Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[Cl:14][C:4]1[CH:5]=[CH:6][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:2][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 4′-chloroacetophenone and 2.53 mL of EtOAc to yield 1.7 grams of Intermediate 28: TLC analysis: Rf=0.73 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 6.13 (s, 1H), 2.2 (s, 3H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[C@@H:22]([OH:24])[CH3:23]>ClCCl>[CH:19]1([C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C@H:14]([C@@H:22]([OH:24])[CH3:23])[CH2:15]2)[CH2:21][CH2:20]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
Benzoyl isothiocyanate (47 μL, 0.35 mmol) was slowly added to a 0° C. solution of (1S)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]ethanol (C29) (0.11 g, 0.37 mmol) in dichloromethane (6 mL), and the reaction mixture was allowed to stir in the ice bath for 18 hours. After removal of solvent in vacuo, the residue was purified via chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product as an off-white foam. Yield: 94 mg, 0.20 mmol, 54%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 11.85 (v br s, 1H), 8.90 (br s, 1H), 7.91 (br d, J=7 Hz, 2H), 7.63-7.68 (m, 1H), 7.52-7.58 (m, 2H), 6.84-6.91 (m, 1H), 6.68-6.82 (br m, 1H), 3.84-3.96 (br m, 1H), 2.90-2.99 (br m, 1H), 1.84-1.94 (br m, 1H), 1.02-1.14 (br m, 1H), 0.47-0.65 (m, 3H), 0.28-0.38 (br m, 1H).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Br>CN(C=O)C.O>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:38][CH2:49][C:48]3[CH:51]=[CH:52][CH:53]=[C:46]([Cl:45])[CH:47]=3)=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1
Reactant: Clc1cccc(CBr)c1
Reactant: NC(=O)C1CCC(=CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cccc(Cl)c1)C1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33.8 %

