Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=[O:9])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.CI.[H-].[Na+].[C:27](OCC)(=O)C>O1CCCC1.O>[S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH3:27])[C:8]([OH:10])=[O:9])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1csc2ccccc12)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1csc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(2R)-3-(Benzo[b]thiophen-3-yl)-2-tert-butoxycarbonylamino-propionic acid (2.65 g; 8.25 mmol) was dissolved in dry tetrahydrofuran. Methyl iodide was added and the reaction mixture was cooled to 0° C. Sodium hydride (60% in mineral oil, 0.80 g, 24.8 mmol) was added. The reaction mixture was stirred for 48 hours at room temperature. Ethyl acetate (25 mL) and water (10 mL) were added dropwise. The solvent was removed in vacuo and the residue was dissolved in ether (1 5 mL) and water (15 mL). The organic phase was washed with an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL). To the aqueous phase was added citric acid (5%) until pH 3 and extracted with ethyl acetate (4×20 mL). The combined organic phases were washed with water (2×30 mL), an aqueous solution of sodium thiosulfate (5%; 30 mL) and water (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was dissolved in ether (10 mL). Dicyclohexylamine (5 mL) was added. The precipitated crystals were filtered off, washed with ether (2×10 mL) and dissolved in water (30 mL). An aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and ethyl acetate (40 mL) were added. The aqueous phase was extrated with ethylacetate (4×30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 3.75 g of (2R)-3-(benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonyl methylamino)propionic acid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[CH2:14][O:15][C:16]3[CH:30]=[CH:29][C:19]([CH2:20][N:21]4[CH2:24][CH:23]([C:25]([O:27]C)=[O:26])[CH2:22]4)=[CH:18][CH:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[CH2:14][O:15][C:16]3[CH:30]=[CH:29][C:19]([CH2:20][N:21]4[CH2:22][CH:23]([C:25]([OH:27])=[O:26])[CH2:24]4)=[CH:18][CH:17]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COC(=O)C1CN(Cc2ccc(OCc3ccc(OC)c(C45CC6CC(CC(C6)C4)C5)c3)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: COc1ccc(COc2ccc(CN3CC(C(=O)O)C3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 61 %

Procedure:
When the product of Step C was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar procedure afforded the title compound in 61% yield, as creamy solid. 1H-NMR (CDCl3:CD3OD) 7.33 (d, 2H, J=8.59 Hz); 7.17-7.12 (m, 2H); 6.92 (d, 2H, J=8.64 Hz); 6.79 (d, 1H, J=8.21 Hz); 4.87 (s, 2H); 4.13 (s, 2H); 4.08-4.02 (m, 4H); 2.0 (s, 6H); 1.97 (s, 3H); 1.68 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>C1COCC1.CCCCC.C(OCC)(=O)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: CN1CCC(O)(c2ccc3[nH]ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 5-bromo-1H-indole (5.0 g, 25.5 mmol) in THF at −10° C. under argon, was added a solution of potassium hydride (1.13 g, 28.1 mmol) in THF (7 mL). The reaction mixture was then cooled to −78° C., and t-butyllithium (52.5 mL of a 1.7 M solution in pentane, 89.3 mmol) was added slowly, via syringe. The mixture was stirred for 15 minutes, and 1-methyl-4-piperidone (6.75 mL, 54.8 mmol) was quickly added. After the mixture was stirred at −78 ° C. for one hour, the solution was warmed to −20° C. and poured into a mixture of a buffer solution (20 mL, pH 7.0) and ethyl acetate (30 mL). The organic layer was washed with brine (30 mL) and dried (Na2SO4). The product was purified by column chromatography over silica gel using 5% 2M ammonia in methanol in dichloromethane as the eluent to provide the title compound (1.95 g, 35%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([CH2:11][S:12][C:13](=[O:15])[CH3:14])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:20][C:21]([NH:23][CH2:24][C:25]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]([CH2:11][S:12][C:13](=[O:15])[CH3:14])[C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(=O)SCC(C(=O)O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Product: CC(=O)SCC(C(=O)O)C1CCN(C(=O)CNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2-(piperidin-4-yl)-3-(acetylthio)propanoic acid (0.6 g, 1.72 mmol) and Boc-glycine-N-hydroxysuccinimide ester (0.52 g, 1.9 mmol) was stirred in 15 mL of dioxane for 18 hours. The reaction mixture was concentrated, partitioned between ethyl acetate and 1 M NaHSO4. The organic layer was concentrated to give 2-(1-(t-butoxycarbonylaminomethylcarbonyl)-piperidin-4-yl)-3-(acetylthio)propanoic acid, which was dissolved in 10 mL of 1:1 methylene chloride-TFA for 1 hour. The reaction mixture was then concentrated. The resulting residue was dissolved in water-methanol, cooled to 0° C. and purged with nitrogen gas. Aqueous NH4OH was added and the resulting reaction mixture was stirred for 1 hour and then concentrated to an oil. Purification by prep HPLC afforded 65 mg of 2-(1-(aminomethylcarbonyl)-piperidin-4-yl)-3-mercaptopropanoic acid; NMR (D2O) 1.2-1.21 (m, 2), 1.51-1.82 (m, 3), 2.30-2.40 (m, 1), 2.48-2.71 (m, 2), 2.90-3.00 (m, 1), 3.55 (m, 1), 3.82 (m, 2), 4.21 (m, 1) ppm.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>CN(C=O)C>[C:15]1([C:2]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[N:21][C:3]=2[C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)C(Br)c2ccccc2)cc1
Reactant: Nc1nccs1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3sccn3c2-c2ccccc2)cc1

