Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]1([CH:55]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:56][C:57](O)=[O:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[O:58]=[C:57]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH2:56][CH:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)CC(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3,3-diphenylpropionic acid, mp 149°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C(=O)Cl)c1cccc(Cl)c1

Procedure:
2-(3-Chlorophenyl)-2-methylpropanoic acid (5.7 g, 28.7 mmol) was stirred in thionyl chloride (100 mL) for 2 hours at reflux. The thionyl chloride was removed under vacuum to give the product (5.69 g).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[K+]>[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:2])=[CH:17][CH:16]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: C=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: C=Cc1ccc(O)cc1
Temperature: 65 °C

Procedure:
50.0 g of 20 percent poly(4-vinylpyridine) methanol solution from Ex. 1 (˜10.0 g of polymer) was placed in a 500 ml single neck flask and stripped of solvent on a rotary evaporator. To the dried polymer was then added 110 g of RO water and 10.0 g of con. hydrochloric acid. The mixture was stirred until a uniform pale yellow aqueous solution was obtained. This solution was then charged into a 500 ml three-necked round bottom flask equipped with a mechanical paddle stirrer, a nitrogen inlet, a pot thermometer, heating mantle and condenser. 0.6 g of potassium persulfate was then added followed by 30.0 g (˜0.288 moles) of styrene. The biphasic stirred mixture was then rapidly heated to 65° C. under nitrogen for 8 hrs. The final latex solids were determined to be 26.7 percent (theory 27.1 percent) or 98.5 percent conversion. A small portion of the final latex was coagulated in dilute potassium hydroxide solution for analysis. NMR indicated a composition of 25.8 percent poly(4-VP) and 74.2 percent polystyrene (theory 25 percent poly(4-VP) and 75 percent PS). Latex particle size was ˜182 nm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[N:15]=1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[N:15]=1
Reactant: CCCCCCCCI
Reactant: Oc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 64 mg (0.00127 mol) of NaH in 1 mL of DMF at 0° C. was added a partial solution of 200 mg (0.00063 mol) of the product of Step F. The reaction was stirred at 0° C. for 30 minutes. Then, 304 mg (0.00127 mol) of 1-iodooctane was added and stirring continued for an additional 30 minutes at 0° C. The reaction mixture was poured into ice-water and extracted with Et2O. The Et2O extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified by passing through a silica gel column eluting with EtOAc:Hexanes (1:4) to give 240 mg of a clear oil. 1H NMR (CDCl3) d 7.40 (m, 1H), 7.20 (d, 1H), 6.98 (Ab q, 2H), 3.92 (t, 2H), 2.80 (m, 2H), 1.70-2.20 (m, 4 H), 1.20-1.45 (m, 12H), 0.90 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([OH:11])[CH2:6]1.O.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1
Reactant: COC(=O)C[C@H]1CCC[C@@H](O)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
rac-cis-(3-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) (Example 5, step 1) was dissolved in 2 ml dichloromethane and tetrapropylammonium perruthenate [TPAP] (102 mg, 0.29 mmol) and 4-methylmorpholine oxide monohydrate (590 mg, 4.35 mmol) were added. The reaction mixture was stirred for 16 hours at room temperature, filtered over dicalite and evaporated to dryness. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→50:50 gradient). The desired compound was obtained as a light yellow liquid (240 mg, 48%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[S:7][CH:8]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:10]=1[C:11]#[N:12]>C1(C)C=CC=CC=1>[C:11]([C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][S:7][C:6]=1[NH:5][C:3]([NH:2][CH3:1])=[O:4])#[N:12]
Reactant: CC(C)c1csc(N)c1C#N
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1scc(C(C)C)c1C#N
Yield: 56 %

Procedure:
11.8 ml (0.2 mole) of methyl isocyanate were added to a solution of 33.2 g (0.2 mole) of 2-amino-3-cyano-4-isopropyl-thiophene in 200 ml of toluene. After the exothermic reaction had subsided, the product which precipitated in the solid form was filtered off. Further portions of reaction product were obtained by concentrating the mother liquor. 25 g of 1-(3-cyano-4-isopropyl-thien-2-yl)-3-methyl-urea of melting point 179°-181° C. were obtained in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:19]1([CH2:22][N:10]2[CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=3[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]2)[CH2:21][CH2:20]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC1CC1)C2

