Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28]([CH3:31])=[N:29][N:30]=[C:10]12)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][CH:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28]([CH3:31])=[N:29][N:30]=[C:10]12
Reactant: [H][H]
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2O

Procedure:
44.6 g of 4-(benzyloxy)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 400 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 mole of hydrogen has been absorbed, the reaction is stopped, filtered and the solvent evaporated. The residue is triturated in ether and the title compound filtered off and dried.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CC#N>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CSc2ccccc21
Temperature: 40 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.080 g, 0.231 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (104KS32-2) (0.050 g, 0.276 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50+1% Et3N) to give the title compound (108LM52-49) (0.045 g, 49%). 1H NMR (CDCl3) δ 7.36 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 4.16 (d, J=7.3 Hz, CH2), 3.34 (s, CH2), 3.10-2.95 (m, 2H), 2.25-2.17 (m, 1H), 2.15-2.03 (m, 3H), 1.94-1.75 (m, 3H), 1.70-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1,40-1.15 (m, 10H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.1, 139.2, 128.7, 127.1, 124.7, 123.4, 119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31,4, 29.9, 28.5, 28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:5]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: OCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCl
Reaction time: 4 h

Procedure:
t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in 25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithium was added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3 mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. After addition of water and extraction with hexane, the product was purified by chromatography on silica gel with 1:3 dichloromethane-hexane, providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil (6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0M tetrabutylammonium fluoride in THF was added. After 3 hr, the mixture was acidified with 1N HCl, extracted with three portions of ethyl acetate, and the extracts dried over magnesium sulfate and evaporated in vacuo. The product was purified by chromatography on silica gel with a 10%-20% gradient of ethyl acetate in hexane, providing the title compound as a white solid, 3.83 g (63% overall).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH2:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3N)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccccc2N)CC1
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of {4-[1-(2-amino-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (178 mg, 0.367 mmol) in THF 8.0 mL) was added a solution of lithium hydroxide monohydrate (176 mg, 7.35 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for 15 hours under nitrogen. The solvent was removed under vacuum and the aqueous solution was diluted with water and slowly neutralized with 1.0 N HCl until the pH was between 5 and 6. The resulting precipitated solids were collected by filtration and washed with water and hexanes. After drying in the air, {4-[1-(2-amino-phenylmethane-sulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (159 mg, 92%) was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s, 1H), 7.86 (dd, J=8.85, 6.59 Hz, 1H), 7.61 (s, 1H), 7.31 (t, J=7.91 Hz, 1H), 7.18 (d, J=7.35 Hz, 1H), 6.99-7.12 (m, 2H), 6.68-6.78 (m, 1H), 6.53-6.67 (m, 1H), 5.14 (br. s, 2H), 4.28-4.51 (m, 4H), 3.76 (d, J=10.93 Hz, 2H), 3.61 (br. s, 5H), 2.41 (br. s, 3H), 1.66 (d, J=11.49 Hz, 2H). MS cald. for C25H26FN2O4S [(M−H)−] 469, obsd. 469.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:10](=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-:23].[Cs+].[Cs+]>CN(C=O)C>[C:5]([O:23][C:22]([N:16]1[CH2:17][CH2:18][CH:19]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([CH3:14])=[N:12][N:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[C:10](=[O:21])[CH:9]=3)=[CH:4][CH:3]=2)[CH2:20][CH2:15]1)=[O:25])([CH3:8])([CH3:6])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(-c2ccccn2)c(=O)cc1-c1ccc(O)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c(=O)cc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
A mixture of 5-(4-hydroxyphenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one (97.7 g, 28 mmol), t-butyl 4-methanesulfonyloxypiperidine-1-carboxylic acid ester (15 g, 55 mmol) and cesium carbonate (18 g, 55 mmol) in 75 mL of DMF was stirred at 100° C. overnight. The reaction mixture was cooled to rt, filtered through celite, and concentrated. The crude product was diluted with 100 mL of CH2Cl2, washed with 2N NaCO3, water, NaCl solution, then dried over Na2SO4, and concentrated. The product was purified by flash chromatography (5% MeOH in CH2Cl2) and triturated with EtOAc and hexane to give 4-[4-(3-methyl-6-oxo-1-pyridin-2-yl-1,6-dihydropyridazin-4-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 72%): MS m/z 463 (M+H).
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[N-:21]=[N+:22]=[N-:23].[Li+]>CS(C)=O>[C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:21]=[N+:22]=[N-:23])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CCl)c1
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step A (13.52 g, 42.80 mmol) in 50 mL of dimethylsulfoxide under nitrogen was added lithium azide (2.3 g, 47.10 mmol). The solution was stirred for 2 h. The reaction mixture was then partitioned with 300 mL of ethyl acetate and 200 mL of water. The ethyl acetate layer was washed with 125 mL of saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil. 1HNMR (300 MHz, CDCl3)δ7.75 (2H, m), 7.47 (2H, m), 7.02 (1H, d, J=8 Hz), 4.94 (1H, q, J=5 Hz), 4.41 (2H, s), 3.80 (3H, s), 2.60 (2H, t, J=6 Hz), 2.30 (1H, m), 2.15 (1H, m), 2.11 (3H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[S:13][CH2:14][CH2:15][C:16](O)=[O:17].ClC(OCC)=O.N1C=CC=CC=1>O1CCCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:12]1[C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[NH:2][C:16](=[O:17])[CH2:15][CH2:14][S:13]1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(SCCC(=O)O)c1ccccc1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CCSC(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1

