Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1>CN(C)C=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N(N=C(c2ccccc2)c2ccccc2)C(=O)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-chilled solution of 1-(diphenylmethylene)-2-p-tolylhydrazine (270 mg, 0.94 mmol; Example 36A) and N,N-diisopropyl-N-ethylamine (120 mg, 0.94 mmol; Aldrich) in N,N-dimethylformamide (2.0 mL) was added 2-(4-chlorophenyl)acetyl chloride (178 mg, 0.94 mmol; Alfa Aesar). After 10 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight (18 hours). The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was carried on to the next step without further purification: LC/MS m/z 439 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]([CH3:18])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:29]#[C:28][C@@:26]([OH:30])([C:23]4[CH:22]=[C:21]([CH3:20])[O:25][N:24]=4)[CH3:27])[CH:15]=[CH:16][C:11]=3[N:10]([CH3:18])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: Cn1c(=O)n(-c2ccnc(N)n2)c2cc(Br)ccc21
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)n(-c2ccnc(N)n2)c(=O)n3C)no1

Procedure:
The title compound was prepared by the method described in Step 2 of Example 142-b by reacting 3-(2-aminopyrimidin-4-yl)-5-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.82 (3H, s), 2.40 (3H, s), 3.38 (3H, s), 6.38 (1H, s), 6.44 (1H, s), 6.97 (2H, s), 7.33-7.22 (2H, m), 7.42 (1H, d, J=5.6 Hz), 8.32 (1H, d, J=5.6 Hz), 8.38 (1H, s); LC-MS: m/z=+391 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:20]=1[C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1>CO.O.[Pd]>[CH3:28][C:24]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
2-(N-benzyloxycarbonyl-L-valyl)amino-6methylbenzoic acid (1.21 g) was dissolved in a mixture of methanol (99 ml) and water (1 ml), and 10% Pd-C (200 mg) was added to the solution. The mixture was stirred under a hydrogen atmosphere at room temperature for three hours. After Pd-C was removed by Hyflo-Super-Cel, the filtrate was concentrated to obtain 830 mg of 6-methyl-2-(L-valylamino)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 11 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (11%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH:16]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13]
Reactant: COC(C=O)OC
Reactant: COc1ccc(F)c(CCN)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(CCNCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2-fluoro-5-methoxy-phenyl)-ethylamine (4.30 g, 25.4 mmol, 1.0 eq.) in MeOH (100 mL), glyoxal dimethyl acetal (60% aqueous solution, 5.73 g, 33.0 mmol, 1.3 eq.) was added. The resulting yellow solution was stirred at r.t. for 18 hours. The yellow solution was cooled to 0° C. and sodium borohydride (1.44 g, 38.1 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the yellow solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and DCM (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give N-(2-fluoro-5-methoxyphenethyl)-2,2-dimethoxyethanamine. The product was used without further purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:19])[CH3:16].[O:30]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:24]=[CH:25][C:26]([NH:29][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:38]=2)=[CH:27][CH:28]=1)=[O:19])[CH3:16]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added to a solution of (−)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1a) (0.116 g, 0.56 mmol) and 3-phenoxybenzaldehyde (1.15 g, 0.56 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour and then partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography (silica gel, hexane:ethyl acetate) to give (−)-(trans)-ethyl-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate (III-2a) (0.167 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 3H), 7.11 (t, J=7.32 Hz, 2H), 7.02 (m, 1H), 6.99 (d, J=8.60 Hz, 2H), 6.92 (d, J=8.42 Hz, 2H), 6.89 (m, 1H), 6.54 (d, J=8.60 Hz, 2H), 4.19 (s, 2H), 4.17 (q, J=7.14 Hz, 2H), 4.03 (br s, 1H), 2.44 (m, 1H), 1.78 (m, 1H), 1.52 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 388 (MH+). Aqueous sodium hydroxide (1.0 mL of a 25% solution) was added to a solution of III-2a (0.167 g, 0.43 mmol) in 4 mL of methanol and the mixture was heated at reflux for 8 hours. The volatile solvents were removed under vacuum, water was added, and the pH was adjusted to 5 with saturated aqueous sodium bisulfate. The mixture was extracted with dichloromethane, the organic phase was dried over sodium sulfate and concentrated to give 0.192 g of the title compound (III-3a) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.34 (t, J=8.42 Hz, 2H), 7.29 (t, J=7.87 Hz, 1H), 7.10 (m, 2H), 6.98 (s, 1H), 6.93 (d, J=7.68 Hz, 2H), 6.81 (d, J=8.42 Hz, 1H), 6.75 (d, J=8.23 Hz, 2H), 6.42 (d, J=8.42 Hz, 2H), 6.08 (m, 1H), 4.20 (m, 2H), 2.02 (m, 1H), 1.44 (m, 1H), 1.15 (m, 1H), 0.91 (m, 1H). ES-MS m/z 360 (MH+). [α]25,D=−187° (dichloromethane, c=4). Product was determined to be >99% ee by chiral SFC according to Method 1.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C1OCCOC1>[Cl:16][C:17]1[CH:22]=[C:21]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Ic1ccc2ncnc(NC3CC3)c2c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Clc1cccc(-c2ccc3ncnc(NC4CC4)c3c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To an 8 mL screw-cap vial was added N-cyclopropyl-6-iodo-quinazolin-4-amine (0.25 mmol 78 mg), (3-chlorophenyl)boronic acid, (1.2 equiv., 0.30 mmol, 47 mg), 1-4 dioxane (0.6 mL), potassium phosphate tribasic, (2M in H2O, 3 equiv., 0.75 mmol, 0.0.38 mL), and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(11) (0.05 equiv.; 0.013 mmol, 9 mg). The reaction was capped and shaken at 60° C. for 1 h. The reaction was cooled to room temperature and the phases separated. Organic phase was then concentrated. Crude was purified by reverse phase HPLC yielding 35 mg of product. 1H NMR (400 MHz, DMSO) δ 8.60-8.49 (m, 2H), 8.44-8.35 (s, 1H), 8.18-8.05 (d, J=8.7, 1H), 7.93-7.87 (s, 1H), 7.84-7.71 (m, 2H), 7.62-7.51 (t, J=7.9 Hz, 1H), 7.51-7.43 (d, J=8.4 Hz, 1H), 3.12-2.98 (m, 1H), 0.90-0.78 (m, 2H), 0.72-0.64 (m, 2H). LCMS M/Z (M+H)=296.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[Si:23]([O:40][CH2:41][CH:42]([NH:45][C:46]([NH:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1)=[O:47])[CH2:43]O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1>ClCCl>[Si:23]([O:40][CH2:41][C:42]1[NH:45][C:46](=[O:47])[N:48]([CH:49]2[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]2)[CH:43]=1)([C:36]([CH3:39])([CH3:37])[CH3:38])([C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(CO)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[nH]c2=O)CC1
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Dess-Martin periodinane (53 mg, 0.126 mmol) was added to a solution of tert-butyl 4-[({[2-{[tert-butyl(diphenyl)silyl]oxy}-1-(hydroxymethyl)ethyl]amino}carbonyl)amino]piperidine-1-carboxylate (50 mg, 0.090 mmol) in dichloromethane (20 mL) at 0° C. After 4 h, the reaction was quenched with a 1:1 mixture of saturated sodium thiosulfate and sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated. Purification by silica gel chromatography (100% dichloromethane→9% methanol {1% ammonium hydroxide)/dichloromethane} gave the title compound (25 mg). MS 536.3 (M+1)
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:1][C@@H:3]3[CH2:5][C@@:4]3([CH2:12][N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2R)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.69-7.55 (m, 5H), 7.36-7.18 (m, 10H), 4.08 (s, 2H), 3.91 (d, J=13.2 Hz, 1H), 3.08-2.98 (m, 2H), 2.81 (d, J=13.2 Hz, 1H), 2.84-2.78 (m, 1H), 2.59-2.43 (m, 2H), 2.52 (s, 3H), 2.27-1.97 (m, 4H), 1.80-1.66 (m, 2H), 1.45-1.39 (m, 1H), 1.09-0.99 (m, 1H), 0.80 (m, 1H). ES-LCMS m/z 557.2 (M+H).
