Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH3:2].[NH2:20]C(N)=S>CN(C=O)C.ClCCl>[CH3:2][C:1]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:20]=1
Reactant: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: NC(N)=S
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 160 °C
Yield: 74 %

Procedure:
2-Oxo-1,2-diphenylethyl acetate 24 (0.20 g, 0.79 mmol) was dissolved in DMF (10 mL). Thiourea was then added and the reaction was refluxed (160° C., oil bath) under nitrogen atmosphere. As the reaction progressed, the color changed from colorless to a light yellow-orange and had an odorous smell. The reaction was monitored by TLC and when complete, the reaction mixture was dissolved in dichloromethane (40 mL) and then washed with water (3×30 mL). The dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the drying agent by filtration and rotary evaporation of the solvent gave a crude oil that was purified by flash chromatography on silica gel (dichloromethane) to provide 25 (74%): Rf: 0.098 (hexane/ethyl acetate, 2:1); FTIR 2920.50; 1220.30; 1502.00, 1588.24 cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.617 (s, 3H); 7.25-7.66 (m, 10H, aromatic); 13C NMR (100 MHz, CDCl3) δ 160.35, 145.41, 134.82, 126.46-132.14, 13.92; HRMS calcd for C16H13NO (M+H)+ 236.1075, Found: 236.1077.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][NH:34][CH2:35][C@@H:22]23)[CH:27]=1>>[CH:3]1([CH2:2][N:34]2[CH2:33][CH2:32][C@@H:23]3[N:24]4[CH2:31][CH2:30][O:29][CH2:28][C:26]5[CH:27]=[C:19]([NH:18][C:9]6[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=6[F:7])[CH:20]=[C:21]([C:25]4=5)[C@@H:22]3[CH2:35]2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Product: Fc1c(Nc2cc3c4c(c2)[C@@H]2CN(CC5CCC5)CC[C@@H]2N4CCOC3)cccc1C(F)(F)F

Procedure:
Using bromomethylcyclobutane and following the procedures described in EXAMPLE 144, (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 was converted into the title compound of EXAMPLE 145. 1H NMR(CDCl3) δ: 7.15 (dd, 1H, J=7.8, 6.8 Hz), 7.05-6.95 (m, 2H), 6.89 (d, 1H, J=1.9 Hz), 6.77 (d, 1H, J=2.0 Hz), 5.73 (d, 1H, J=3.0 Hz), 4.63 (ABq, 2H, JAB=14.1 Hz), 4.24 (app d, 1H, J=12.8 Hz), 3.75 (app t, 1H), 3.50-3.30 (m, 2H), 3.25 (dd, 1H, J=13.1, 2.8 Hz), 2.95-2.30 (overlapping multiplets, 7H), 2.15-1.65 (overlapping multiplets, 9H). LRMS (ES)+: 476.4 (M+H)+.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:51]([C:54]([CH3:67])([CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55](O)=[O:56])(=[O:53])[CH3:52]>>[C:51]([C:54]([CH3:67])([CH2:58][CH2:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]([NH:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:56])(=[O:53])[CH3:52]
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Reactant: CC(=O)C(C)(CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(C)(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
The amount of 2-acetyl-2-methyl-5-phenylpentanoic acid in 20 ml dichloromethane from Example 38A is reacted analogously to Example 39A with 300 mg (2.20 mmol) of 1-hydroxy-1H-benzotriazole, 670 mg (6.60 mmol) of 4-methylmorpholine, 420 mg (2.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 620 mg (2.14 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-methyl-5-phenyl-pentanamide.
Reaction SMILES: [CH:1]1([N:4]([CH3:17])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][Si](C)(C)C)[CH:6]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=2)[CH3:17])[CH2:2][CH2:3]1
Reactant: CN(c1cccc(C#C[Si](C)(C)C)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(N(C)C2CC2)c1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
A solution of cyclopropyl-methyl-(3-trimethylsilanylethynyl-phenyl)-amine (Intermediate 114, 0.05 g, 0.2 mmol) in methanol (5 mL) was treated with potassium carbonate (0.063 g, 0.46 mmol) and the resulting reaction mixture was heated at 80° C. for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.035 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:25])([F:24])[F:26])[N:17]=[C:16]2[O:6][CH:7]([CH3:9])[CH3:8])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(OC(C)C)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[2-isopropoxy-6 -oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz): 7 83 ppm (d,1H), 7.39 ppm (d,1H), 6.64 ppm (s,1H), 5.34 ppm (m,1H), 5.27 ppm (m,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H), 1.28 ppm (d,3H), 1.27 ppm (d,3H);
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:40])([F:39])[C:30]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[C:30]([OH:38])([C:29]([F:28])([F:39])[F:40])[C:34]([F:37])([F:36])[F:35])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F) and 3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=473.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Cl-].[Cl-].[Cl-].[Al+3].O.Cl[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH2:3][CH2:2][OH:1])[C:16]3[C:11]([C:10]=2[CH:9]=1)=[CH:12][C:13]([C:10]([CH3:11])([CH3:5])[CH3:9])=[CH:14][CH:15]=3)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)Cl
Reactant: OCCn1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n2CCO
Reaction time: 0.02 h
Yield: 84 %