Procedure:
To a stirred solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethylidene)cyclohexanecarboxamide (177 mg, 0.320 mmol) in anhydrous DMF (3 mL) at 0° C. was added NaH (9.0 mg, 0.384 mmol). The resulting suspension was allowed to stir at room temperature for 45 min. To the resulting solution was added 3-chlorobenzyl bromide (79 mg, 0.384 mmol). After stirring overnight, the reaction mixture was carefully diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude product was taken to next step without further purification. To a solution of the crude ether was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 80° C. for 2 h. The solution was allowed to cool to room temperature and the pH was adjusted to ˜10 with 10% NaOH (aq). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layer were washed with water, brine, and dried. The solvent was removed in vacuo to afford the crude residue, which was purified by flash column chromatography on silica gel to afford the desired product (47 mg, 0.108 mmol, 34%). 1H NMR (DMSO-d6): 1.44-1.52 (m, 4H), 1.69-1.79 (m, 4H), 2.19-2.23 (m, 1H), 3.85 (s, 2H), 4.05-4.11 (m, 2H), 6.63 (d, 1H, J=10.5 Hz), 6.88-6.93 (m, 2H), 6.99 (t, 1H, J=6.8 Hz), 7.09-7.11 (m, 2H), 7.18 (d, 1H, J=7.6 Hz), 7.25 (t, 1H, J=7.6 Hz), 7.41-7.48 (m, 2H), 7.65 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]([CH3:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[CH:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([CH3:23])[CH3:22]
Reactant: CC(C)Oc1ccccc1C1CN(Cc2ccccc2)CCO1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)Oc1ccccc1C1CNCCO1
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere combine 4-benzyl-2-(2-isopropoxyphenyl)morpholine (0.51 g, 2 mmol), 10% PdOH/Carbon (0.51 g, 10 mol %) and anhydrous ammonium formate (0.53 g, 10 mmol). Heat the resulting mixture to reflux and stir. Monitor the progress of the reaction via thin layer chromatography. After completion, filter reaction mixture through a pad of Celite®; collect the filtrate; and remove the solvent under reduced pressure to give the title compound as an oil (0.25 g, 63%). MS (m/z): 433 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21]>CS(C)=O.O>[CH3:21][O:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: CN(C)CCCO
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
3-(Dimethylamino)propan-1-ol (1 g, 10.6 mmol) was dissolved in dimethylsulfoxide (20 ml) and sodium hydride (0.42 g, 10.5 mmol) was added. After stirring at room temperature for 15 min, 1-chloro-2-methoxy-4-nitrobenzene (1 g, 5.3 mmol) in dimethylsulfoxide (10 ml) was added and the reaction mixture stirred 4 h at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase dried over magnesium sulphate and filtered. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 85%, ethyl acetate-methanol) to obtain 480 mg (34% yield) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:32]([O:31][C:29](=[O:30])[C:28]([C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])=[O:34])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccncc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-tert-Butoxycarbonylamino-pyridin-4-yl)-oxo-acetic acid ethyl ester was prepared according to a procedure described by Estel, etc (J. Heterocycl. Chem., 1989, 26, 105-): To a solution of pyridin-3-yl-carbamic acid tert-butyl ester (8.50 g, 43.8 mmol) and TMEDA (16.5 mL, 109 mmol) in THF (200 mL) at −78° C. was cannulated tert.-BuLi (64.1 mL, 1.7 M in pentane) over 30 min under nitrogen. The mixture was then stirred for 2 hours between −10° C. and −20° C. After cooling to −60° C. diethyl oxalate (17.8 mL, 131 mmol) was added and the mixture allowed to warm to 0° C. After 3 hours the mixture was poured onto ice/1M HCl (120 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (100 mL), brine (75 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (gradient, hexane/ethyl acetate 5:2, 2:1), to give 3.04 g (24% yield) of compound 146 as a yellow oil.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]([OH:38])([C@H:30]([S:32][CH:33]([CH2:36]O)[CH2:34][OH:35])[CH3:31])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:11]([C:10]1[CH:13]=[CH:14][C:7](/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C@H:2]2[O:35][CH2:34][C@H:33]([S:32][C@H:30]([CH3:31])[C@:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])([OH:38])[CH2:24][N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)[CH2:36][O:1]2)=[CH:8][CH:9]=1)#[N:12]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of 240 mg (1.31 mmol) of 4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [prepared as described in Step 1(i) above], 392 mg (1.09 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]-thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350)], 249 mg (1.31 mmol) of p-toluenesulfonic acid monohydrate, 16 ml of dichloromethane and 3.9 g of molecular sieves 4A was stirred at ambient temperature over night. Aqueous sodium hydrogen carbonate was then added to the reaction mixture and insoluble material was removed by filtration. The resulting filtrate was extracted with ethyl acetate and the organic layer was dried and then concentrated. The resulting residue was purified by chromatography on silica gel (15 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 465 mg (yield 81%) of the title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford crystals.
Reaction SMILES: [NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26].[C:34](Cl)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[C:34]([NH:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:13])=[O:14])[C:3]1=[O:26])(=[O:36])[CH3:35]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(NC(C)=O)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g of the compound obtained in EXAMPLE 16 in 10 ml of pyridine is cooled in an ice bath and 0.51 ml of acetyl chloride is added. The reaction medium is stirred for 3 hours at RT and poured into water. It is extracted with AcOEt, washed with water and with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is taken up with DCM and the precipitate formed is filtered off to give 2.8 g of the expected product, a sample of which is crystallized from an MeOH/iso ether mixture. M.p.=205°-210° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(F)c4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3cccc(F)c3)C2)n1
Temperature: 150 °C
Yield: 70.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-fluorophenyl)-3-piperidinecarboxamide (90 mg, 0.207 mmol), 3 mL of EtOH, Hunig's base (0.109 mL, 0.621 mmol), and hydrazine anhydrous (0.026 mL, 0.829 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned into black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.35-1.44 (m, 1H), 1.69 (m, 1H), 1.91-2.11 (m, 2H), 2.12-2.27 (m, 1H), 2.61-2.78 (m, 1H), 3.39-3.80 (m, 1H), 4.24-4.41 (m, 1H), 4.68-5.17 (m, 1H), 6.85 (m, 2H), 7.22-7.47 (m, 3H), 7.51-7.60 (m, 1H), 7.79 (m, 1H), 7.89-8.01 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[N:4][N:3]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:10]
Reactant: CCN
Reactant: Cc1nnc(C=O)s1
Solvent: C1CCOC1
Product: CCNCc1nnc(C)s1

