Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([CH2:27][CH2:28][N:29]=[N:30][N:31]([CH3:36])[C:32](=[O:35])[NH:33][CH3:34])[Si](C(C)(C)C)(C)C>O1CCCC1>[OH:19][CH2:27][CH2:28][N:29]=[N:30][N:31]([CH3:36])[C:32](=[O:35])[NH:33][CH3:34]
Reactant: CNC(=O)N(C)N=NCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)N(C)N=NCCO

Procedure:
5c. A 1.0M solution (100 mL) of tetra-n-butylammonium fluoride in tetrahydrofuran was added dropwise to a stirred solution of 1-(2-(tert-butyldimethylsiloxy)ethyl)-3-methyl-3-(N-methylcarbamoyl)triazene in tetra-hydrofuran at -10° C. over 1 h. The volume of the solution was then reduced 50% with a rotary evaporator at 25° C. and the resultant solution was chromatographed on a column of 250 g of Silica Gel 60 (EM, neutral, 70-230 mesh) packed in ether. The column was eluted with 5 L of ether. The last 3 L of eluent were concentrated on a rotary evaporator and the residue (6.7 g) recrystallized from methylene chloride-ether to give 4.24 g of 1-(2-hydroxyethyl)-3-methyl-3-(N-methylcarbamoyl)triazene, 5c, (0.0265 mol, 27.8%): mp 72°-74° C.; IR (CH2Cl2) 3600, 3450, 2955, 1690, 1510, 1190, 1050 cm10-1 ; UV (CH3CN) λ max 245 (log ε 4.04); 1H NMR (CDCl3, Me4Si) δ 1.78 (1H ,t,J=6 Hz), 2.94 (3H,d,J=5 Hz), 3.26 (3H,s), 3.97 (2H,t,J=5 Hz), 4.02 (2H,m-A2B2X), 6.34 (1H,b); proton decoupled 13C NMR (CDCl3, Me4Si) δ 26.86, 27.60, 60.72, 155.54; exact mass calcd m/z for C5H12N4 o2 160.0960, found 160.0967 (by EI).
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([O:12]C)=[O:11])[C:5]([O:7]C)=O)(=O)[CH3:2].C[O-].[Na+].CO.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[CH3:21][C:20]1[N:23]=[C:5]([OH:7])[C:4]([CH2:9][C:10]([OH:12])=[O:11])=[C:1]([CH3:2])[N:22]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C)c(CC(=O)O)c(O)n1
Yield: 93.3 %

Procedure:
Dimethyl acetylsuccinate (188 g, 1 mol) is dissolved in sodiummethylate/methanol (1.1 mol in 500 ml) and added within 30 minutes to a solution of acetamidine hydrochloride (104 g, 1.1 mol) at 60° C. with stirring. After refluxing the mixture for 14 hours, the precipitated salt is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The resulting solid is suspended in acetone, filtered and dried to give (2,6-dimethyl-4-hydroxy-5-pyrimidinyl) acetic acid crystalline product (170 g, 93%). 1H-NMR (DMSO):12.3 (s, 1H); 3.2 (s, 2H); 2.2. (s, 3H); 2.1 (s, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[CH2:29]1[C:37]2[C:32](=[CH:33][C:34](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:40](=[O:41])/[CH:39]=[CH:38]/[C:34]4[CH:33]=[C:32]5[C:37](=[CH:36][CH:35]=4)[CH2:29][CH2:30][CH2:31]5)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCC2
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCC3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-indan-5-ylprop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O2: 525 (M+H). Found: 525
Reaction SMILES: C1([C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:9]=O)C=CC=CC=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>O1CCCC1.C(OCC)(=O)C.C(C(C)=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:14]3[CH2:15][N:16]([C:32]4[CH:31]=[CH:9][CH:8]=[CH:7][CH:11]=4)[C:11]4[N:12]([CH:9]=[CH:8][CH:7]=4)[CH:13]=3)[CH2:25][CH2:24]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: O=CC=C(c1ccccc1)c1ncccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCN(C3=Cn4cccc4N(c4ccccc4)C3)CC2)cc1
Temperature: 65 °C
Yield: 94.9 %