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), [B] Cyclopropylmethyl bromide (0.55 mL, 0.0057 mol), Sodium iodide (0.003 g, 0.00002 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was reacted in an analogous manner to example 743-C to give 4-Cyclopropylmethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a red oil. (0.56 g, 92%). LCMS (m/e) 306 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.92 (s, 1H), 7.44 (s, 1H), 3.95 (s, 3H), 3.66 (s, 2H), 3.26 (s, 2H), 3.13 (s, 2H), 2.89 (s, 1H), 2.73 s, 1H), 2.44-2.42 (d, 2H, J=6.57 Hz), 1.30-1.20 (br, 1H), 0.95-0.87 (br, 2H), 0.50 (d, 2H, J=7.83 Hz), 0.18-0.16 (d, 2H, J=4.80 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:13][C:14]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:15]=1[C:16]([NH:18][C:19]1[S:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:22](C2C=CC=CN=2)[N:23]=1)=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:22]2[N:23]=[C:19]([NH:18][C:16](=[O:17])[C:15]3[C:14]([F:13])=[CH:43][CH:42]=[CH:41][C:40]=3[F:44])[S:20][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: COc1ccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cc1OC

Procedure:
Compound 109 was prepared from 22a and 3,4-dimethoxyphenylmagnesium bromide as described for the preparation of Compound 107.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[CH:5]=1)([O-:3])=[O:2].[CH3:13][O-:14].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cccc([N+](=O)[O-])c1

Procedure:
m-Nitroanisole was prepared by reacting m-dinitrobenzene with sodium methoxide at 25° C. for 16 hours in hexamethylphosphotriamide solvent (N. Kornblum et al., J. Org. Chem., 41, 1560 (1976)).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4](O)[CH:3]=1.P(Br)(Br)([Br:12])=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:12][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([OH:8])[CH:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)cc(O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(O)n1
Temperature: 110 °C
Yield: 46.2 %

Procedure:
A solution of 6-methylpyridine-2,4-diol (1.75 g, 14.0 mmol) in dry DMF (6.0 mL) is stirred under N2 and phosphorus oxybromide (3.05 g, 10.6 mmol) is added in one portion. The mixture is heated at 110° C. for 45 min and then cooled and diluted with water (7 mL). Na2CO3 (s) is added to bring the pH to 7 and the resulting suspension is cooled to 0° C. The product is collected by suction filtration, rinsing with cold water and diethyl ether, and dried overnight in a vacuum desiccator to afford the title compound as a light brown solid (920 mg).
Reaction SMILES: [Cl-].[C:2]1([N+:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:9]=[N:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#[N+]c1ccccc1
Reactant: Nc1ccccc1
Agent: [Cl-]
Product: Nc1ccccc1N=Nc1ccccc1

Procedure:
In a method for preparing the compound: ##STR3## wherein aniline is diazotized in aqueous hydrochloric acid employing sodium nitrite as the diazotizing agent to form benzenediazonium chloride, the benzenediazonium chloride is coupled into aniline to form aminoazobenzene, and the aminoazobenzene is diazotized and coupled into phenol; the improvement comprising: diazotizing the aniline employing an excess of sodium nitrite of up to about 10% of the amount stoichiometrically required to diazotize one-half of the aniline on a molar basis; coupling the resultant benzenediazonium chloride with the remaining aniline to form a mixture of aminoazobenzene and excess benzenediazonium chloride in aqueous hydrochloric acid; heating said mixture to about 40° C. and allowing said excess benzenediazonium chloride to decompose and, subsequently, without isolation, diazotizing said aminoazobenzene and coupling it into phenol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]([CH2:31][CH3:32])[CH3:30])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]([CH2:31][CH3:32])[CH3:30])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1
Reactant: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Agent: O=C=O
Solvent: CO
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccccc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 5) was purified using chiral SFC to afford peak A (Example 5A) and peak B (Example 5B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 22 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.5 min, tR (peak B) 16.7 min. The absolute stereochemistry of individual enantiomers (Examples 5A and 5B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:49][N:50]([CH3:56])[CH:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][N:53]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:52]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 3R)-(+)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at room temperature for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated. A solid was precipitated by addition of diethyl ether:hexane=1:2 to the residue. The solvent was removed, and the residue was dried under reduced pressure to provide the titled compound as white powder (33.2 mg, 79%).
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1>C(O)(C(F)(F)F)=O>[F:40][CH:2]([F:1])[C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH2:32])[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)F)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)F)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 24.6 %

