Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[CH:1]1([C:6]2[NH:33][C:31](=[O:32])[NH:30][CH:21]([C:20]3[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]([OH:26])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=3)[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1)C1CCCC1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(C3CCCC3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 3 %

Procedure:
A mixture of 1-cyclopentyl-2-phenylethanone (Intermediate 91) (1.6 mmol, 300 mg), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (1.91 mmol, 404 mg), and urea (4.8 mmol, 288 mg) in anhydrous ethanol (5 mL) was added concentrated HCl (0.2 mL), the above mixture was refluxed for 13 hours. The reaction mixture was concentrated and the residue was purified by column chromatography, followed by preparative HPLC to afford the product Compound 172 as yellow solid (20 mg, yield: 2.96%). 1H NMR (DMSO 400 MHz): δ 10.23 (s, 1H), 8.25 (s, 1H), 6.98-7.33 (m, 8H), 5.00 (d, J=2.4 Hz, 1H), 3.94-4.04 (m, 2H), 2.65-2.69 (t, J=9.2 Hz, 1H), 1.24-1.79 (m, 11H); MS (ESI): m/z 424.1 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:44])/[CH:24]=[CH:25]/[C:26]3[CH:43]=[CH:42][C:29]([O:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)=[CH:28][CH:27]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:44])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:42][CH:43]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(CCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1)C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CNCCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Yield: 98 %

Procedure:
A solution of Example 190 (0.33 g, 0.55 mmol) in DCM (30 mL) was treated with zinc bromide (0.63 g, 5 equiv.) for 16 hours at 30° C. A gummy solid was formed. Extraction with DCM:MeOH, washing with water, drying over Na2SO4 and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.Cl>ClCCl.O>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: CNOC
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of thiophene-2-carbonyl chloride (100.6 mL, 940 mmol) and N,O-dimethylhydroxylamine hydrochloride (100.9 g, 1.03 mol) in dichloromethane (1 L) at 0° C. was added dropwise triethylamine (262 mL, 1.88 mol). After stirring at room temperature for 3 h, the reaction mixture was poured into a mixture of water (2 L) and concentrated aq. HCl (36%, 80 mL), the layers were separated and the aqueous layer extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (200 mL), then dried over MgSO4 and concentrated in vacuo to afford N-methoxy-N-methylthiophene-2-carboxamide [153.4 g, yield 95%; HPLC/MS: m/z=172 (M+H); log P(HCOOH)=1.44].
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[C:10](=[O:20])[N:9]3[C:21]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[NH:22][C:23](=[O:24])[C:8]=23)[CH2:3][CH2:2]1.[OH-].[NH4+].[H][H]>CO.O1CCCC1.[Pd].ClCCl>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[C:10](=[O:20])[N:9]3[C:21]4([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[NH:22][C:23](=[O:24])[C:8]3=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)=[N:15][CH:16]=1
Reactant: [H][H]
Reactant: O=C1NC2(CCCCC2)n2c1c(C1=CCOCC1)cc(Nc1ccncn1)c2=O
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC2(CCCCC2)n2c1c(C1CCOCC1)cc(Nc1ccncn1)c2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A double neck round bottom flask was charged with 8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 0.22 g, 0.57 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). Palladium on carbon (0.10 g) was added followed by ammonium hydroxide (1.0 mL) under nitrogen atmosphere. The reaction was filled with hydrogen and stirred at room temperature for 3 d. After completion of reaction monitored by TLC and LCMS, the reaction mass was diluted with 5% methanol in dichloromethane (100 mL) and passed through celite bed and washed with 10% methanol/dichloromethane (3×50 mL). Solvent was removed under vacuum and crude material was purified by prep HPLC to afford 6′-(pyrimidin-4-ylamino)-8′-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 201) as a white solid. Yield: 0.11 g, 49%; MS (ESI) m/z 396.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (6, 1H), 9.40 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.38 (d, J=5.88 Hz, 1H), 7.37 (d, J=5.88 Hz, 1H), 4.20 (m, 1H), 3.96 (m, 2H), 3.42 (t, J=11.3 Hz, 2H), 3.01 (m, 2H), 1.70 (m, 9H), 1.58 (m, 2H), 1.22 (m, 1H).
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl.O[NH:38][C:39](=[NH:41])[CH3:40].CCN(CC)CC>O1CCOCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:11]2[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[N:15]=[C:10]2[C:7]2[CH:6]=[CH:5][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: CC(=N)NO
Reactant: COC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoic acid methyl ester (50 mg, 0.11 mmol) in dioxane is added NaOH (1N, 400 μL, 0.4 mmol) and stirred at room temperature for 14 h. The mixture is then neutralized by adding HCl (1N, 400 μL, 0.4 mmol) and concentrated. The resulted residue is treated with SOCl2 (1 mL) at room temperature for 1 h and excess SOCl2 is removed under vacuum. The residue is dissolved in CH2Cl2 and added N-hydroxy-acetamidine (12 mg, 0.16 mmol) followed by Et3N (17 mg, 0.16 mmol). After stirring at room temperature for 1 h, the mixture is treated with water (2 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated, the residue is dissolved in EtOH (4 mL), NaOAc (40 mg) is added and the mixture is heated to 80° C. for 5 h. After cooling down to room temperature, the solvent is removed and the residue is purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3) δ(ppm) 8.35(s, 1H), 8.12(d, 2H), 8.01(d, 2H), 7.48-7.54 (m, 4H), 7.37 (t, 1H), 7.32(d, 2H), 7.10(d, 2H), 2.47(s, 3H); HPLC-MS calculated for C26H17ClN6O2 (M+H+): 481.1. Found: 481.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1>[Pd].CO.O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: Nc1nc(C(=O)O)c(C(=O)c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C(=O)c2sc(N)nc2C(=O)O)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-amino-5-(4-nitrobenzoyl)-4-thiazolecarboxylic acid (2.6 g) and 10% palladium on carbon (1 g, 50% wet) in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml) was hydrogenated under atmospheric pressure for 2 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was triturated with ether and the precipitates were collected by filtration, washed with ether and dried in vacuo to give 2-amino-5-(4-aminobenzoyl)-4-thiazolecarboxylic acid (2.10 g, yield: 90.0%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:23][C:24]1[C:32]2[C:27](=[C:28]([NH2:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.O>CS(C)=O>[Cl:13][C:4]1[N:3]=[C:2]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:27]=2[NH:26][CH:25]=[C:24]3[CH3:23])[C:7]2[C:8](=[O:12])[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: Cc1c[nH]c2c(N)cccc12
Reactant: O=c1[nH]ncc2cc(Cl)nc(Cl)c12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c[nH]c2c(Nc3nc(Cl)cc4cn[nH]c(=O)c34)cccc12
Temperature: 140 °C