Procedure:
0.7 g (2.1 mM) of methyl 4-[bromo(phenyl)acetyl]benzoate and 2-aminothiazole (2.5 eq) are stirred in 20 ml DMF at 90° C. for 6 h. The DMF is evaporated and the crude product is purified by column chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:44](Cl)(=[O:46])[CH3:45].ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[C:44]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([NH:23][C:21]2[N:22]=[C:17]3[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=4)=[C:15]([CH3:43])[C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][N:18]3[N:20]=2)=[O:25])[CH2:32][CH2:31]1)(=[O:46])[CH3:45]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: CC(=O)N1CCC(NC(=O)Nc2nc3c(-c4cccc(C(F)(F)F)c4)c(C)c(-c4ccnn4-c4ccc(C#N)cc4)cn3n2)CC1

Procedure:
The title compound was prepared from 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 50 mg, 0.085 mmol) and acetyl chloride (80 mg, 0.102 mmol) using a similar method to that employed for Intermediate 17 (30 mg).
Reaction SMILES: [CH:1]1([C:7]2[N:8]([C:12]3[C:21]([N+:22]([O-])=O)=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:25][CH3:26])[CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+].N>O1CCCC1.C(OCC)(=O)C.O>[NH2:22][C:21]1[C:12]([N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][C:14]([O:25][CH3:26])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)cc1OC
Agent: N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(-n2ccnc2C2CCCCC2)cc1OC
Yield: 73.7 %

Procedure:
To 13.51 g of methyl 4-(2-cyclohexyl-1H-imidazol-1-yl)-2-methoxy-5-nitrobenzoate as synthesized in above Production Example 27, acetic acid 55 mL and water 55 mL were added and heated to form a solution, to which 22.59 g of 87% sodium hyposulfite was added little by little, followed by heating under reflux for 3.2 hours. The reaction liquid was cooled with ice, to which ethyl acetate and tetrahydrofuran were added, and it was rendered weakly alkaline by addition of 25% aqueous ammonia little by little. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate and removed of the solvent by distillation to provide 9.13 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[I-:37].[K+].[OH-].[K+].BrCCCCCCCCCC>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][C:9]([I:37])=[CH:8][CH:7]=3)[C:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:13]=2[CH:14]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: [I-]
Agent: CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 24 h
Yield: 81 %

