Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:3][CH:4]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:18][CH2:19][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:25]=2[CH2:26]1)([CH3:36])[CH3:35]
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)cc2)C(C)C)c1
Yield: 80.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[N:42]#[C:43]Br>O1CCOCC1.O>[NH2:42][C:43]1[O:22][C:21]([C:20]2[CH:19]=[C:18]([C@H:13]([CH:11]3[CH2:12][N:9]([C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:29]4[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:35]#[N:36])[CH2:10]3)[C:14]([F:17])([CH3:16])[CH3:15])[CH:27]=[C:26]([F:28])[CH:25]=2)=[N:23][N:24]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2nnc(N)o2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 53 mg (0.104 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl) methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide in 3 mL of dioxane, 11.4 mg (0.135 mmol) of NaHCO3 in 1 mL of water was added 13 mg (0.125 mmol) cyanogen bromide and the solution was stirred at rt. After 2.5 h, it was concentrated to remove solvents. The residue was dissolved in 20 mL of CH2Cl2 and 5 mL of water and the pH was adjusted to 7-8 with aq NaHCO3. The aqueous layer was extracted with CH2Cl2, and the combined organic layer was concentrated. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.28(d, 3H, J=22 Hz), 2.34 (br, 1H) 2.88 (br, 1H), 2.96 (m, 1H), 3.10 (dr, 1H), 3.24 (m, 1H), 3.63 (br, 1H), 4.27 (s, 1H), 5.50(s, 2H), 7.01-7.66 (m, 11H); Mass Spectrum: m/e=534 (M+1, 35Cl), 536 (M+1, 37Cl).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[N:11][C:4]=2[NH:3]1.[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2ccc(C(=O)O)nc2N1
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
This acid was prepared from 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (from Prep. 4 d) (890 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.1 g) in a DMF solution (50 mL). After 1.5 h at room temperature, dilution with water (50 mL), filtration and drying in vacuo afforded the acid as a white solid (750 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C([O-])(=[O:18])C.[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:18])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1O
Temperature: 80 °C
Yield: 81.3 %

Procedure:
A mixture of 10 g of 2,4-dichloro-5-nitrobenzotrifluoride, 4.15 g of potassium acetate and 60 ml of DMF was stirred while heating at 60° C. for one hour and at 80° C. for three hours. To the reaction mixture, 4.15 g of potassium acetate was added. The reaction mixture was stirred while heating at 80° C. for further one hour. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7.55 g of 5-chloro-2-nitro-4-trifluoromethylphenol.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.O>C1C=CC=CC=1>[CH2:1]([O:8][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Clc1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
7.6 g of benzylalcohol was dissolved in 65 ml of benzene, and 2.8 g of 60% sodium hydride was added little by little to the solution under stirring not so as to foam too much at room temperature. After the addition, stirring was continued for 10 min. at room temperature, followed by reflux for 1 hour. Subsequently, the solution was cooled to 50° to 60° C., and added dropwise with a solution of 10 g of 2,6-dichloropyrazine in 65 ml of benzene for 10 min. Then, after reflux for 4 hours, the reaction was finished. After cooling below 10° C., about 100 ml of water was added, and the separated benzene layer was collected. The residue obtained by distilling off the solvent was purified by silica-gel column chromatography (developing solvent: n-hexane and ethyl acetate) to obtain 12.8 g of 2-benzyloxy-6-chloropyrazine as a colourless oil (yield: 86.5%) nD25 1.5818.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][O:22]C3CCCCO3)[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Add 4-{4-bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (13.2 g; 0.029 mol; 1.0 equiv), p-toluene sulphonic acid (6.5 g; 0.034 mol; 1.2 equiv) to methanol (200 mL) and stir at RT for 30 min. Concentrate and partition between saturated NaHCO3 aqueous and EA. Evaporate the organic layer to give the title compound (10.0 g; 93%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][C:38]([OH:44])=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:45]>CO>[ClH:45].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41]([CH:40]=[CH:39][C:38]([OH:44])=[CH:37]3)=[CH:42][CH:43]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccc(O)cc3c2)C1