Procedure:
By cyclizing 3-[(2-amino-5-nitrophenyl)(2-chlorophenyl)methylthio]propionic acid hydrochloride in analogy to Example 1(c), but in tetrahydrofuran and using ethyl chloroformate and pyridine, there is obtained 6-(2-chlorophenyl)-1,3,4,6-tetrahydro-8-nitro-2H-5,1-benzothiazocin-2-one of melting point 285°.
Reaction SMILES: [ClH:1].Cl.N1([CH2:9][CH:10]([C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)CCNCC1.FC(F)(F)OC1C=C(C2C=CC=C(C(C3(O)CCCCC3)C[N:52]3[CH2:57][CH2:56][N:55](C(OC(C)(C)C)=O)[CH2:54][CH2:53]3)C=2)C=CC=1>>[ClH:1].[ClH:1].[N:52]1([CH:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]2([CH:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:25])[F:27])[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:9])[OH:34])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1
Reactant: OC1(C(CN2CCNCC2)c2cccc(-c3cccc(OC(F)(F)F)c3)c2)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3cccc(OC(F)(F)F)c3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CC(c1cccc(-c2cccc(OC(F)(F)F)c2)c1)C1(O)CCCCC1N1CCNCC1

Procedure:
In an analogous manner to Example 135, step 4 1-{2-piperazin-1-yl-1-[3′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(3′-trifluoromethoxy-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 449; HRMS: calcd for C25H31F3N2O2+H, 449.24159; found (ESI, [M+H]+), 449.2434.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:15])([CH2:7][C:8]1([CH3:14])[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH2:4][CH2:5][CH3:6].C(O[Cl:21])(C)(C)C>CO>[Cl-:21].[Cl:1][N:9]1[C:8]([CH2:7][N+:3]([CH3:2])([CH3:15])[CH2:4][CH2:5][CH3:6])([CH3:14])[CH2:12][O:11][C:10]1=[O:13]
Reactant: CC(C)(C)OCl
Reactant: CCC[N+](C)(C)CC1(C)COC(=O)N1
Agent: [Cl-]
Solvent: CO
Product: CCC[N+](C)(C)CC1(C)COC(=O)N1Cl
Yield: 15 %

Procedure:
To a solution of N,N-dimethyl-N-((4-methyl-2-oxooxazolidin-4-yl)methyl)propan-1-aminium chloride (6.51 mmol) in MeOH (5 ml) was added, dropwise, tert-butylhypochlorite (˜2.5 ml) until the reaction mixture was clear with white precipitate. The solution was filtered through a 0.45 μm nylon filter, then evaporated and purified on preparative HPLC (H2O/MeOH) to afford the title compound as a white foam (248.1 mg, 0.9648 mmol, 15% over two steps). 1H NMR (D2O, 400 MHz) δ 0.99 (t, J=7.2 Hz, 3H), 1.64 (s, 3H), 1.8-2.0 (m, 2H), 3.24 (s, 3H), 3.26 (s, 3H), 3.40-3.45 (m, 2H), 3.75 (d, J=15.2 Hz, 1H), 3.82 (d, J=15.2 Hz, 1H), 4.62 (d, J=9.6 Hz, 1H), 4.90 (d, J=9.6 Hz, 1H). ESI/APCI expected for C10H20ClN2O2+: 235.12. Found: 235.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
Separately, thionyl chloride (5 ml) is added to 4-fluorobenzoic acid (1.2 g) and the mixture is warmed at 60° C. for 3 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain 4-fluorobenzoyl chloride. To this chloride is added a solution of trans-4-(4'-heptylphenyl)cyclohexanol obtained above (2 g) in pyridine (2 ml) and toluene (50 ml), followed by vigorous shaking. The resulting reaction liquid is allowed to stand at room temperature overnight, followed by pouring it into water (50 ml) and further adding toluene (50 ml) to carry out extraction. The toluene layer is washed with 6N hydrochloric acid and then with 2N aqueous solution of sodium hydroxide, followed by washing with water until the layer becomes neutral, drying over anhydrous sodium sulfate and distilling off toluene under reduced pressure. The residual oily substance is recrystallized from ethanol to obtain the objective 4-fluorobenzoic acid trans-4-(4"-heptylphenyl)cyclohexyl ester. Yield: 2.6 g, 90.0%, C-Sm: 62.0°-62.3° C., Sm-N point: 78.4° C., N-I point: 102.1°-102.7° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (1.0 g, 0.0041 mol) and 1,1'-carbonyldiimidazole (1.35 g, 0.0082 mol) in dimethylformamide (10 ml) is heated at 95°-100° C. with stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.42 g, 0.0041 mol) is added and the resulting mixture is heated at 100° C. for 1-5 hours. The precipitate is filtered off, washed with tetrahydrofuran and recrystallized from dimethylformamide to give the product (0.6 g.), mp 295°-296° C.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]([OH:24])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:10]=1)=O.C(Cl)Cl.N>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]([CH:21]([CH3:23])[CH3:22])([OH:24])[CH:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)C(O)(C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(O)(C#Cc1cccc(CCCN)c1)C(C)C