Procedure:
Tert-butyl (1-(4-(1-(difluoromethyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.073 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and the residue was dried to give the desired product as an off-white solid (8 mg, 65% yield). LCMS (Method D): RT=0.803 min, M+1=446. 1H-NMR (500 MHz, CD3OD) δ 8.20 (1H, s), 7.53-7.47 (3H, m), 7.46-7.41 (2H, m), 7.39-7.33 (3H, m), 7.30-7.23 (2H, m), 5.77 (2H, s), 2.83-2.70 (2H, m), 2.63-2.53 (2H, m), 2.30-2.19 (1H, m), 2.06-1.90 (1H, m).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.Cl.O1CCOCC1>>[ClH:29].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]4)[CH2:11][CH2:10]2)=[CH:32][CH:31]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(Cl)cc4)CC3)cccc2n1
Yield: 56 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 4-chlorobenzyl bromide (66 mg; 0.32 mmol) via Method BB to a solid, which was stirred in the presence of 4M HCl in dioxane (4 eq). Solids were filtered and rinsed once with ether to give title compound. (66 mg; 56% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 11.3 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.7 (m, 4H), 7.52 (d, J=6.8 Hz, 2H), 7.02 (m, 2H), 4.66 (br s, 3H), 4.26 (d, J=4.8 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.34 (br d, J=11.6 Hz, 2H), 2.87 (m, 2H), 2.2 (m, 1H), 1.81 (m, 4H). MS m/z (ESI) 398 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (260 mg, 1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in THF (3 mL) at rt, was added dropwise a solution of phenyl chloroformate (170 mg, 1.1 mmol) in THF (2 mL) and the reaction mixture was stirred for a further 15 h. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added to the reaction mixtureand stirring continued for an additional 4 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford crude phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg) which was used without further purification. LC-MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[S:7][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([O:25][CH3:26])[CH:13]=1)=[O:10].CCN(CC)CC.CS(Cl)(=O)=O.[H-].[Na+].Cl>C(Cl)Cl>[CH3:26][O:25][C:14]1[CH:13]=[C:12]([N:11]2[CH2:2][CH2:3][C:4]3[N:5]=[C:6]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[S:7][C:8]=3[C:9]2=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: COc1ccc(-c2nc(CCO)c(C(=O)Nc3ccc(OC(=O)C(C)(C)C)c(OC)c3)s2)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(s2)C(=O)N(c2ccc(OC(=O)C(C)(C)C)c(OC)c2)CC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 163.8 %

Procedure:
Dissolve 2,2-dimethyl-propionic acid 4-{[4-(2-hydroxy-ethyl)-2-(4-methoxy-phenyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenyl ester (480 mg, 0.98 mmol) and NEt3 (177 mL, 1.27 mmol) in dry CH2Cl2 and cool to 0° C. Add dropwise methanesulfonyl chloride (98.1 mL, 1.27 mmol) and stir for 30 min. Quench the reaction mixture with saturated NH4Cl solution and extract with CH2Cl2 (3×10 mL). Dry, filter, and concentrate. Redissolve the crude material in dry DMF (6.5 mL) and chill to 0° C. Add portionwise NaH (60% dispersion, 51 mg, 1.27 mmol) then warm to ambient temperature overnight. Add 1N HCl (20 mL) and extract with EtOAc (3×10 mL). Collect insoluble solid from portioned layers via filtration. Wash the filtrate with water (40 mL), dry, filter, and concentrate. Combine the resulting material with the collected solid to give the title compound as a yellow solid (749 mg, 99%). MS (ES+) 467.3 (M+1)+. 1H NMR (400 MHz, CD3OD): δ 7.96 (d, 2H, J=8.4 Hz), 7.14 (d, 1H, J=2.2 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.04 (dd, 1H, J=8.8, 2.2 Hz), 6.96 (dd, 1H, J=8.4, 2.2 Hz), 4.15 (t, 2H, J=7.0 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.27 (t, 2H, J=7.5 Hz), 1.35 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:10])=[C:5]([CH3:12])[CH:4]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1cc(Cl)ccc1[C@H](C)N
Agent: Cl
Product: Cc1cc(Cl)ccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-chloro-2-methylphenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:29])[NH:13][CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:20]([CH3:22])[CH:21]=2)[CH3:15])[CH:9]=[C:8]([Cl:30])[N:7]=1)(=O)C.[OH-].[Na+].Cl>C1COCC1>[Cl:30][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([CH2:5][OH:4])[N:7]=1)[C:12]([NH:13][CH:14]([C:16]1[CH:17]=[N:18][C:19]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[C:20]([CH3:22])[CH:21]=1)[CH3:15])=[O:29]
Reactant: CC(=O)OCc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)NC(=O)c2cc(Cl)nc(CO)c2)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.9 %

Procedure:
To a stirred solution of (6-chloro-4-((1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamoyl)pyridin-2-yl)methyl acetate (95 mg, 0.21 mmol, Step-2, single enantiomer) in THF (5 mL) is added 2M aqueous sodium hydroxide solution (0.16 mL, 0.32 mmol) at room temperature, and the mixture is stirred at room temperature for 1 day. The reaction mixture is neutralized with 2M hydrochloric acid (0.16 mL, 0.32 mmol) and extracted with dichloromethane (50 mL×2). The organic layer is washed with brine, dried over sodium sulfate. The organic solvent is removed under reduced pressure to give 72 mg (84% yield) of the title compound as yellow oil.