Reaction SMILES: [ClH:1].C([O:10][CH2:11][CH:12]1[CH:15]2[C:16]3[C:21]([CH2:22][CH2:23][N:14]2[CH2:13]1)=[CH:20][C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)(=O)C1C=CC=CC=1.Cl>C(O)C>[ClH:1].[OH:10][CH2:11][CH:12]1[CH:15]2[C:16]3[C:21]([CH2:22][CH2:23][N:14]2[CH2:13]1)=[CH:20][C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3
Reactant: COc1cc2c(cc1OC)C1C(COC(=O)c3ccccc3)CN1CC2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)CN1CC2
Yield: 61 %

Procedure:
0.01 mole (3.22 g) of 1-(benzoyloxymethyl)-7,8-dimethoxy-1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinoline hydrochloride is boiled in a mixture of 50 ml of a 5% hydrochloric acid solution and 20 ml of ethanol for 2 hours. The mixture is evaporated and the evaporation residue is triturated with ether to yield the aimed compound with a melting point (after recrystallization from ethanol) of 219° to 221° C. (decomp.).
Reaction SMILES: [Si](OC(C1OC(I)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.[Si]([O:35][CH:36]([C:49]1[O:50][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:52][N:53]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.FS(C(C(OC)=O)(F)F)(=O)=O.[NH4+].[Cl-]>CN(C=O)C.[Cu]I>[C:43]1([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([C:49]2[O:50][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:52][N:53]=2)=[O:35])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C(F)(F)F)o1
Agent: [Cu]I
Agent: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(I)o1
Agent: COC(=O)C(F)(F)S(=O)(=O)F
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(CCCCCCc1ccccc1)c1ncc(C(F)(F)F)o1
Temperature: 70 °C
Yield: 76.8 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(trifluoromethyl)oxazole 2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-iodooxazole (24 mg, 0.048 mmol), HMPA (5 equiv), CuI (1.2 equiv) and FSO2CF2CO2CH3 (5 equiv) were dissolved in DMF (1 mL) and heated to 70° C. in a sealed vial for 5 h. The mixture was cooled to room temperature, saturated aqueous NH4Cl was added and the aqueous layer was extracted with ether. The ether layer was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl and dried over sodium sulfate. Flash chromatography (0-2% EtOAc/hexanes) yielded the title compound as a light yellow oil (12 mg, 55%): 1H NMR (CDCl3, 600 MHz) δ 7.38 (s, 1H), 7.28-7.25 (m, 2H), 7.18-7.15 (m, 3H), 4.81 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.8 Hz), 1.90-1.82 (m, 2H), 1.61-1.59 (m, 2H), 1.43-1.33 (m, 6H), 0.87 (s, 9H), 0.07 (s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 168.5, 143.6, 140.5 (d, J=45 Hz), 129.2, 129.1, 128.8 (d, J=2.7 Hz), 126.5, 119.7 (d, J=265 Hz), 69.3, 37.0, 36.8, 32.2, 29.9, 26.5, 26.5, 25.8, 19.0, −4.4, −4.4.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:27])[C:24]([OH:26])=O)[CH:20]=[CH:21][CH:22]=1.[CH3:28][C:29]([CH3:32])([NH2:31])[CH3:30].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]([NH:31][C:24](=[O:26])[CH:23]([OH:27])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)([CH3:32])[CH3:30]
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1

Procedure:
Dicyclohexylcarbodiimide (11.05 g) was added in portions to a cooled, stirred mixture of 3-chloro-α-hydroxybenzeneacetic acid (10 g), 1,1-dimethylethanamine (3.92 g, 5.63 ml) and 1-hydroxybenzotriazole (7.24 g) in dry dimethylformamide (100 ml). The mixture was stirred at ambient temperature for 20 h., filtered and the filtrate evaporated. The residual oil was taken up in ethyl acetate, filtered, and the filtrate washed sequentially with sodium carbonate solution, hydrochloric acid (2N) and water. The organic layer was dried (MgSO4), filtered, and evaporated to an oil which was chromatographed on silica. Elution with chloroform gave N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzeneacetamide, 1.71 g, as an oil which crystallized in standing, m.p. 93°-99° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=3[O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:20])[CH2:4]1>C1COCC1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=4[O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:20])[C:6]=2[CH:7]=1