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenyl)propyl)acetamide following the method used in Example 2 followed by flash chromatography (9:1 CH2Cl2: 7 M NH3 in MeOH) gave 1-(3-(3-aminopropyl)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol as a clear oil. Yield (0.835 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 7.15-7.26 (m, 4H), 4.82 (br s, 1H), 2.56 (t, J=7.6 Hz, 2H), 2.47-2.52 (m, 2H), 1.86 (quint, J=6.8 Hz, 2H), 1.59 (quint, J=6.8 Hz, 2H), 1.56 (br.s, 2H), 1.05 (d, J=6.8 Hz, 6H), 1.03 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[N:46]=[C:47]([NH2:49])[CH3:48]>CN1C(=O)CCC1>[F:29][C:20]1[CH:21]=[C:22]([C:23]2[O:25][N:49]=[C:47]([CH3:48])[N:46]=2)[CH:26]=[C:27]([F:28])[C:19]=1[C:14]1[C:13](=[O:30])[CH:12]=[CH:11][N:10]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:9]2[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC(N)=NO
Reactant: O=C(O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: Cc1noc(-c2cc(F)c(-c3c(=O)ccn4c(-c5ccc(F)cc5F)cccc34)c(F)c2)n1
Temperature: 90 °C

Procedure:
A solution of 4-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-3,5-difluorobenzoic acid (Example 38, 50 mg, 0.12 mmol) in NMP (1.2 mL) was added EDC (46 mg, 0.24 mmol), and HOBT (24 mg, 0.18 mmol) at room temperature. The reaction was stirred at room temperature for 30 minutes before N′-hydroxyethanimidamide was added. The reaction was heated to 90° C. for 6 hours and yielded an 80% conversion of product via LCMS. The reaction was quenched with NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 0.5 N HCl, water, brine, dried over MgSO4, and concentrated. The residue was purified via silica gel chromatography (100% EtOAc) to give the title compound (9 mg).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)(=[O:18])[CH3:17].Cl>CN(C)C=O>[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][S:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])(=[O:18])[CH3:17]
Reactant: N#Cc1cccc(S)c1
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.7 %

Procedure:
3-Mercaptobenzonitrile (0.40 g) and potassium carbonate (0.61 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added 4-bromobutyl acetate (0.63 g), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/5) to give the title compound (0.75 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[N:3]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=[C:7]([N:4]4[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: Cc1ccn(-c2cc(N)cc(C(F)(F)F)c2)n1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4ccc(C)n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (250 mg, 1.036 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.036 mmol) in pyridine (5 mL) was added T3P® (3298 mg, 5.18 mmol) in portions. The mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (280 mg, 0.357 mmol, 34.5% yield). 1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.50-7.43 (m, 3H), 7.41 (d, J=9.0 Hz, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.36 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:22](=[O:29])[CH:23]=[C:24]([OH:28])[C:25]([OH:27])=[O:26].[Li+].[OH-]>CO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:22](=[O:29])[CH:23]=[C:24]([OH:28])[C:25]([OH:27])=[O:26])=[CH:6]2)=[CH:17][CH:16]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2cc(C(=O)C=C(O)C(=O)O)c3cc(Cl)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
To a solution of 82 mg (0.2 mmol) of 4-[5-chloro-1-(4-methoxycarbonylbenzyl)indol-3-yl-]2-hydroxy-4-oxo-2-butenoic acid, prepared in a manner similar to that described in Example 23, in 75% MeOH (35 ml) was added 42 mg (1.0 mmol) of LiOH. After the mixture was stirred for 5 hours at room temperature, the solvent was removed under reduced pressure. The residue was acidified with 1 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was evaporated and the residue was recrystallized from ethyl acetate/ether to give 63 mg of the titled compound. Yield: 79%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:48][CH2:49]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1

Procedure:
The title compound was prepared [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (391 mg, 82%).