% MeOH/EtOAc)/Hexanes (0-50%:700 mL, 50-100%:700 mL, 100%; 700 mL, 27 mL fractions) to yield the product F-1 as an off-white solid (0.025, 50%).
Reaction SMILES: CN1CCOCC1.[Cl:8][CH2:9][C:10](Cl)=[O:11].[C:13]([NH:16][C:17]1[C:18]([NH2:42])=[C:19]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:26]=3)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([NH:16][C:17]1[C:18]([NH:42][C:10](=[O:11])[CH2:9][Cl:8])=[C:19]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:26]=3)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH3:14]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3N)[nH]c2c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-methyl morpholine (1 eq) and chloroacetylchloride (1 eq) were added to a stirred solution of methyl 2-[3-(acetylamino)-2-aminophenyl]-3-cyclohexyl-1H-indole-6-carboxylate in CH2Cl2 (0.03 M) under N2. After stirring at RT for 1 h, further N-methyl morpholine (1 eq) and chloroacetylchloride (1 eq) were introduced. The reaction was stirred for another hour before diluting with CH2Cl2 and washing with 1N HCl (aq), water and brine. The organics were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown solid that was taken on in the subsequent step without further purification (91%). MS (ES+) m/z 482 (M+H)+, 484 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.86-7.49 (m, 8H), 7.07 (m, 3H), 6.73 (m, 1H), 6.60 (d, 1H), 6.56 (s, 1H), 6.42 (m, 1H), 4.33 (s, 2H), 4.32 (s, 2H), 4.27 (s, 2H), 1.46 (s, 9H); MS 534 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27]([OH:29])=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NCC(=O)O
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a 25 ml flask was added ethyl 2-((S)-3-(4-fluorophenyl)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylamino)acetate 103.1.C (331 mg, 0.78 mmole), lithium hydroxide monohydrate (65.3 mg, 1.56 mmole), 1 ml of water and 6 ml of tetrahydrofuran. After 3 hours, 0.78 ml of 2N-hydrogen chloride solution was added to neutralize. The solvent was removed by rotary evaporation. The crude product was purified by silica gel chromatography to give 103.2 (268 mg, 87% yield) as colorless amorphous. LCMS ESI (pos.) m/e: 398 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J=5.5 Hz, 2H), 7.72 (d, J=6.3 Hz, 2H), 7.33 (dd, J=8.4, 5.7 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 6.81 (s, 1H), 3.66 (s, 3H), 3.58 (t, J=6.8 Hz, 1H), 3.21 (d, J=16.9 Hz, 1H), 3.11 (d, J=17.2 Hz, 1H), 3.02 (dd, J=13.6, 5.9 Hz, 1H), 2.89 (dd, J=13.6, 7.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc(NS(C)(=O)=O)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.4 %

Procedure:
90 mg (0.22 mmol) of the compound prepared in Example 17 was dissolved in 1 ml of dichloromethane, to which 58 μl (0.34 mmol) of methanesulfonyl chloride and 17 μl (0.22 mmol) of diaisopropylethylamine were added. The reaction was stirred for 10 hours at room temperature, 67 mg (yield: 64%) of the target compound was obtained through reaction accomplished by the same procedure as used in Example 33.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH2:6]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[CH:7]=[CH2:8]>>[CH2:6]([N:9]([CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[C:1](=[O:5])[CH2:2][OH:3])[CH:7]=[CH2:8]
Reactant: O=C(O)CO
Reactant: C=CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C=CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 24 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[2-(allylamino)ethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 11, preparation of starting materials) to give the title compound in 24% yield; NMR spectrum (DMSO-d6) 3.79-4.19 (m, 6H), 4.38-4.63 (m, 3H), 5.06-5.19 (m, 2H), 5.31 (s, 2H), 5.69-5.90 (m, 1H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33-7.39 (m, 2H), 7.56-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.98 (s, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 520.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]([F:38])([F:37])[F:26])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-trifluoromethylphenylboronic acid (CAS RN 1423-27-4). Off-white solid (60%). MS (ESI): m/z=493.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)(=O)C(O)=O>C(O)(=O)C.O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(CO)cc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
4,6-Di-t-butyl-2-(4-methoxybenzyl) phenol was prepared as follows: A solution of 2,4-di-t-butylphenol (57.5 g), 4-methoxybenzyl alcohol (34.5 g) and oxalic acid (2 g) in acetic acid (80 ml) and water (2 ml) was refluxed for 7 hours, diluted with water, and extracted with chloroform. Distillation of the chloroform extract gave an oil (b.p. 200°-210° C. at 2 mm Hg) which crystallized (58 g; 71.4%). The product was recrystallized from methanol to give glistening colorless needles, m.p. 84°-85°; (Found: C, 81.0; H, 9.21. Calc. for C22H30O2 : C, 80.9; H, 9.26%). The pmr spectrum exhibited the following: δ1.30, 9H, S; δ1.38, 9H, S; δ3.79, 3H, S; δ3.83, 2H, S; δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.02, 1H, D (J=2 Hz); δ7.14, 2H, D (J=8 Hz); δ7.23, 1H, D (J=Hz).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH:10][CH:11]1[CH2:13][CH2:12]1)[C:7](=[O:9])[CH3:8])[CH3:3].[N:15]1([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[C:24](O)=[O:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:14])[CH:6]([N:10]([CH:11]1[CH2:12][CH2:13]1)[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:22]=1)[C:7](=[O:9])[CH3:8])[CH3:3]