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 7-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidine-3-yloxymethyl]-naphthalen-2-ol hydrochloride (1:1) as an amorphous, beige foam; MS: 498 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH:7]([F:9])[F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.Cl.C>CC(N(C)C)=O>[C:21]1([C:19]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH:7]([F:9])[F:8])=[CH:28][CH:27]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(O)(C(=O)O)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1)C(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-difluoromethylpropionic acid (1.07 g, 7.65 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.91 g, 7.65 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Aminobenzophenone (1.0 g, 5.1 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured into hydrochloric acid solution (1M) and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (Na2SO4) and decolorization (Charcoal) the solution was evaporated in vacuo. A off-white foam was obtained which was triturated with hexane/ethyl acetate. The crude product was filtered through a short silica gel column with chloroform and crystallized from chloroform/hexane to give the title tertiary carbinol (0.89 g, 55%) as shiny, buff-colored crystals; mp=123°-124° C. 1H--NMR (300 MHz, d6 --DMSO): 1.45 (s, 3H, CH3), 6.17 (t, J=55 Hz, 1H, CHF2), 6.77 (s, 1H, OH), 7.56 (t, 2H, ArH), 7.65-7.76 (m, 5H, ArH), 7.96 (d, J=8.7 Hz, 2H, ArH), 10.19 (s, 1H, NH). MS (CI, CH4): 320(M+1, 100).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1CCCCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a stirred solution of 3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.03 mmol) and triethylamine (0.66 g, 6.53 mmol) at rt, was added phenyl chloroformate (0.94 g, 6.01 mmol). The reaction mixture was stirred at rt for 15 h. The reaction mixture was partitioned between a mixture of dichloromethane (20 mL) and water (20 mL) and the organic layer was washed thrice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow oil. Trituration with cyclohexane afforded phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.01 g, 63%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 6.71-7.55 (m, 10H), 6.18 (s, 1H), 1.92 (m, 1H), 0.91 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:36](OC(=O)C)(=O)[CH3:37].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>N1C=CC=CC=1>[CH3:36][C:37]1[O:23][C:22]([C:20]2[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)=[CH:12][CH:13]=3)[CH:21]=2)=[N:24][N:25]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1nnc(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3)c(-c3ccccc3C(F)(F)F)n2)o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a 0° C. solution of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (192 mg, 0.383 mmol) in 1 mL pyridine was added acetic anhydride (0.085 mL, 0.767 mmol). The ice bath was removed and the reaction stirred for 1 h. The solvent was removed in vacuo and approximately 3 mL of PPA was added to the flask. The reaction was heated to 120° C. for 2 h. Upon completion of the reaction 10 mL ice water was added to the reaction. The mixture was transferred to a 150 mL Erlenmeyer flask and neutralized with 2M Na2CO3. Solid NaCl was added the solution was extracted with ethyl acetate 3×20 mL. The combined organic layers were dried with MgSO4 and the solvent was removed in vacuo. The residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 2-methyl-5-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole (25 mgs, 13%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 8.53 (s, 1H), 8.15-8.14 (m, 1H), 8.05-8.02 (m, 1H), 7.93-7.90 (m, 1H), 7.88-7.83 (m, 3H), 7.75-7.71 (m, 3H), 7.69-7.66 (m, 1H), 7.41 (d, J=8.58 Hz, 2H), 3.28 (s, 3H), 2.58 (s, 3H); MS (ES): 525.0 [M+H]+ and 547.3 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.[F:12][C:13]([F:17])([F:16])[CH2:14]I>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:5]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: FC(F)(F)CI
Product: COC(=O)c1cccc(SCC(F)(F)F)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
3-(2,2,2-Trifluoroethylthio)benzoic acid methyl ester was prepared 3-mercaptobenzoic acid methyl ester and trifluoroethyl iodide by following Method C. The reaction was conducted at room temperature overnight. The crude residue was chromatographed in 10-20% EtOAc/hexanes to afford 3-(2,2,2-trifluoroethylthio)benzoic acid methyl ester (82% yield).