Procedure:
A solution of 3-phenyl-3-(2-pyrimidinyl)propenal (1.25 g) in tetrahydrofuran (125 cc) is added to 4-(4-methylbenzyl)piperazine (11.2 g). The solution is stirred and heated to a temperature in the region of 65° C. for 3 hours. After being coiled to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl acetate (10 cc) and the solution obtained is poured onto silica (25 g) contained in a column 1.5 cm in diameter. Elution is performed with a mixture (750 cc) of ethyl acetate and cyclohexane (50:50 by volume); the corresponding eluates are discarded. Elution is then performed with the same mixture (300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (20 cc). Oxalic acid (120 mg) dissolved in methyl ethyl ketone (20 cc) is added and the mixture is stirred for approximately 15 minutes at a temperature in the region of 20° C. The precipitate formed is separated by filtration and then recrystallized in boiling isopropyl alcohol (50 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylpyrrolo[1,2-a]pyrimidine oxalate (300 mg), m.p. 205° C., is thereby obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([OH:14])[C:8]=2[CH2:7][C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:5]1.Cl.C(NC[C@H]1C2C=CC(O)=C(O)C=2C[C@@H](C2CCCCC2)O1)C=C.Cl.C(NC[C@H]1C2C=CC(O)=C(O)C=2C[C@@H](C2C=CC=CC=2)O1)C=C>>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([OH:14])[C:8]=2[CH2:7][C@@H:6]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[O:5]1
Reactant: NC[C@@H]1O[C@H](c2ccccc2)Cc2c1ccc(O)c2O
Agent: C=CCNC[C@@H]1O[C@H](C2CCCCC2)Cc2c1ccc(O)c2O
Agent: C=CCNC[C@@H]1O[C@H](c2ccccc2)Cc2c1ccc(O)c2O
Agent: Cl
Product: NC[C@@H]1O[C@H](C2CCCCC2)Cc2c1ccc(O)c2O

Procedure:
cis-1-(aminomethyl)-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride; cis-1-[(allylamino)methyl]-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranhydrochloride; cis-1-[(allylamino)methyl]-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranhydrochloride;
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: COC(=O)c1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 94.5 %

Procedure:
EX-612B) To a mixture of methyl 3-[[(3-phenoxyphenyl)amino]methyl]benzoate (6.2 g, 0.019 mol) from EX-612A and 1,1,1-trifluoro-2,3-epoxypropane (8.58 g, 0.077 mol) in 12 mL of acetonitrile was added ytterbium (III) trifluoromethanesulfonate (1.2 g, 0.0019 mol). The resulting mixture was heated at 50° C. in a sealed glass tube for 18 h. The reaction mixture was cooled to room temperature, then diluted with water and methylene chloride. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 8.0 g (96%) of the desired methyl 3-[[(3-phenoxy-phenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate product as a yellow oil. Anal. calcd. for C24H22F3NO4.1.4 H2O: C, 61.25; H, 5.31; N, 2.98. found: C, 61.52; H, 5.06; N, 2.89. HRMS calcd.: 446.1579 [M+H]+, found: 446.1596. 1H NMR (CDCl3) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). 19F NMR (CDCl3) δ −79.0 (d, 3F).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18]>>[Cl:1][C:2]1[N:3]([CH2:16][C:17](=[O:18])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:4]2[CH:14]=[C:13]3[C:8](=[CH:7][C:5]=2[N:6]=1)[CH:9]=[CH:10][CH:11]=[CH:12]3
Reactant: O=C(CBr)c1ccccn1
Reactant: Clc1nc2cc3ccccc3cc2[nH]1
Product: O=C(Cn1c(Cl)nc2cc3ccccc3cc21)c1ccccn1
Yield: 75.6 %

Procedure:
In a manner analogous to Example 28 steps a)→d) 2-chloro-1H-naphtho[2,3-d]imidazole (7.5 g) was reacted with 2-bromoacetylpyridine (8.7 g) to give 2-chloro-1-(2-oxo-2-(2-pyridyl)ethyl)naphtho[2,3-d]imidazole (9 g). This was reacted with thiourea (5.5 g) then NH4OH solution (100 ml) to give 2-mercapto-1-(2-oxo-2-(2-pyridyl)ethyl)naphtho[2,3-d]imidazole which compound was reduced with NaBH4 to give 2-mercapto-1-(2-hydroxy-2-(2-pyridyl)ethyl)naphtho[2,3-a]imidazole (1.3 g). Treatment of this with polyphosphoric acid (23 g) gave the title compound (0.75 g.) mp 197.5°-198.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCCO2)nc1
Yield: 101.9 %

Procedure:
To solution of 5-bromo-2-formylpyridine (10 g, 53.8 mmol), 1,3-propanediol (3.89 mL, 53.8 mmol) in toluene (30 mL) was added CSA (1.249 g, 5.38 mmol). The reaction mixture was heated to reflux for 4 h with a Dean-Stark trap. The reaction mixture was quenched by addition of saturated solution of sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford compound 278 (13.37 g, 54.8 mmol, 101% yield, crude) as a brown solid that was used in the next step with no additional purification. MS (m/z): 244.06-246.06 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH:33][CH3:34].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][C:24]([C:27](=[O:29])[N:33]([CH3:34])[CH3:32])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:30])[CH3:31])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C(=O)O)nc3)cc2)OC1(C)C
Reactant: CNC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Reaction time: 14 h