Procedure:
prepared by reaction of 5-methyl-[1,3,4]thiadiazole-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=[O:47].C(N(CC)C(C)C)(C)C>O1CCCC1.[I-].[K+]>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=3)[C:46]([OH:48])=[O:47])=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21a (1.6 g, 2.56 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), 3-mercaptobenzoic acid (390 mg, 2.53 mmol, 0.99 equiv), potassium iodide (21.2 mg, 0.13 mmol, 0.05 equiv), and N,N-diisopropylethylamine (660 mg, 5.12 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 40° C. in an oil bath. The reaction progress was monitored by TLC/LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 1.12 g (63%) of product as a yellow to green solid. 1H-NMR (400 MHz, CDCl3, ppm): δ 11.68(s, 1H), 9.75(s, 1H), 8.60-8.56(d, J=9.2 Hz, 1H), 8.00(s, 1H), 7.91(s, 3H), 7.88-7.81(m, 2H), 7.80-7.79(d, J=2.1 Hz, 1H), 7.66-7.65(d, J=2.4 Hz, 4H), 7.53-7.38(m, 2H), 7.33-7.25(m, 1H), 7.10-7.08(m, 1H), 4.20(s, 2H), 3.17(s, 4H), 1.69-1.54(m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:25])=[C:11]([C:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[Mg].[F-].[K+]>CO>[CH:22]1([CH2:21][CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]=2[F:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:23][CH2:24]1
Reactant: COC(=O)C=C(CC1CC1)c1cccc(O[Si](C)(C)C(C)(C)C)c1F
Agent: [F-]
Agent: [K+]
Agent: [Mg]
Solvent: CO
Product: COC(=O)CC(CC1CC1)c1cccc(O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A 250 mL round bottom flask was charged with 84.D (4.95 g, 13.6 mmol) and MeOH (60 mL) and flushed with N2. To the solution were added magnesium turnings (0.990 g, 40.7 mmol) in one portion (a few turnings were fractured by hammering prior to addition to expose clean metallic edges). The gently bubbling mixture was stirred overnight at room temperature. To the mixture was added potassium fluoride (0.789 g, 13.6 mmol). The resulting mixture was stirred for 1 hour, quenched with 1 N HCl (90 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 84.E (2.70 g, 79% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[S:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH2:8].[CH:16]1([C:20](O)=[O:21])[CH2:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[S:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH:8][C:20]([CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)C1CCC1
Reactant: CCCCCn1c(N)c(N)c(=O)[nH]c1=S
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1c(NC(=O)C2CCC2)c(N)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The mixture of 5,6-diamino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1060 mg, 0.00464 mol), cyclobutane carboxylic acid (0.55 g, 5.5 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (2.2 g, 5.1 mmol) and triethylamine (1.3 mL, 9.3 mmol) in DMF (20 mL) was stirred at room temperature for 4 hours. The mixture was diluted with water. The precipatate formed was filtered and dried to yield the desired product (1.20 g, 83.27%). LCMS calculated for C14H23N4O2S (M+H): 311.2. Found 311.2.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH3:20])[C:6]1=[O:21])=[O:4].[NH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[C:29]1([NH:28][C:26]([C:25]2[CH:24]=[C:23]([NH:22][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH3:20])[C:6]3=[O:21])=[O:4])[CH:37]=[CH:36][CH:35]=2)=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1C(=O)N(C)c2ccc(C3(C)OCCO3)cc21
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Product: CC(=O)c1ccc2c(c1)C(C(=O)Nc1cccc(C(=O)Nc3ccccc3)c1)C(=O)N2C

Procedure:
Prepared as in Example 1 from 1-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-phenyl-benzamide. Purified by trituration in hexanes/ethyl acetate. mp 178-179° C.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][CH3:33])[CH2:26][CH2:25]3)[C:19]2=[O:34])=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][CH3:33])[CH2:28][CH2:29]3)[C:19]2=[O:34])=[CH:14][CH:13]=1
Reactant: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: COCCN1CCN(C[C@H]2CCN(c3ccc(Cl)cc3)C2=O)CC1

Procedure:
A solution of L-tartaric acid (150 mg) in ethanol (1.5 ml) was added to 1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidinone (351 mg) in ethanol (6 ml). The solid material thus precipitated was collected and subjected to desalting in an aqueous solution of sodium carbonate to obtain the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@@H:16]1[CH2:21][C@@:20]([OH:26])([C:22]([O:24][CH3:25])=[O:23])[CH2:19][C@@H:18]([CH:27]=[CH2:28])[C@@H:17]1[OH:29])(=O)C1C=CC=CC=1>CO>[OH:26][C@:20]1([C:22]([O:24][CH3:25])=[O:23])[CH2:19][C@@H:18]([CH:27]=[CH2:28])[C@H:17]([OH:29])[C@H:16]([OH:15])[CH2:21]1
Reactant: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](OC(=O)c2ccccc2)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
Potassium carbonate can be added to a room temperature solution of Example 17E in methanol. After stirring for 1 hour, the reaction mixture can be filtered, and concentrated. The concentrate can be purified by flash chromatography to afford the desired product.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]([OH:12])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]=1[NH2:39]>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][C:28]=1[NH:39][C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: COc1ccc(N2CCOCC2)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N2CCOCC2)cc1NC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with scheme 3, to a suspension of a corresponding benzoimidazole-2-carboxylic acid (XIII) was added CDI and stirred at ambient temperature for about 1 h. Then the mixture is refluxed for about 30 min. After cooling to ambient temperature, 2-methoxy-5-morpholin-4-yl-phenylamine (for R1=morpholinyl, IX) was added and the reaction mixture was heated to reflux for about 16 h. After workup, the corresponding 1H-benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (XIV) was obtained, which was then taken up in toluene and treated with Lawesson reagent. The reaction mixture was heated to reflux for about 2 h and after workup, the corresponding 1H-benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (IV) was obtained, which was then taken up in water and treated with KOH and potassium hexacyano ferrate at reflux for about 24 h to obtain the corresponding 2-(1H-benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (Ib).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>CN(C=O)C.O>[C:2]([Si:5]([CH3:7])([CH3:6])[O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(OCCO)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28 %

Procedure:
TBDMSCl silylation reagent in DMF (60 mL) was added to 3-(2-hydroxy-ethoxy)-benzaldehyde (4.985 g, 30.00 mmol). The mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 eluted with 95:5 CH2Cl2/MeOH to give 2.38 g (28%) of a clear oil.