Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][NH2:9])[CH3:3].[O:11]1[C:15]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12]1.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1COCC1.CO>[CH2:2]([O:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][NH:9][CH2:20][C:17]1[CH:18]=[CH:19][C:14]2[CH:13]=[CH:12][O:11][C:15]=2[CH:16]=1)[CH3:3]
Reactant: O=Cc1ccc2ccoc2c1
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCNCc1ccc2ccoc2c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-amino-butyric acid ethyl ester hydrochloride (1 eq.) in THF was added TEA (2.5 eq.). The mixture was stirred 5 min at 20° C., then benzofuran-6-carbaldehyde (0.95 eq.) and MgSO4 (3 eq.) were added. The reaction was refluxed for 2 h, then cooled to 20° C. and filtered. The filtrate was added to a suspension of NaBH4 (2 to 6 eq.) in MeOH at −15° C. The reaction was stirred for 2 h at −15° C. The reaction was quenched with the addition of aqueous HCl 2N until pH=2. The aqueous layer was washed twice with EtOAc. The organic layers were discarded. Solid KOH was added to the aqueous layer. The crude was extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 95/5) to afford 4-[(benzofuran-6-ylmethyl)-amino]-butyric acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH2:36][CH3:37])[CH:7]([CH3:8])[CH:6]([O:9][C:10](=[O:32])[CH:11]([CH2:28][CH2:29][CH2:30][CH3:31])[C:12]([O:14][CH:15]2[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18][C:17]([CH3:26])([CH2:24][CH3:25])[CH:16]2[CH3:27])=[O:13])[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3]1.[C:38]([C:42]1[CH:43]=[C:44]([CH:49]=[C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:51]=1[OH:52])[CH2:45]N(C)C)([CH3:41])([CH3:40])[CH3:39].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:26][C:17]1([CH2:24][CH3:25])[CH:16]([CH3:27])[CH:15]([O:14][C:12](=[O:13])[C:11]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:45][C:44]2[CH:49]=[C:50]([C:53]([CH3:54])([CH3:56])[CH3:55])[C:51]([OH:52])=[C:42]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:43]=2)[C:10]([O:9][CH:6]2[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3][C:2]([CH3:1])([CH2:36][CH3:37])[CH:7]2[CH3:8])=[O:32])[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18]1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCC(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C

Procedure:
26.2 g (0.05 mole) of butylmalonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl)ester and 13.2 g (0.05 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl) dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.25 g of lithium amide, the mixture is refluxed for 4 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase is repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo. As residue there is obtained butyl-(3,5-di-tert.butyl-4-hydroxybenzyl)malonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl) ester in the form of viscous oil (Compound No. 32).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.Cl.Cl[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2
Reactant: NCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1cscn1
Agent: Cl
Product: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 91 %

Procedure:
The procedure described in Example 65 (preparation of starting materials) was repeated using 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol and 4-(chloromethyl)-1,3-thiazole hydrochloride to give 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine in 91% yield; NMR spectrum (DMSO-d6 400 MHz) 3.02-3.19 (bs, 2H), 4.22-4.36 (m, 2H), 5.33 (s, 2H), 7.14 (d, 1H), 7.27-7.40 (m, 2H), 7.67-7.86 (m, 3H), 8.23 (s, 1H), 8.52 (s, 1H), 9.15 (s, 1H) (3 exchangeables); Mass spectrum MH+ 427.9.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][C:25]1=[O:40].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:40])[CH2:26]4)=[N:35][CH:34]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(N2CCN(C)C(=O)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(=O)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) and methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 0.98 mmol) in toluene (5.00 mL) at 25° C. The resulting solution was stirred at 60° C. for 24 h. The reaction mixture was added to methanol (100 mL), then treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (204 mg, 45%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Oc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1Oc1ccccc1
Yield: 26.1 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 2 using 2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g), the title compound (3 g) was obtained. melting point: 89° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:22][C:23]#[C:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([SnH:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][N:9]([CH2:22]/[CH:23]=[C:24](\[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])/[Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCOP(=O)(C#CCN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-])P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of Diethyl 3-[N-benzyloxy,N-(2-nitrobenzenesulfonyl)amino]-propynylphosphonate (109) (10.4 g, 21.6 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh3)4) (474 mg, 0.430 mmol) in dry THF (100 mL) was added tributyltin hydride (BU3SnH) (6.28 g, 21.6 mmol) over a period of 40 min at 0° C. The reaction mixture was stirred at 0° C. for one hour and was allowed to warm to room temperature over a period of time of 2 hours. The solvent was removed under reduced pressure and the crude oil was purified by column chromatography using a mixture of pentane/acetone (volume ratio 3/1), yielding 15 g of an amber oil (90%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[F:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl)-5-[3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.90 g) and potassium carbonate (0.40 g) and 2-fluoro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.60 g of desired compound (melting point: 109.0°-111.0° C.).
Reaction SMILES: Cl.N1C=CC=CC=1C[N:9]1[C:13]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10]1.O1CCOCC1.[Se](=O)=O>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([C:13]2[NH:9][CH:10]=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(Cl)cc2)n(Cc2ccccn2)c1
Agent: Cl
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 97.3 %