Procedure:
To a mechanically stirred mixture of 7-iodo-2-bromofluorene (example 2; 41.34 g, 0.1 114 mol), DMSO (100 mL), potassium iodide (1.79 g), and powdered potassium hydroxide (28 g) cooled in a cold water bath, 1-bromodecane (53 mL) was added dropwise, and the mixture was stirred for 24 hours. The oil that separated on dilution with water, was extracted with toluene. Toluene extract was washed with water, dried and concentrated. The residual oil was passed through a column of 300 g alumina. Elution with 900 mL hexanes gave the product as an oil, 65 g. This was left in 200 mL of isopropanola when the product solidified, 58.63 g (81% yield), m.p. 43-45° C. Mass Spec. (m/z): 698 (M+ diiodo), 650, 652 (M+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([N+:13]([O-])=O)[C:7]=1[OH:16]>C(O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH2:13])[C:7]=1[OH:16]
Reactant: O=C(NCC(F)(F)F)c1cc(F)cc([N+](=O)[O-])c1O
Solvent: CCO
Product: Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
7.05 g (25 mmol) of 5-fluoro-2-hydroxy-3-nitrobenzoic acid-(2,2,2,-trifluoro-ethyl)amide is dissolved in 70 ml of ethanol, 5.65 (25 mmol) of SnCl2 ·H2O is added and the suspension is stirred for 2 hours at 70° C. The reaction mixture is then concentrated by evaporation to oil and used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[N:10]#[C:11]Br.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][C:11]#[N:10]
Reactant: Cc1cc(Cl)ccc1O
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1cc(Cl)ccc1OC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-chloro-2-methyl phenol (10g, 0.07 mol) and cyanogen bromide (7.4g, 0.07 mol) were stirred in acetone at 0° C. and triethylamine (9.7 ml, 0.07 mol) was added dropwise. The mixture was stirred at 0° C. for a further 2 hours, then filtered. The filtrate was concentrated using a rotary evaporator to leave the desired product as a fawn solid. This was used without further purification. The melting point of the product, after recrystallisation from ethyl acetate/hexane, was found to be 60° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OC([N:23]=[C:24]([N:26](C(OC(C)(C)C)=O)[O:27][CH2:28][CH2:29][NH:30][C:31](=[O:54])[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[C:35]([NH:41][CH2:42][C:43]([F:52])([F:51])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)[C:34]=1[F:53])[NH2:25])=O)(C)(C)C>C(Cl)Cl>[C:24]([NH:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:54])[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[C:35]([NH:41][CH2:42][C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=2)([F:51])[F:52])[C:34]=1[F:53])(=[NH:23])[NH2:25]
Reactant: CC(C)(C)OC(=O)N=C(N)N(OCCNC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(Cl)c2)c1F)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCC(F)(F)c2cccc(Cl)c2)c(F)c1CC(=O)NCCONC(=N)N
Reaction time: 10 h
Yield: 84.1 %

