Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.[CH2:6]([C:10]1[N:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:45][N:44]=[N:43][N:42]=3)=[CH:31][CH:30]=2)[C:12]([C:16]([O:18][CH2:19][P:20]([O:25]CC)([O:22]CC)=[O:21])=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9].CO>C(#N)C>[CH2:6]([C:10]1[N:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:45][N:44]=[N:43][N:42]=3)=[CH:31][CH:30]=2)[C:12]([C:16]([O:18][CH2:19][P:20](=[O:21])([OH:22])[OH:25])=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OCP(=O)(O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromotrimethylsilane (1.70 mL, 13.1 mmol) was added to a stirred, 0° C. mixture of (diethoxyphosphoryl)methyl 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (3.49 g, 5.95 mmol) in acetonitrile and the mixture was stirred at room temperature for 1 hour. Methanol (20 mL) was added, stirred for 30 minutes then concentrated in vacuo to afford the title compound as crude, which was used in the subsequent step without further purification. LC-MS: m/z 531.0 (M+H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([NH:17][C:18]2[C:19](=[O:38])[N:20]([C:24]3[C:25]([CH3:37])=[CH:26][C:27]([F:36])=[C:28]([CH:35]=3)[C:29]([NH:31][CH:32]3[CH2:34][CH2:33]3)=[O:30])[CH:21]=[CH:22][N:23]=2)[CH2:16][CH2:15]1>O1CCOCC1.C1COCC1>[CH:32]1([NH:31][C:29](=[O:30])[C:28]2[CH:35]=[C:24]([N:20]3[CH:21]=[CH:22][N:23]=[C:18]([NH:17][C:14]4([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][CH2:6][CH2:5][NH:3][CH2:1][CH3:2])[CH2:16][CH2:15]4)[C:19]3=[O:38])[C:25]([CH3:37])=[CH:26][C:27]=2[F:36])[CH2:34][CH2:33]1
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CCN
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)c(F)cc3C)c2=O)CC1

Procedure:
A solution of ethylamine (2.012 mL of 2M in THF) and 5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide (Example 318h, 100 mg) in dioxane (3 mL) was heated for 24 h at 100° C. in a sealed tube. Further ethylamine (2.012 mL of a 2M solution in THF) was added and the reaction was heated for a further 24 h. Purification by preparative HPLC (Xbridge column eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (10 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:15])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7]2.[OH-:16].[Na+]>CC#N.O>[CH3:15][N:4]1[C:3]([CH2:2][OH:16])=[C:11]2[C:6]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10]2)=[N:5]1
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1CBr
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
3-(Bromomethyl)-2-methyl-6-nitro-2H-indazole (4.20 g, ˜14.9 mmol) in CH3CN (500 ml) and water (200 ml) was treated with NaOH to give pH˜11. The solution was stirred at rt for 2 days then conc. in vacuo and repeatedly extracted with dichloromethane and chloroform. The combined organic extracts were evaporated, and the crude product was purified by silica gel column chromatography to give (2-methyl-6-nitro-2H-indazol-3-yl)methanol (1.03 g, 33% TY). MS (ES+, m/z) 208.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:47]=[CH:46][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][C:39](O)=[CH:40][CH:41]=4)[CH2:36]3)=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)#[N:17]>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:47]=[CH:46][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][C:39]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:40][CH:41]=4)[CH2:36]3)=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)#[N:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cccc(-c2ccc(C(=O)NCCCCN3CCc4ccc(O)cc4C3)cc2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2ccc(C(=O)NCCCCN3CCc4ccc(OS(=O)(=O)C(F)(F)F)cc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.21 ml, 1.25 mmol) was added dropwise with stirring to an ice cooled solution of 2-(4-(4-(3-cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (0.41 g, 0.96 mmol) in anhydrous pyridine (5 ml). After stirring at room temperature for 18 h. the mixture was poured into 10% aqueous copper (II) sulphate (100 ml). The mixture was extracted with ethyl acetate (2×50 ml) and the combined extracts washed with 10% aqueous copper (II) sulfate (2×50 ml). water (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (0.263 g, 49%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=O)CCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CC(C)OC(C)C1