Procedure:
Ethyl 1-(2-pyridylmethyl)-5-(4-chlorobenzoyl)pyrrole-3-carboxylate hydrochloride (4.05 g.) was combined with 150 ml. of dioxane, 5 ml. of water and 10 g. of selenium dioxide and refluxed for 18 hours. The reaction mixture was filtered, the filtrate diluted with 150 ml. of ether and 150 ml. of water, and equilibrated. The organic phase was separated, back-washed with two 100 ml. portions of water, and concentrated to yield solid ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (2.7 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][N:27](CC5C=CC=CC=5)[CH2:26][C@H:25]4[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(OC(Cl)=O)C.C(N(CC)CC)C.[F:58][C:59]([F:74])([F:73])[C:60]1[CH:61]=[C:62]([CH:66]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:68]=1)[C:63](Cl)=[O:64]>C1(C)C=CC=CC=1.O.CO>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][CH2:20][N:21]([C@H:24]4[CH2:29][CH2:28][N:27]([C:63](=[O:64])[C:62]5[CH:61]=[C:60]([C:59]([F:74])([F:73])[F:58])[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=5)[CH2:26][C@H:25]4[C:37]4[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=4)[CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN([C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccc(Cl)cc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
Rac-cis-4-[1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.68 g, 2.84 mmol) was dissolved in toluene (60 mL) and 1-chloroethyl-chloroformate (0.348 mL, 3.13 mmol) were added. The reaction mixture was refluxed overnight. Methanol (55 mL) was added and reflux was continued for 4 h. The solvents were evaporated. The crude intermediate was dissolved in dichloromethane (50 mL) and triethylamine (1.99 mL, 14.2 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.643 mL, 3.55 mmol) were added. The reaction mixture was stirred at room temperature overnight and than diluted with 50 mL water. The organic phase was separated and the aqueous layer was extracted twice with 50 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with cyclohexane/ethyl acetate 1:1 gave rac-cis-4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.84 g, 87%) as an off-white solid, MS: m/e=742.3 (M+H+).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[I:13])=[O:5].[OH:14]S(O)(=O)=O>>[I:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:14]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccccc1I
Product: O=C1Nc2c(I)cccc2C1=O
Temperature: 85 °C
Yield: 87 %

Procedure:
2-(hydroxyimino)-N-(2-iodophenyl)acetamide (3.2 g, 0.011 mmol) was added to conc. H2SO4 (15 mL) in small portions at 60° C. The reaction mixture was further heated at 85° C. for 5 h. After the reaction completion, the reaction mixture was cooled to room temperature and poured into crushed ice. A brown color solid product precipitated. It was then filtered and washed with chilled water several times, then dried in a vacuum oven to get 2.9 g of the required product as a red coloured solid (87%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH:30]=O)=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:20][C:19]([CH2:30][NH:13][CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH3:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Reactant: CC(N)c1ccnc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The 1-quinolin-4-yl-ethylamine (510 mg, 3 mmol) and 6,4′-dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) were stirred with acetic acid (300 mg, J. T. Baker) in methyl alcohol (15 mL0 at room temperature for 4 h. To the reaction solution was added sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich) at 0° C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with saturated aqueous sodium bicarbonate (30 mL). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by ethyl acetate (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo. The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 72% yield (287 mg, 0.72 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11].[Mg].BrCC.CON(C)[C:22]([C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)=[O:23]>O.C1COCC1>[CH3:29][C:27]1[O:26][N:25]=[C:24]([C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])=[O:23])[CH:28]=1
Reactant: CON(C)C(=O)c1cc(C)on1
Reactant: CCOC(C)OCc1ccccc1Br
Agent: [Mg]
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OCc1ccccc1C(=O)c1cc(C)on1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (12.96 g, 0.05 mol) and THF (45 ml) was added to a mixture of magnesium (1.82 g, 0.075 mol) and bromoethane (0.2 ml) and THF (5 ml) at 45 to 55° C. under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 55° C. for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-5, N-dimethyl-3-isoxazolcarboxamide (5.62 g, 0.033 mol) and THF (40 ml) cooled to −50° C. The mixture was stirred at −60° C. to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone (8.61 g, yield: 90.2%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([O:10]C)[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[CH:14][N:13]=2)=[CH:6][N:5]=1)[CH3:2].Br>C(O)(=O)C>[CH2:1]([NH:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:20]=3)=[CH:14][N:13]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)c(=O)[nH]1
Yield: 51.4 %