Procedure:
To 5,7-dichloro-3H-pyrido[3,4-d]pyridazin-4-one (180 mg, 0.833 mmol) in DMSO (1 ml) in a sealable vial, was added DIPEA (0.189 ml, 1.083 mmol) and 3-methyl-1H-indol-7-amine (158 mg, 1.083 mmol). The vial was capped to close and the mixture heated on a sandbath at 140° C. for 1 h. The resultant mixture was poured into water (20 ml), and extracted with EtOAc (20 ml). Organic phase was washed with water then brine, dried over Na2SO4, then concentrated under vacuum. The residue was triterated with DCM, then collected by filtration and dried to give title compound as a yellow-mustard coloured solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[OH:23][C:24]1C=CC(NC(N)=S)=CC=1.C(=O)C>C(Cl)Cl.CO>[CH3:24][O:23][C:19]1[CH:20]=[C:15]([C:12]2[S:11][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[N:14][CH:13]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NC(=S)Nc1ccc(O)cc1
Reactant: COc1ccc(Nc2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: CC=O
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(-c2cnc(Nc3ccc(O)cc3)s2)c1

Procedure:
The title compound is prepared as described in Example 4 for (4-methoxy-phenyl)-[5-(4-methoxy-phenyl)-thiazol-2-yl]-amine but using (4-hydroxy-phenyl)-thiourea and 3-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 312.9 [M−H]−; single peak at tR=6.81 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](/[CH:18]=[CH:19]/[CH3:20])=[CH:15][N:14]1[C:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[CH:25][C:24]=1[NH:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:71])[C@@H:55]([NH:57][C:58](=[O:70])[C@@H:59]([NH:63][C:64](=[O:69])[O:65][CH2:66][CH:67]=[CH2:68])[CH:60]([CH3:62])[CH3:61])[CH3:56])=[CH:49][CH:48]=1)=[O:44])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[OH:11][C@@H:12]1[N:42]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:71])[C@@H:55]([NH:57][C:58](=[O:70])[C@@H:59]([NH:63][C:64]([O:65][CH2:66][CH:67]=[CH2:68])=[O:69])[CH:60]([CH3:61])[CH3:62])[CH3:56])=[CH:49][CH:48]=2)=[O:44])[C:24]2[CH:25]=[C:26]([O:31][Si:32]([CH:39]([CH3:40])[CH3:41])([CH:36]([CH3:37])[CH3:38])[CH:33]([CH3:35])[CH3:34])[C:27]([O:29][CH3:30])=[CH:28][C:23]=2[C:21](=[O:22])[N:14]2[CH:15]=[C:16](/[CH:18]=[CH:19]/[CH3:20])[CH2:17][C@@H:13]12
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)Nc2cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2CO)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O)cc1)C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
Dry dimethyl sulfoxide (0.180 g, 2.3 mmol, 3.0 eq) was added dropwise to a solution of oxalyl chloride (0.147 g, 1.1 mmol, 1.5 eq) in DCM (10 mL) at −78° C. under an atmosphere of nitrogen. Maintaining the temperature at −78° C., after 20 minutes, a solution of the primary alcohol 15 (0.666 g, 0.77 mmol, 1.0 eq) in DCM (10 mL) was added dropwise. After a further 15 minutes, dry triethylamine (0.390 g, 3.85 mmol, 5.0 eq) was added, and the reaction mixture allowed to warm to room temperature. The reaction mixture was washed successively with cold 0.1N HCl (10 mL), saturated sodium hydrogen carbonate (10 mL) and brine (5 mL). The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 50/50 v/v n-hexane/EtOAc to 25/75 v/v n-hexane/EtOAc) to afford the product as a white solid (0.356 g, 54%). LC/MS (3.487 min (ES+)), m/z: 862.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.34 (br s, 1H), 7.47 (d, 2H, J=7.6 Hz), 7.17 (s, 1H), 7.14 (d, 2H, J=7.5 Hz), 6.86 (br s, 1H), 6.65 (br s, 1H), 6.42 (d, 1H, J=7.6 Hz), 6.22 (d, 1H, J=14.4 Hz), 5.80 (m, 1H), 5.40 (m, 1H), 5.53 (m, 1H), 5.32 (m, 1H), 5.21 (d, 2H, J=9.6 Hz), 5.06 (d, 1H, J=12.3 Hz), 4.90 (m, 1H), 4.58 (m, 3H), 3.98 (m, 1H), 3.84 (m, 1H), 3.81 (s, 3H), 3.50 (m, 1H), 3.05 (dd, 1H, J=16.0, 10.3 Hz), 2.76 (m, 1H), 2.15 (m, 1H), 1.80 (dd, 3H, J=6.7, 0.8 Hz), 1.44 (d, 3H, J=7.1 Hz), 1.16 (m, 3H), 1.01 (d, 18H, J=6.6 Hz), 0.96 (d, 3H, J=6.8 Hz), 0.92 (d, 3H, J=6.8 Hz).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCCCCC.C([Li:18])CCC.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:18]