Procedure:
A solution of TFA (7.5 mL, 97 mmol) and anisole (3.0 mL, 27.6 mmol) in DCM (23 mL) was added to N-[2-(N′,N″-bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(3-chlorophenyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (2.18 g, 3.26 mmol), as prepared in the preceding step, at room temperature. The dark yellow solution was stirred for 10 h, and then concentrated. The residue was subjected to flash chromatography (DCM/MeOH saturated with gaseous NH3; 95:5→90:10) to yield 1.286 g (84%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.57-7.55 (m, 1H), 7.51-7.40 (m, 3H), 7.27 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.77 (t, J=8.4 Hz, 1H), 3.93 (t, J=13.6 Hz, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.74 (d, J=2.0 Hz, 2H), 3.43 (t, J=5.4 Hz, 2H). LC/MS (ESI) calcd for C20H21ClF3N6O2 (MH+) 469.1. found 469.2.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]4[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH:8]=3)[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Product: Cc1ccc(Oc2cccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methylphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 443.2 (M+H)+.
Reaction SMILES: COC1C=CC(CSC2NC(C)=C(C(OCC)=O)C([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)N=2)=CC=1.N1C=CC=CC=1.ClC(OC(C)C)=O.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][S:54][C:55]2[N:56]([C:76]([O:78][CH:79]([CH3:81])[CH3:80])=[O:77])[CH:57](C3C=CC=C([N+]([O-])=O)C=3)[C:58]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:59]([CH3:61])[N:60]=2)=[CH:49][CH:48]=1>ClCCl>[CH3:81][CH:79]([O:78][C:76]([N:56]1[CH2:57][C:58]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:59]([CH3:61])[N:60]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH:55]1[S:54][CH2:53][C:50]1[CH:49]=[CH:48][C:47]([O:46][CH3:45])=[CH:52][CH:51]=1)=[O:77])[CH3:80]
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc([N+](=O)[O-])c2)C(SCc2ccc(OC)cc2)N(C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (2.0 g., 4.5 mmole) in dichloromethane (20 ml.) containing pyridine (0.71 g., 9.1 mmole) is cooled to -10° and treated dropwise with a solution of isopropyl chloroformate (0.66 g., 5.4 mmole) in dichloromethane (3 ml.). After stirring at room temperature for 16 hours, dichloromethane is added and the solution is washed with water, 1N hydrochloric acid, sodium bicarbonate, and brine. The dried solution is evaporated to give 2.6 g. of an oil. Flash chromatography using dichloromethane gives 2.3 g. of 2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, 5-ethyl 1-(1-methylethyl) ester as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[NH:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C@H:26]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C@@H:30]([O:37]C(=O)C)[C@H:29]([C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[CH2:19][CH2:18]1>CO>[O:7]=[C:8]1[NH:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]1[CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C@H:26]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C@@H:30]([OH:37])[C@H:29]([C:41]3[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=3)[CH2:28][CH2:27]2)=[O:24])[CH2:21][CH2:22]1
Reactant: CC(=O)O[C@@H]1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)[C@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
MS(ESI)[M+H+]=578.26. Potassium carbonate (785 mg, 5.68 mmol) was added to the methanol (5 mL) solution of (5S,6S,9R)-5-acetoxy-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (328 mg, 0.568 mmol) at room temperature. The reaction was stirred at room temperature for 1 h before removal of the solvent. The crude was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed again with water before dried (sodium sulfate), filtered and concentrated. Flash chromatography using methanol in methylene chloride from 0 to 10% gave the desired product (135.3 mg, 42%). HPLC tR=2.17 min, MS(ESI)[M+H+]=536.26, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.61 (br. s., 1H) 8.52 (d, J=3.78 Hz, 1H) 7.97-8.14 (m, 2H) 7.23-7.58 (m, 2H) 7.02 (dd, J=7.81, 5.29 Hz, 1H) 6.80-6.90 (m, 2H) 6.75 (tt, J=8.84, 2.23 Hz, 1H) 5.94 (br. s., 1H) 5.15 (d, J=9.57 Hz, 1H) 4.31-4.79 (m, 3H) 2.87-3.26 (m, 2H) 2.68-2.80 (m, 1H) 2.03-2.55 (m, 5H) 1.76-2.00 (m, 3H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −108.58 (br. s., 2F).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[NH:20][CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][C:21]3([N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:18](=[O:34])[CH:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:20]3)[CH2:22][CH2:23]2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC2(CCN(C(=S)Nc3ccccc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Phenyl isothiocyanate (203 mg, 1.50 mmol) was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (505 mg, 1.50 mmol) in toluene (14.3 ml) with stirring under a blanket of nitrogen at RT and the reaction mixture was stirred at 50° C. for 8 h. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-thiocarboxylic acid phenylamide was obtained by means of preparative HPLC.
Reaction SMILES: [CH2:1]([C:3]([NH:8][C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1([CH2:4][CH3:5])[CH2:6][O:7][C:34](=[O:36])[N:8]1[C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1(CC)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2-{[1-Ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.29 g, 0.89 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL) and diisopropylethyl amine (0.37 mL, 2.1 mmol) was added and the mixture was cooled to 0° C. Triphosgene (108 mg, 1.07 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10%-15% ethyl acetate in hexane) afforded the title compound (230 mg, 73%) as a white solid. HRMS: calcd for C19H19N3O2S+H+, 354.12707. Found (ESI-FT/MS, [M+H]1+), 354.127; Analytical HPLC: purity 98.1% at 210-370 nm, 10.7 min.; 98.8% at 316 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:20])[C:11]([Cl:19])=[C:12](C(O)=O)[N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:20])[C:11]([Cl:19])=[CH:12][N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)c(Cl)c1C(=O)O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c(=O)c(OCc2ccccc2)c1
Yield: 94.2 %

Procedure:
5-(Benzyloxy)-3-chloro-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (3.50 g, 11.9 mmol) was heated in DMF (10 mL) for one hour. The reaction mixture was concentrated by rotary evaporation and the residue was triturated with ethyl acetate/ether to give 3-(benzyloxy)-5-chloro-1-methylpyridin-4(1H)-one (2.80 g) as a pale brown solid. Yield=94%; 1H NMR (DMSO-D6, 90 MHz) δ (ppm): 8.08 (d, J=1.8 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.19-7.58 (m, 5H), 5.01 (s, 2H) and 3.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH:13]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])([CH3:15])[CH3:14]>C(O)(C)C>[CH:13]([O:16][C:17]([C:18]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])[CH:5]=[C:6]([CH3:7])[NH:21][C:19]=1[NH2:20])=[O:22])([CH3:15])[CH3:14]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: CC(=O)C=Cc1ccccc1Cl
Solvent: CC(C)O
Product: CC1=CC(c2ccccc2Cl)C(C(=O)OC(C)C)=C(N)N1
Yield: 51 %

Procedure:
Upon heating a solution of 18.1 g of 2-chlorobenzylideneacetone and 14.1 g of amidinoacetic acid isopropyl ester in 200 ml of isopropanol for 3 hours, 2-amino-6-methyl4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester of melting point 161°C (isopropanol) is obtained. Yield: 51 percent of theory.