Procedure:
Using the procedure of Example 7, N-ethyl-4-methoxy-5-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.080 g, 0.20 mmol) was combined with acetic acid (3 mL) and HBr (0.090 mL, 0.79 mmol) to afford 2-(ethylamino)-5-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (40 mg, 51%). 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.66 (s, 1H), 8.43 (m, 2H), 8.38 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.62 (dd, J=8.8, 2.9 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 63.80 (br s, 1H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 3.35 (m, 2H), 1.12 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 390.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:19][C:18]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 99.5 %

Procedure:
4-Trifluoromethylaniline (3.00 g, 18.6 mmol) was dissolved in pyridine (1.62 g, 20.5 mmol), the solution was added with acetic anhydride (2.38 g, 23.3 mmol) with stirring on an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then azeotroped with toluene, and the resulting residue was suspended in hexane, and taken by filtration. The residue was washed with hexane, and then dried under reduced pressure to obtain 4-trifluoromethylacetanilide (3.76 g, 99%) as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([CH2:16]O)=[CH:6]2.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([CH2:16][Cl:20])=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2cc(CO)c(C)nc2cc1OC
Product: COc1cc2cc(CCl)c(C)nc2cc1OC

Procedure:
6,7-Dimethoxy-2-methylquinoline-3-methanol (2.31 g, 9.9 mmol) was dissolved in thionylchloride (50 ml) and refluxed for 2 h. The solution was concentrated and the residue partitioned between ethyl acetate and aqeous NaHCO3. The layers were separated and the aqeous phase extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over MgSO4. Evaporation of the solvent gave 2.48 g 6,7-dimethoxy-3-chloromethyl-2-methylquinoline.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)Cl
Product: CC(C)(C)c1ccc[nH]1

Procedure:
wherein X1, X2, Z, and R1 are as defined above. The pyrrole can reacted with t-butylchloride under Friedel-Craft alkylation condition to give the tert-butylpyrrole 2, which can then be nitrated. The ester is then hydrolyzed, e.g., with LiOH, and coupled to give amide 4. Compound 4 is then reduced to give the amine which is reacted with isocyanate to give compound 5, which is an exemplary compound of Formula I.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH:31]([CH3:33])[CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([OH:29])=O)[CH2:8]2)=[CH:3][CH:2]=1.[NH2:40][C@:41]1([C:46]([NH:48][S:49]([CH:52]2[CH2:54][CH2:53]2)(=[O:51])=[O:50])=[O:47])[CH2:43][C@H:42]1[CH:44]=[CH2:45].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:30][CH:31]([CH3:32])[CH3:33])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:14]([CH3:16])([CH3:17])[CH3:15])[C@H:9]([C:27](=[O:29])[NH:40][C@:41]3([C:46](=[O:47])[NH:48][S:49]([CH:52]4[CH2:54][CH2:53]4)(=[O:51])=[O:50])[CH2:43][C@H:42]3[CH:44]=[CH2:45])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)S[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylic acid (28 mg, 0.050 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (23.03 mg, 0.056 mmol), and HATU (28.5 mg, 0.075 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.035 mL, 0.202 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by prep-HPLC to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(isopropylthio)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (23 mg, 59% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.03-1.07 (m, 3H), 1.09-1.12 (m, 11H), 1.21-1.28 (m, 4H), 1.40-1.51 (m, 2H), 1.52 (s, 9H), 1.87 (dd, J=7.93, 5.49 Hz, 1H), 2.20 (q, J=8.85 Hz, 1H), 2.30 (t, J=11.60 Hz, 1H), 2.54-2.62 (m, 1H), 2.81 (dd, J=12.05, 6.26 Hz, 1H), 2.90-2.98 (m, 1H), 3.87 (dd, J=10.99, 6.41 Hz, 1H), 3.97 (d, J=0.99 Hz, 1H), 4.51 (d, J=9.77 Hz, 1H), 5.08-5.19 (m, 2H), 5.29 (d, J=17.09 Hz, 1H), 5.69-5.81 (m, 1H), 7.37 (t, J=7.32 Hz, 1H), 7.46 (t, J=7.78 Hz, 2H), 7.60 (dd, J=10.68, 7.93 Hz, 4H), 7.71 (d, J=8.55 Hz, 2H). LC-MS (retention time: 3.42 min, method B), MS m/z 767 (M+H).