Procedure:
To a stirred solution of 5-[4-((4S,5R)-3-tert-Butoxycarbonyl-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl)-phenyl]-pyridine-2-carboxylic acid (220 mg, 0.511 mmol) in dry tetrahydrofuran (6 mL) is added solution of N,N-dimethyl amine, 2 M in tetrahydrofuran (28 mg, 0.31 mL, 0.61 mmol), diisopropylamine (198 mg, 1.534 mmol) and 50% solution of triphenylphosphine in ethyl acetate (244 mg, 0.49 mL, 0.767 mmol) at room temperature. Resulting reaction mixture stirred at same temperature for 14 hours. Diluted with water and ethyl acetate, organic layer is separated and aqueous layer is extracted with ethyl acetate. Combined organic layer is dried over sodium sulphate, solvent is evaporated in vacuo under reduced pressure to obtain crude material purified by column chromatography eluting in 3% methanol in CH2Cl2 to afford title compound (100 mg): 1H-NMR (400 MHz, DMSO-d6) δ: 1.44 (s, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 3.00 (s, 3H), 3.03 (s, 3H), 3.60-3.61 (m, 0.5H), 3.84-3.90 (m, 1.5H), 4.00-4.05 (m, 0.5H), 4.08-4.12 (m, 0.5H), 5.13 (d, 1H, J=7.24 Hz), 7.60 (d, 2H, J=8.24 Hz), 7.64 (d, 1H, J=8.20 Hz), 7.81 (d, 2H, J=8.32 Hz), 8.22 (dd, 1H, J=8.16 Hz, J=2.32 Hz), 8.91 (d, 1H, J=1.88 Hz), LC-MS (m/z): [M+H]=458.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: COc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
2.06 g of 5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.14 g of 3-chloro-5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xix) of the present invention).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:11]1([C:14]2[C:15]3[S:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2SCC3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc2c(c(N3CCNCC3)n1)SCC2

Procedure:
69 mg 4-(6,7-Dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 2 mL 4 mol/L HCl solution in dioxane for 5 h. The mixture was evaporated. The residue was crystallized from isopropanol and diethylether to yield 48 mg of the desired product. (M+H)+: 223
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[CH:22]([OH:24])[CH3:23])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[F:19][C:17]1[CH:18]=[C:13]([CH:12]2[NH:8][C@H:9]([C@H:22]([OH:24])[CH3:23])[CH2:10][CH2:11]2)[CH:14]=[C:15]([F:21])[C:16]=1[F:20]
Reactant: CC(O)[C@H]1CCC(c2cc(F)c(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@@H]1CCC(c2cc(F)c(F)c(F)c2)N1
Yield: 98.7 %

Procedure:
To a solution of (S)-2-((R)-1-hydroxylethyl-5-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylic acid t-butyl ester (3.71 g) in ethyl acetate (20 mL) was added 4 N hydrochloric acid/ethyl acetate (26.8 mL), and the resultant solution was stirred at room temperature for 2 hours. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with 5 N aqueous sodium hydroxide and dichloromethane. The organic layer was partitioned and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, to thereby obtain the titled compound (2.6 g). The physical properties of this crude product were as follows.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:30][C:31]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a suspension of 15 mg of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 6) in 2 mL of THF was added 7.6 mg of phenyl isocyanate. The mixture was stirred at room temperature overnight. An additional 7.6 mg of phenyl isocyanate was added and the mixture was stirred for an additional 24 h, then concentrated. The residue was purified by flash chromatography, eluting with 1:1 hexanes-acetone, to yield 12 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 8.37 (d, J=5.3, 1H) 8.17 (d, J=7.3 Hz, 1H), 7.36-7.44 (m, 2H), 7.22-7.34 (m, 3H), 7.00 (t, J=7.3 Hz, 1H), 6.78 (d, J=5.3 Hz, 1H), 6.52 (s, 1H), 5.75 (br s, 1H), 3.97 (dd, J=3.4, 13.0 Hz, 1H), 3.77 (dt, J=4.4, 13.0 Hz, 1H), 3.41-3.57 (m, 2H), 3.14 (br t, J=10.5 Hz, 1H), 3.02 (dd, J=8.9, 13.3 Hz, 1H), 1.92-2.08(m, 2H), 1.72-1.84 (m, 1H), 1.53-1.64 (m, 1H), 1.41 (ddt, J=3.9, 9.8, 10.1 Hz, 1H). Mass spectrum (EST) 428.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]Br)=[CH:5][CH:4]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][SH:15])=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCS)cc1
Reaction time: 2 h