Reactant: [Li]CCCC
Reactant: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[N-]C(C)C
Product: [Li+]
Reaction time: 0.17 h

Procedure:
A tetrahydrofuran (8 ml) solution of diisopropylamine (1.0 ml, 7.1 mmol) was cooled to 5° C., then n-butyllithium hexane solution (4.1 ml, 1.58 M, 6.5 mmol) was dropwise added thereto while 10 minutes, thus lithium diisopropylamide tetrahydrofuran solution was obtained.
Reaction SMILES: CC([N:5]([C:9]1([C:14]([NH:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)C(=O)[O-])(C)C.[ClH:22].CCOC(C)=O.CCCCCC.II>C(OCC)(=O)C.C(O)(C)C>[ClH:22].[NH2:5][C:9]1([C:14]([NH:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)N(C(=O)[O-])C1(C(=O)Nn2cccc2)CCCC1
Agent: Cl
Agent: II
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: NC1(C(=O)Nn2cccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[1-[(1H-pyrrol-1-ylamino)carbonyl]cyclopentyl]carbamate (2.90 g) in ethyl acetate/isopropanol (30 ml, 3:1) was added excess ethereal HCl. After stirring for 18 hours at room temperature, the reaction appeared complete by TLC (silica gel, 30%EtOAc/hexane, I2 stain). The solid was filtered under nitrogen and recrystallized from ether/methanol to afford 1.40 g of the product, m.p. 218°-220° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23](OC)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[OH:24][CH2:23][C@H:11]1[C@@H:10]([NH:9][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12]1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of (3R,4S)-1-tert-butyl 3-methyl 4-((S)-1-phenylethylamino)piperidine-1,3-dicarboxylate (47 g, 0.13 mol, See: S. S. Ko, et al, WO PCT 2002002525 for preparation of the enantiomer of this compound) in anhydrous ether (500 mL) at 0° C. was added 1M-LAH (100 mL, 0.1 mol) dropwise, and the mixture was stirred at 0˜15° C. for 3 h. The reaction was quenched with a portion-wise adition of Na2SO4.10H2O (excess) and stirring for 1 h at rt. It was filtered through Celite and the solvent was evaporated off to give (3R,4S)-tert-butyl 3-(hydroxymethyl)-4-((S)-1-phenylethylamino)piperidine-1-carboxylate (quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A solution of 3,4-dimethoxybenzoic acid (9.1 g, 0.05 mol) and carbonyldiimidazole (8.1 g, 0.05 mol) in 100 ml of THF was stirred for 3 h protected from moisture. The resulting solution was treated with 2-phenylethylamine (6.1 g, 0.05 mol) dissolved in 10 ml of THF. After 2 h of stirring, the solvent was evaporated and the solid residue was washed with dilute NaOH, dilute HCl, and water. The crude Al was recrystallized from 75 ml of EtOH to afford 9.35 g (57%) of N-(3,4-dimethoxybenzoyl)-2-phenylethylamine, mp 123-124°.
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:29]([CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:30]=[CH2:31]>C(Cl)(Cl)Cl>[CH2:29]([CH:32]=[CH:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]2[O:8][CH:39]2[CH:40]=1)[CH2:30][CH3:31]
Reactant: C=CCCCCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCC=CCC1=CC2OC2C=C1
Reaction time: 144 h
Yield: 76 %