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:39]=[CH:38][C:11]([C:12]([NH:14][C:15](=[O:37])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:18]=2)=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15](=[O:37])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:13])=[CH:38][CH:39]=1)(=[NH:6])[NH2:7]
Reactant: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(=N)N)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(=N)N)cc2)cc1)C(=O)O

Procedure:
In a similar manner to Example 3, t-butyl 3-(4-[3-(4-amidinobenzoyl)ureido]phenyl)-2-(2-ethoxyethyl)propionate, acetate salt (82 mg), and trifluoroacetic acid (5 ml) were reacted to give the title compound (64 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.08 (3H, t), 1.70 (2H, m), 2.73 (3H, m), 3.35 (4H, m), 7.19 (2H, d), 7.48 (2H, d), 7.92 (2H, d), 8.18 (21H, d), 9.35 (4H, br s), 10.64 (1H, s), 11.25 (1H, br s), 12.05 (1H, br s); Mass Spectrum m/Z 427 (M+H)+ ; Elemental Analysis: calculated for C22H26N4O5. 1.4 CF3CO2H: C, 50.8%; H, 4.7%; N, 9.6%; found: C, 50.6%; H, 4.8%; N, 9.8%.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:27])([F:26])[C:10]([N:12]([CH2:19][P:20]([O:24]Cl)([O:22]Cl)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]>CCOCC>[F:8][C:9]([F:27])([F:26])[C:10]([N:12]([CH2:19][P:20]([O:24][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:22][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: NC1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONC1CCCCC1)ONC1CCCCC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of cyclohexylamine (14.6 g, 0.147 mole) in 100 ml. of ether was added dropwise with stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (11.55 g, 0.035 mole) in 200 ml. of ether. The reaction was stirred overnight at room temperature, then filtered and the filtrate concentrated in vacuo to yield a gum-solid. Upon trituration with petroleum ether, ethyl N-trifluoroacetyl-N-(bis(cyclohexylamino)phosphonomethyl)glycinate (6.65 g) was obtained as a white solid, m.p. 118.5°-123° C.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[O:24][CH3:23])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4OC)C3)c3ccccc3n2)c1
Yield: 11 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 49 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.92 and 3.15 (2t, 2H), 3.57 and 4.17 (2t, 2H), 3.82-3.98 (m, 9H), 4.47 and 5.07 (2s, 2H), 6.53 and 6.91 (2d, 1H), 6.72 and 7.02 (2d, 1H), 7.11-7.14 (m, 1H), 7.44-7.50 (t, 1H), 7.63-7.69 (m, 1H), 7.98-8.09 (m, 2H), 8.29-8.38 (m, 3H); MS (ESI) m/z 456 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[S:22][CH:23]=[N:24][N:25]=1>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Brc1nncs1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: Cc1c(C)c(N2CCN(c3nncs3)CC2)c(C)c2c1OC(C)C2
Yield: 13.9 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 2-bromo-1,3,4-thiadiazole (165 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesis the title compound 24 mg (yield 14%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1c(F)ccc(F)c1F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)ccc(F)c4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 262. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.91 (s, 1H), 7.66-7.53 (m, 3H), 7.37-7.26 (m, 1H), 5.08 (t, J=5.6 Hz, 1H), 3.92-3.71 (m, 2H), 3.69 (s, 3H), 3.46-3.33 (m, 1H), 3.33-3.21 (m, 1H), 3.02 (s, 3H), 2.47-2.35 (m, 1H), 1.76-1.63 (m, 1H), 1.62-1.50 (m, 2H). LCMS (ES+) m/z 497 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[N:5][C:4]=1[Cl:8])[CH3:22]
Reactant: Clc1cc(Br)ccn1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Br)ccnc1Cl
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
To a solution of 4-bromo-2-chloropyridine (21.2 mmol) in 60 mL THF was added dropwise 11.7 mL of a solution of LDA (2M in THF) at −78° C. After stirring at −78° C. for 35 min, a solution of ethyl chloroformate (20.7 mmol) in 5 mL THF was added and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (8/2) gives the desired product as brown oil;
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:1][N:2]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:28]([C:26]2[N:27]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:24][C:25]=2[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:7][CH:8]=1
Reactant: CC(C)CCN(C)c1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 7.6 %

Procedure:
Methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine (110 mg, 0.49 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (138 mg, 0.54 mmol), Et3N (352 uL, 2.5 mmol) and BOP (227 mg. 0.514 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl}-amide as a light purple solid (16 mg). ES-MS calcd for C22H23F3N4O2 (m/e) 432.51, obsd 433.2 M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22]CC3C=CC=CC=3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 207 mg (0.418 mmol) of rac-[1-{[7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl]amino}methyl}-1-methylbutyl)carbamic acid tert-butyl ester (Example 140A) in 6 ml of absolute ethanol was admixed with 47 mg of palladium on charcoal (loading 10% by weight, activated) and 1.3 ml of cyclohexene. The reaction mixture was heated to reflux under an argon atmosphere for 2.5 hours. The resulting mixture was cooled to room temperature, filtered through a layer of Celite and concentrated under reduced pressure, which gave 206 mg (99% yield, 81% pure) of the target compound.