Procedure:
A mixture of 3-(p-methoxyphenyl)-1-propylbromide (14 g; 61 mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours. Evaporation of the solvent provided a clear glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide. After stirring the resulting mixture for two hours, the product was extracted into ether (3×), and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated. Chromatographic purification of the crude thiol on a silica gel column eluting with 2% either in hexane delivered 10.2 g of 3-(p-methoxyphenyl)-1-propylmercaptan as a clear liquid. 1H NMR (300 MHz, CDCl3): δ 1.34 (t, 1H); 1.88-1.92 (m, 2H); 2.49-2.53 (m, 2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 (m, 2H); 7.06-7.24 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=1
Reactant: CCOC(=O)c1cc(OCCNC(=O)OC(C)(C)C)cc(C(=O)OCC)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(OCCN)cc(C(=O)OCC)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.64 g of diethyl 4-(2-tert-butoxycarbonylamino-ethoxy)-pyridine-2,6-dicarboxylate (described on page 101 of WO 07085930) in 27 ml of dioxane was added 20.7 ml of 4N hydrochloric acid in dioxane. The mixture was stirred for about 20 hours at room temperature and then concentrated under reduced pressure. The evaporation residue was taken up in about 70 ml of dioxane, and then concentrated again under reduced pressure. The operation was repeated 3×. The mixture was taken up in 50 ml of tert-butyl methyl ether and the suspension obtained was filtered through a sinter of porosity 4. The cake was washed with tert-butyl methyl ether, and dried in a desiccator under reduced pressure at room temperature. 2 g of diethyl 4-(2-amino-ethoxy)-pyridine-2,6-dicarboxylate monohydrochloride were obtained. 1H NMR (400 MHz, DMSO-ds): 1.35 (t, J=7.2 Hz, 6H); 3.26 (m, 2H); 4.39 (q, J=7.2 Hz, 4H); 4.45 (m, 2H); 7.77 (s, 2H); 8.16 (broad m, 3H). LC/MS (C): tr=2.39 min; [M+H]+: m/z 283.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].CN(C=O)C.[CH:16]([NH:18][NH2:19])=O.[H-].[Na+]>O>[N:19]1[N:18]=[CH:16][N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:10][C:9]=12
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)sc1nncn12
Temperature: 160 °C

Procedure:
Five grams (30.0 mmoles) of o-chlorophenylisothiocyanate were dissolved in 50 ml. of dry DMF. A solution of 1.8 g. (30.0 mmoles) of formylhydrazine in 50 ml. of dry DMF was added dropwise rapidly to the stirred reaction mixture. The temperature of the reaction rose to about 45° C. The temperature was maintained between 60° C. and 100° C. for 24 hours. Thirty millimoles, 1.5 g., of sodium hydride as a 50% mineral oil suspension was added to the reaction mixture. The reaction was completed by heating at reflux temperature (160° C.) for about 185 hours. The cooled mixture was poured into water. The aqueous mixture was extracted with n-hexane to remove mineral oil. The product was extracted with ethyl acetate. The ethyl acetate extract was washed (water), dried (MgSO4) and evaporated in vacuo to a residual oil. The oil was covered with dry ether and the product crystallized upon standing. The yield of s-triazolo[3,4-b]benzothiazole, m.p. about 175-176° C., was 200 mg.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>CN(C)C=O.C(OCC)C>[CH3:1][O:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: Oc1cnc2ccccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.05 g of anhydrous potassium carbonate and 0.48 ml of methyliodide are added to a solution of 1.0 g of 3-hydroxyquinoline in 8.5 ml of dimethylformamide and the reaction mixture is stirred at room temperature for 18 h. It is diluted with diethyl ether, the resulting suspension is filtered and the filtrate is concentrated. The crude product is purified by FC over 60 g of silica gel (mobile phase F) to give 3-methoxyquinoline: Rf (A)=0.53.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:12])[C:5]=2[N:6]=1
Reactant: BrBr
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)c2nc(N)sc2c1
Reaction time: 2 h
Yield: 92 %

Procedure:
16.4 g of 2-amino-6-methylbenzothiazole was dissolved in 500 ml of chloroform. To this solution was added dropwise 16.0 g of bromine dissolved in 10 ml of chloroform at room temperature. The reaction mixture was stirred for 2 hours and then washed once with 10% aqueous sodium hydroxide solution and water, respectively. The organic layer was separated, dried with anhydrous sodium sulfate and then evaporated to obtain the title compound in the yield of 92%.