Procedure:
To a solution of 9-(2-hydroxy ethyl)carbazole (1.65 g, 7.81 mmol) in 2-chloro-2-methylpropane (25.0 ml) was added aluminum trichloride (0.54 g, 4.05 mmol) at room temperature under nitrogen atmosphere and stirring. After 1 minute, the addition of AlCl3, insoluble 9-(2-hydroxyethyl)carbazole disappeared. The reaction was carried out at room temperature for 25 minutes, and water (20.0 ml) was added. The product was extracted with ethyl acetate (3×20.0 ml). The organic layer was washed with water (3×60.0 ml), and then ethyl acetate was evaporated under vacuum. The product was applied to a silica gel column [ethyl acetate/hexanes (3.5:6.5)] to yield 2.1 g (84.0%) of a white solid after recrystallization from dichloromethane/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22](O)(=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N=C=NCCCCCC)CCCCC>C(Cl)Cl>[C:22]([O:18][CH2:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=1)(=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCCC(=O)O
Agent: CCCCCCN=C=NCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)OCCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of the compound 22 (345 mg, 1 mmol), undecanoic acid (186 mg, 1 mmol) and N,N-dimethylaminopyridine (122 mg, 1 mmol) in methylene chloride (3 mL) was added 1,3-dihexylcarbodiimide (206 mg, 1 mmol) under ice-cooling, and stirred at room temperature overnight. The precipitated insoluble matter was filtered, and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (hexane - ethyl acetate (1:1)) to give the compound 106 (461 mg, 90%) as oil. Rf 0.50 (1:1 EtOAc - hexane). 1H-NMR (CDCl3): δH0.88 (3 H, S, t-like, CH3), 1.23 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.25 (14 H, bs, --CH2 --), 3.09 (1 H, sep, J 6.9 Hz, (CH3)2CH), 3.10 (2 H, t, J 7.2 Hz, CH2), 3.49 (3 H, s, NCH3), 4.42 (2 H, t, J 7.2 Hz), 6.80 (2 H, d, J 1.8 Hz, arom 2- and 6-H), 7.11 (1 H, t, J 1.8 Hz, arom 4-H) Elementary analysis (for C26H38N2O2SCl2) Calcd. : C, 60.81% H, 7.46% N, 5.45% S, 6.24% Cl, 13.81% Found: C, 60.55% H, 7.39% N, 5.54% S, 6.14% Cl, 13.81%
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 193 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=92-96° C., 400 MHz 1H NMR (CDCl3) δ: 7.99-7.97 (d, J=8.21 Hz, 1H), 7.667-7.662 (d, J=1.95 Hz, 1H), 7.46-7.43 (dd, J=1.56, 7.82 Hz, 1H), 7.33-7.23 (m, 5H), 4.01-3.94 (m, 1H), 3.33 (br s, 1H), 2.93-2.82 (m, 4H), 2.74-2.70 (m, 3H), 2.51-2.41 (m, 3H), 2.14-2.10 (d, J=13.7 Hz, 2H), 1.94-1.80 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)C1OC=CN=1)CCC.N#N>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)c(C(=O)O)n1
Temperature: 120 °C
Yield: 192.7 %