Reactant: COc1cc(OCCN(C)C)c2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1cc(OCCN(C)C)c2[nH]c(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)cc2c1
Yield: 123.5 %

Procedure:
A solution of 14g (120 mg, 0.23 mmol) in THF (45 mL) was hydrogenated over PtO2 (30 mg) at 55 psi for 1.5 h. After removal of the catalyst the solution was concentrated to a small volume under reduced pressure below 30° C., and then diluted with petroleum ether to give 15g (140 mg. 92%), mp 109-111 (C. 1H NMR [(CD3)2SO] δ 11.41 (s, 1 H, NH), 8.07 (d, J=8.8 Hz, 1 H, H-6), 7.75 (d, J=8.2 Hz, 1 H, H-9), 7.64 (s, 1 H, H-4), 7.45 (t, J=7.5 Hz, 1 H, H-8), 7.28 (t, J=7.6 Hz, 1 H, H-7), 7.00 (d, J=1.2 Hz, 1 H, H-3'), 6.73 (d, J=1.9 Hz, 1 H, H-4' or 6'), 6.48 (d, J=2.0 Hz, 1 H, H-4'or 6'), 5.98, 5.96 (2×s, 2 H, NH2), 4.66 (dd, J=10.7, 9.0 Hz, 1 H, H-2), 4.41 (dd, J=11.0, 1.4 Hz, 1 H, H-2), 4.19 (t, J=5.7 Hz, 2 H, OCH2), 4.12-4.04 (m, 1 H, H-1), 3.96 (dd, J=10.9, 3.0 Hz, 1 H, CHHCl), 3.77 (s, 3 H, OCH3), 3.72 (dd, J=11.0, 8.2 Hz, 1 H, CHHCl), 2.73 (t, J=5.7 Hz, 2 H, OCH2CH2), 2.28 (s, 6 H, N(CH3)2).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13]Br>>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C)cc1
Reactant: BrBr
Product: CCOC(=O)c1ccc(CBr)cc1

Procedure:
An ethyl 4-methylbenzoate (EMB) solution (1134 g in chlorobenzene (CB), ~43 wt. %, 2.93 mol) was charged into a 2-Liter round bottomed flask equipped with mechanical stirrer (300 RPM stirring rate) and a cooling condenser, and heated. The temperature controller was set at 140° C., and a scrubber was connected to the condenser. Liquid bromine (275 g, 1.72 mol or ~59 mol %, Aldrich, 99.5+%, A.C.S. reagent) was fed via Viton tubings, and the bromine feed rate was adjusted to 1.00 mL/minute for the first 30 mol % of bromine and then to 0.50 mL/minute for the rest of the addition at 140° C. Heating and stirring was continued for a few minutes after all bromine was added and the hot mixture was purged with nitrogen for 20 minutes, then allowed to cool to obtain 1183 g crude reaction mixture (some materials were used for routine analysis). The GC wt. % analysis of the crude reaction mixture indicated the following:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: Nc1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)Nc2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 ml) was added 2-aminoquinoline (64 mg, 0.44 mmol), EDAC (93 mg, 0.48 mmol), HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([O:17]C)=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[OH-].[Na+].Cl>O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:3]=1
Reactant: COC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)O)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Methyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 11) (32.9 g, 0.1 mol) was added into a solution of NaOH (8.0 g, 0.2 mol) in water (250 mL) prepared in advance, and reacted by stirring at room temperature overnight. After filtration the filtrate was transferred into reaction flask and pH value was adjusted to 6-6.5 with hydrochloric acid (6N) when the temperature is controlled between 20° C. and 25° C. Grew the grain by stirring for 2 h, and then filtrated and dried to give Compound 12 (21.2 g, yield: 78.3%).