Procedure:
To perbenzoic acid in chloroform prepared from 65.5 g of benzoylperoxide was added 1.45 g of p-allylpropylbenzene and the mixture was allowed to stand at 5° C for 6 days. After the completion of the reaction, the mixture was washed with 2% sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 12.1 g (yield 76%) of p-n-propylallylbenzene oxide as colourless liquid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Cl:24][C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:25]([Cl:24])=[O:27])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: CCCNc1ccc2nc(S)sc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(C(=O)Cl)c1ccc2nc(S)sc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 200.5 %

Procedure:
Into a 250 ml three-neck, round bottomed flask were added 6-(propylamino)-1,3-benzothiazole-2-thiol (500 mg, 2.23 mmol), chloroform (100 ml), and saturated aqueous NaHCO3 (75 ml). The solution was stirred (mechanical stirrer) for 10 min at 0° C. (ice-bath) for 10 min. Stirring was stopped, and a solution of triphosgene (235 mg 0.80 mmol) in CH2Cl2 (2 ml) was added to the lower (organic) phase. Stirring was resumed for 40 min, then the layers were separated, and the aqueous phase was extracted 2× with chloroform. The combined organic fractions were dried (MgSO4), filtered, and concentrated to afford 0.46 g (72%) of the carbamoyl chloride as a waxy solid. IR (neat) 1737 cm−1 (C═O).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=1)([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.C(Cl)Cl>C1COCC1.CCO>[C:11]([O:10][C:8](=[O:9])[C:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=1)([CH3:15])[C:6]([OH:31])=[O:5])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(C)(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(CC(C)(C(=O)O)C(=O)OC(C)(C)C)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
1M NaOH (2 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid tert-butyl ester ethyl ester (0.42g, 1.03 mmol) in THF/EtOH (4 mL, 1:1) . The reaction mixture was stirred at 50° C. for 16 h. CH2Cl2 was added and the mixture was washed with 0.5 M HCl and brine and dried. Concentration under reduced pressure gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid mono-tert-butyl ester (348 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:26][C@@H:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]5[OH:33])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (502 mg, 1 mmol) from Step 1 of Example 49 and (1R,2R)-2-aminocyclohexanol in DMA (4 mL) was added DIEA (1 mL, 6 mmol). The mixture was heated in a sealed tube at 110° C. for 16 h. The mixture was cooled to rt and added dropwise with stirring to H2O (200 mL). After the mixture was stirred for 30 min, the solid was collected by filtration to afford (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (443 mg, 80%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.37 (s, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.46 (s, 2H), 4.76 (d, J=5.1 Hz, 1H), 3.86 (s, 3H), 3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.55-1.69 (m, 2H), 1.11-1.33 (m, 4H). LCMS (ESI) m/z 486 and 488 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>>[CH2:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][CH2:23][S:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]1)[CH2:35][CH3:36]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Reactant: CCCc1ccccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1ccccc1OCCCCSCC1COC(CCC(=O)OCC)(CCC(=O)OCC)S1

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0 g, 0.006 mol), the bromide produced in Example 22 (1.63 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 2.78 g (87%) of the product as an oil.