Procedure:
This intermediate (37.8 g.) was prepared using the procedure described in Example 4a except using 24.5 ml. (0.2 mole) of 2,6-dimethylmorpholine, 28.6 ml. (0.2 mole) of ethyl 4-bromobutyrate, 30.3 ml. (0.2 mole) of triethylamine, and 60 ml. of toluene and was isolated as a colorless liquid boiling 96.5°-97° C. at 4 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1>[C:14]([NH:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([N:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:35](=[O:37])[CH3:36])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N(C(C)=O)S(=O)(=O)c3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
N-{5-[6-Chloro-5-(phenylsulfonylamino)pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl)acetamide was dissolved in THF. Triethylamine (0.113 mL, 0.811 mmol) was added. The solution was placed in an ice-bath and acetyl chloride (0.058 mL, 0.81 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then evaporated. Water and ethyl acetate were added. The organic phase was dried with magnesium sulfate, filtered and evaporated. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.2 minutes) in 91% yield; 1H NMR Spectrum: (DMSOd6) 12.33 (1H, s); 8.69 (1H, d); 8.24 (1H, d); 8.06-8.00 (2H, m); 7.82 (1H, t); 7.72-7.67 (2H); 2.42 (3H, s); 2.17 (3H, s); 1.96 (3H, s); Mass Spectrum: M+H+ 465 and 467.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])[CH:2]=1.C(=O)(O)[O-].[Na+].C1COCC1.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:34]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([F:14])[CH:12]=1)([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: Nc1cc(F)c(-c2cccnc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1

Procedure:
4-(3-Pyridyl)-3,5-difluoroaniline (PREPARATION 2, 625 mg, 3.03 mmol), sodium bicarbonate (382 mg, 4.55 mmol, 1.5 eq) and dry THF (60 ml) are combined. The resulting mixture is placed under an atmosphere of nitrogen and benzylchloroformate (394 μl, 4.55 mmol, 1.5 eq) is added. The reaction is allowed to stir at 20-25°. After this time, the reaction is added to methylene chloride (150 ml) and washed with saturated sodium bicarbonate then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to a solid which is puried by silica gel chromatography (200 g of silica gel, eluted with acetonitrile/chloroform (3/97 - 11, 5/95 - 21), the title compound is recovered as a solid, mp 188°-190°; FTIR (neat) cm-1 3030, 1737, 1642, 1478, 1408, 1231, 1029, 723; MS CEI, m/z) 340, 296, 232, 205, 91, 79; NMR (CD3CL3) δ 8.59, 8.53-8.51, 7.95-7.92, 7.56-7.51, 7.44-7.31, 7.28 and 5.21.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10](=[O:12])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10]([O:12][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(C2C(=O)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4-fluoro-benzyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (30 mg, 0.09 mmol) in dichloromethane (1 ml) and triethylamine (52 μl, 0.37 mmol) is added the pivaloyl chloride (34 μl, 0.37 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 4-(4-fluoro-benzyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (31 mg).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH:30]1[CH2:32][CH2:31]1)C>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH:30]6[CH2:32][CH2:31]6)[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)C#CC1CC1
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: CCO
Product: O=c1cc(C2CC2)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.7 g, 2.23 mmol) (Example 20) in ethanol (40 mL) was added 0.462 g (3.35 mmol) of cyclopropyl-propynoic acid ethyl ester (Example 99). The reaction mixture was stirred at 82° C. for 30 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with MeOH/CH2Cl2 to afford 0.145 g of the title compound. [α]D25 −10.51 (c 0.5, CHCl3).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[C:6]1([C:2]([C:3]([Cl:16])=[O:4])([F:12])[F:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(F)(F)c1ccccc1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a flask charged with 2,2-difluoro-2-phenylacetic acid (0.8 g, 5.06 mmol), as prepared in the preceding step, under argon in an ice-bath was added oxalyl chloride (5 mL), and the reaction mixture stirred for 15 min. A solution of dimethylformamide (DMF) (37 mg, 0.506 mmol) in DCM (0.5 mL) was added. After 2 hours, the ice-bath was removed, and the mixture continued to stir for 1 hour. The solvents were evaporated, DCM was added, and then evaporated in vacuo giving the title compound (0.88 g, 98% yield), that was used immediately without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)O1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)=[CH:7][C:6]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1F
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1ccccc1)c1cc(-c2ccc3[nH]ncc3c2)ccc1F
Temperature: 150 °C
Yield: 60 %