Procedure:
In a microwave vial was dissolved the title compound of step B (185 mg, 0.8 mmol) and 2-(tributylstannyl)oxazole (0.22 mL, 1 mmol) in PhCH3 (2.4 mL). The solution was degassed with N2 and Pd(PPh3)4 (92 mg, 0.1 mmol) were added. The reaction was purged with N2 and heated at 120° C. for 20 m using microwave irradiation. The reaction was cooled to rt, filtered through a pad of celite and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). The mixture was diluted with H2O and extracted with EtOAc. The combined organics were dried (MgSO4) and purified via silica gel chromatography (0-50% EtOAc in heptane) to give the title compound (56 mg, 32%). MS (ESI) mass calcd. for C11H10N2O3, 218.2; m/z found 219.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH:14](I)[CH2:13][NH:12][C:11](=[O:16])[C:10]1[S:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:19][C:9]3=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:14][CH2:13][NH:12][C:11](=[O:16])[C:10]1[S:17][C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[N:19][C:9]3=1
Reactant: O=C1OC2(c3ccc(Cl)cc31)c1nc(N3CCOCC3)sc1C(=O)NCC2I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C1OC2(CCNC(=O)c3sc(N4CCOCC4)nc32)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
A solution of 5-chloro-7′-iodo-2′-(morpholin-4-yl)-6′,7′-dihydro-3H-spiro[2-benzofuran-1,8′-[1,3]thiazolo[5,4-c]azepine]-3,4′(5′H)-dione (0.0430 g, 0.0809 mmol) and 2,2′-azo-bis-isobutyronitrile (0.000664 g, 0.00404 mmol) in toluene (2.0 mL) was heated at 80° C. for 10 minutes, then added tri-n-butyltin hydride (0.0644 mL, 0.239 mmol) dropwise. The solution was stirred at 80° C. for 16 hours. The reaction was incomplete by LCMS and TLC, so added additional and 2,2′-azo-bis-isobutyronitrile (2 mg) and tri-n-butyltin hydride (0.050 mL) and stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by preparative HPLC to give the product (0.0100 g, 31%). LCMS: (AA) ES+ 406, 408. 1H NMR (400 MHz, d6-DMSO) δ: 8.50-8.28 (m, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.78 (dd, J=8.2, 2.0 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 3.60-3.51 (m, 4H), 3.52-3.42 (m, 1H), 3.32 (m, 1H), 3.23-3.06 (m, 4H), 2.72-2.60 (m, 1H), 2.37-2.24 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1(S)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([S:8][C:11]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 304 (M+, 76), 303 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Yield: 82 %

Procedure:
The desired compound was prepared according to the procedure of Example 16, step E, using methyl 5-chloro-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-4-[(trimethylsilyl)ethynyl]benzoate and (3,5-difluorophenyl)boronic acid as the starting materials in 82% yield. LCMS for C19H17ClF2NO4Si (M+H)+: m/z=424.1; Found: 423.9.
Reaction SMILES: [OH-].[K+].C1OCCOCCOCCOCCOCCOC1.C([O:23][C:24]([C:26]1([CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=[O:25])C.Cl>C1(C)C=CC=CC=1.O>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][C:26]([CH2:39][CH:40]2[CH2:41][CH2:42]2)([C:24]([OH:25])=[O:23])[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCOC(=O)C1(CC2CC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)O)CC1