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(NC1CC1)C(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(C)=O)N(C(=O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1)C1CC1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To 0.4 g (2 mmol) of 2-cyclopropylamino-3-oxo-butyric acid ethyl ester hydrochloride salt, 0.6 g (2 mmol) of 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid, 0.4 g (2 mmol) of EDCI and 0.3 g (2 mmol) of HOBT was added 2 ml of DMF and 0.6 ml (4 mmol) of triethylamine. The mixture was stirred for 3 h after which time the solvent was removed by evaporation; the residue was then re-dissolved in EtOAc, washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, dried with sodium sulfate and re-concentrated to afford 0.8 g (93%) of crude 2-[cyclopropyl-(3-morpholin-4-yl-5-trifluoromethyl-benzoyl)-amino]-3-oxo-butyric acid ethyl ester. This material was re-dissolved in 5 ml of EtOH and 1 g (8 mmol) of ammonium trifluoroacetate was added. The solvent was evaporated and the residue heated to 130° C. for 16 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 6:4] afforded 0.4 g (55%) of the title compound as colorless solid. MS: 424.2 (MH+).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1>CCO.[Pd]>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH2:11])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
tert-butyl N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-D-ornithinate (0.67 g, 1.83 mmole) and Pd on charcoal (95%, 0.115 g) were mixed in EtOH (95%, 20 mL) and stirred under H2-atmosphere for 5 hours and 15 minutes. The mixture was filtered through Celite 521 and the solvent was evaporated under reduced pressure to give 0.45 g (85%) of the desired product.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:14][N:15]2[CH:19]=[C:18]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)[CH:17]=[N:16]2)[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.C(OP(CC1C=CC(NC2N=C(NC3C=CC(C4C=C(C(OC)=O)N(CCCO)C=4)=NC=3C(=O)NC)C(C(F)(F)F)=CN=2)=C(OC)C=1)(O)=O)C>>[CH3:27][C:22]1([CH3:28])[C:23]([CH3:25])([CH3:26])[O:24][B:20]([C:18]2[CH:17]=[N:16][N:15]([CH2:14][C:10]3([CH2:9][OH:8])[CH2:11][O:12][CH2:13]3)[CH:19]=2)[O:21]1
Reactant: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)COC3)c2)OC1(C)C
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cc(C(=O)OC)n(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1
Product: CC1(C)OB(c2cnn(CC3(CO)COC3)c2)OC1(C)C
Yield: 95.3 %

Procedure:
1-({3-[(Benzyloxy)methyl]oxetan-3-yl}methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 44C, 1.37 mg, 3.56 mmol) was hydrogenated using the procedure from Compound 38A to afford 998 mg of the title compound (95%). 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.67 (s, 1H), 4.65 (d, J=6.3 Hz, 2H), 4.49 (s, 2H), 4.42 (d, J=6.3 Hz, 2H), 3.57 (s, 2H), 1.32 (s, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]3[CH2:39][C:40](O)=[O:41])=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.CN(C)C=O.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:40](=[O:41])[CH2:39][CH:27]1[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31][N:26]1[C:24]([O:23][CH2:22][CH:20]1[C:21]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Reactant: Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)Nc2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromoaniline (3.69 g, 21.44 mmol), and 2-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (10 g, 21.44 mmol) in a 1:1 solution of N,N-dimethylformamide:pyridine (100 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.27 g, 53.6 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and was subsequently washed with brine (3×) and 1 M HCl (3×). The organic solution was then concentrated onto silica gel and purified via flash chromatography (10-70% ethyl acetate/hexanes) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H), 7.81-7.95 (m, J=7.67 Hz, 2H), 7.53-7.75 (m, 4H), 7.22-7.48 (m, 5H), 7.10 (dd, J=7.21 Hz, 1H), 4.56 (s, 1H), 4.17-4.42 (m, 3H), 3.61-3.98 (m, 3H), 2.89-3.18 (m, 2H), 2.62-2.88 (m, 2H), 2.49-2.58 (m, 1H), 1.32-1.50 (m, 9H); MS (APCI+) m/z 522.2 (M-Boc+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[CH:39][CH:40]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CCc2ccc(CCl)cc2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(CCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5.60 g (12.71 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 3.79 g (15.25 mmol) of 1-(chloromethyl)-4-[2-(4-fluorophenyl)ethyl]benzene and 2.64 g (19.07 mmol) of potassium carbonate in 200 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 6.8 g (10.42 mmol, 82% of theory) of the target compound.