Procedure:
The following reagents were mixed in no particular order and heated to 150° C. in a microwave for 1000 seconds: (5-bromo-2-fluorophenyl)(phenyl)methanone (from example 9, step 1) (278 mg, 1.0 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (486 mg, 2.0 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (70 mg, 0.10 mmol), dimethoxyethane (2 mL), ethanol (1 mL) and a 2M aqueous solution of sodium carbonate (1 mL, 2.0 mmol). The reaction mixture was then filtered through a plug of celite, rinsed with methanol and concentrated to dryness. Purification from silica gel eluting with a 50% solution of ethyl acetate and hexanes affords [2-fluoro-5-(1H-indazol-5-yl)phenyl](phenyl)methanone (187 mg, 0.6 mmol) 1H NMR (400 MHz, DMSO-D6) δ ppm 13.1 (s, 1 H) 8.1 (s, 1 H) 8.1 (s, 1 H) 8.0 (m, J=5.9 Hz, 1 H) 7.8 (m, J=7.5 Hz, 3 H) 7.7 (m, 2 H) 7.6 (m, 3 H) 7.5 (dd, J=9.1, 9.1 Hz, 1 H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>CN(C=O)C>[N:19]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(OCCBr)c1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCN2CCSCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-bromoethoxy)benzaldehyde (3.91 g, 17.07 mmol), K2CO3 (3.1 g), thiomorpholine (1.9 ml) and DMF (30 ml) was warmed on a steambath overnight. Additional K2CO3 (0.7 g) and thiomorpholine (1.0 ml) were added and the reaction mixture was warmed on a steam bath overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate was stripped to afford an amber oil. The oil was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with EtOAc (100%) to afford, as an oil, 3-[2-(4-thiomorpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([B:23]([OH:24])[OH:22])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C(C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a mixture of 2-(t-butyl)-4-bromoanisole (23.07 g, 0.0949 mol) in THF (238 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (65.3 mL, 1.6 M, 0.1044 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellowish residue solidified overnight. The solid was collected and washed with hexane and dried under high vacuum to afford 12.68 g of 3-(t-butyl)-4-methoxyphenyl boronic acid (64%). 1H NMR (300 MHz; DMSO-d6): δ 1.33 (s, 9H), 3.81 (s, 3H), 6.91 (d, J=7.8 Hz, 1H), 7.62–7.79 (m, 2H), 7.78 (brs, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N:3]1[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH:21]1([CH2:24][N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][N:3]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]2=[O:1])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)[nH]c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O

Procedure:
A stirred mixture of tert-butyl (2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetate from Step B (107 mg, 0.39 mmol), cyclopropylmethyl bromide (105 mg, 0.78 mmol), and cesium carbonate (153 mg, 0.47 mmol) in acetone (5 mL) was heated at reflux for 3 days. The reaction mixture was concentrated under reduced pressure, partitioned between brine and CH2Cl2, and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50 to provide the title compound. MS: m/z=273 (M-C4H7).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11](=[O:19])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([C:21]1[CH:22]=[CH:23][C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[C:10]=2[CH:20]=1)(=[O:30])[CH3:29]
Reactant: O=C1c2ccccc2CN(Cc2ccccc2)c2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(=O)c1ccccc1CN2Cc1ccccc1
Yield: 14.6 %

Procedure:
5,6-Dihydro-5-benzyl-11-oxodibenz[b,e]azepine (6.2 g), anhydrous aluminum chloride (6.07 g), acetyl chloride (4.87 g) and methylene chloride (60 ml) were treated in the same manner as described in Example 25 to obtain the desired compound (1.03 g).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([NH:44][C@H:45]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:46]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:46]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.2 %

Procedure:
6.5 ml of trifluoroacetic acid and 0.21 ml of trifluoromethanesulfonic acid were added to a suspension of 835 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 1.3 ml of anisole, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was first washed with hexane to remove the anisole and then mixed with diethyl ether. The mixture was cooled to -78° C., and the solidified product was broken up and separated by decantation. Several repetitions of this procedure yielded 940 mg of the title compound as a powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH2:25]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Product: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (89.3 mg, 0.5 mmol), 2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.86 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H), 2.57 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28]>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=c1[nH]cc(-c2cccnc2Cl)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cccnc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a suspension of 5-(2-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride salt (Prep95, 803 mg, 3.10 mmol) and K2CO3 (428 mg, 3.10 mmol) in DMF (15 ml), 90% 3-bromo-1,1dimethoxy-propane (516 μl, 3.41 mmol) was added in three portions over 5 days. The mixture was contemporarily stirred at room temperature. Solvent was then removed in vacuum at 40° C. The residue washed with petroleum ether and then with ethyl acetate. Ethyl acetate phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 400 mg of the final compound as a white solid (40% yield)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH2:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][NH:36][CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A3) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.