Procedure:
Potassium hydroxide powder (85% assay, 2.16 gm, 0.0327 mol) and 18-crown-6 ether (350 mg) are added to a solution of 4-cyclopropylmethylpiperidine-1,4-dicarboxylic acid-1-tertbutyl ester-4-ethyl ester (1.2 gm, 0.0039 mol) in dry toluene (15 mL). The reaction mixture is refluxed for 30 minutes. It is then treated with demineralized water (15 mL) at room temperature and pH is adjusted to ˜3-4 using 2N HCl (20 mL). The aqueous layer is extracted with ethyl acetate (2×15 mL) and the combined extract is dried over sodium sulfate. Removal of solvent gives 4-cyclopropylmethylpiperidine-1,4-dicarboxylic acid monotertbutyl ester.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10])=[N+]=[N-].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:24]1([P:17](=[N:1][C:4]2[CH:8]=[CH:7][S:6][C:5]=2[CH:9]=[O:10])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=Nc1ccsc1C=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1sccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3-azido-2-thiophenecarbaldehyde (11-1, 1.00 g, 6.53 mmol, 1 equiv, prepared by the method of Gronowitz, S., Westerlund, C., and Hornfeldt, A.-B. Acta. Chem. Scand. B 1975, 29, 224-232) and triphenylphosphine (1.71 g, 6.53 mmol, 1.00 equiv) in THF (30 mL) was stirred at 23° C. for 6 h. The reaction mixture was concentrated to give 3-[(triphenylphosphoranylidene)amino]-2-thiophenecarbaldehyde (11-2). 1H NMR (400 MHz, CD3OD) δ 10.35 (s, 1H), 7.72 (m, 6H), 7.58 (m, 2H), 7.49 (m, 6H), 7.27 (dd, 1H, J=4.5, 0.8 Hz), 6.09 (d, 1H, J=4.5 Hz).
Reaction SMILES: [CH:1]1([CH:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O>[CH:17]1([CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cncn1C(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cncn1C(C1CCCCC1)C1CCCCC1
Reaction time: 2 h

Procedure:
A mixture of 6 parts methyl 1-[(dicyclohexyl)methyl]-1H-imidazol-5-carboxylate, 6 parts of a sodium hydroxide solution 50% and 100 parts of water is stirred for 2 hours at reflux temperature. The reaction mixture is acidified with concentrated hydrochloric acid and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is boiled for 2 hours in acetonitrile. The precipitated product is filtered off and dried, yielding 1-[(dicyclohexyl)methyl]-1H-imidazole-5-carboxylic acid; mp. 253° C. (compound 4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21]C2C=CC(OC)=CC=2)[CH2:14][CH2:13]1.CO[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][CH2:38][C:37]2[CH:40]=[CH:41][CH:34]=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCCc2ccccc2)CC1

Procedure:
Compound 25 was prepared in a manner similar to that of 16, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=410.4.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:11]I>O1CCCC1>[CH3:11][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:10]
Reactant: OCCCCCCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCO
Reaction time: 8 h

Procedure:
Sodium hydride (NaH) (50%, 6.12 g) suspended in tetrahydrofuran (TEF) (60 ml) was added to a solution of 1,6-hexanediol (15.0 g) in THP (200 ml), and kept at 60° C. until gas evolution stopped. After cooling, a solution of methyl iodide (12 ml) in THF (35 ml) was added and kept overnight at room temperature. The crude product obtaind after the usual work-up was chromatographed to give 6-methoxy-1-hexanol. Yield; 8.16 g
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 12 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (720 mg, 2 mmol) and sec-butylamine (0.7 mL, 7 mmol) in 20 mL of DMF was added PyBOP (1550 mg, 3 mmol) and TEA (3 mL, 15 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by preparative HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) followed by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (100 mg, yield 13%). MS calcd for (C19H24BN3O5S): 417.2. MS found (ESI negative): (M−H)−=416.4. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 9.17 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.10 (dd, J=8.4, 2 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.34 (dd, J=8.8, 2.4 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 3.78 (s, 2H), 3.71 (m, 1H), 1.40 (m, 2H), 1.05 (d, J=6.4 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).