Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Cl)c4)ncnc3cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 43 h
Yield: 98.1 %

Procedure:
To a stirred heterogeneous mixture of compound 213 (2.50 g, 5.86 mmol) and DCM (60 ml) was added trifluoroacetic acid (4.49 ml, 58.6 mmol), followed by anisole (1.28 mL, 11.7 mmol), and the mixture was stirred further at room temperature for 43 h. It was poured into petroleum ether (600 mL) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). To the solid left behind was added 5M NH3 (80 mL) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 mL), petroleum ether-ethyl acetate=3:1 (3×20 mL), and dried to give N4-(3,4-dichlorophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (222) (1.76 g, 98%), mp 277-280° C.; 1H NMR δ [(CD3)2SO] 9.83 (s, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.5 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C13H9Cl2N5.0.5H2O: C, 49.54; H, 3.20; N, 22.22. Found C, 49.70; H, 3.08; N, 22.28.
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].BrC[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH:1]=[O:4])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1cc(I)ccc1CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(I)cc1[N+](=O)[O-]
Temperature: 86 °C
Reaction time: 19 h
Yield: 60.9 %

Procedure:
NaHCO3 (3.32 g, 39.48 mmol) was added to a solution of 1-bromomethyl-4-iodo-2-nitrobenzene (2.25 g, 6.58 mmol) in anhydrous DMSO (150 mL). The mixture was stirred at 86° C. for 19 hours under a nitrogen atmosphere, then cooled down to room temperature, diluted with water (300 mL), and extracted with methylene chloride four times (250 mL). The combined organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 4-iodo-2-nitrobenzaldehyde (1.11 g, 61%). 1H NMR (400 MHz, CDCl3): δ 10.38 (d, 1H, J=1.6 Hz, CHO), 8.45 (d, 1H, J=1.5 Hz, Ph-H), 8.15 (dd, 1H, J=1.5 and 8.0 Hz, Ph-H), 7.67 (d, 1H, J=8.1 Hz, Ph-H); 13C NMR (100 MHz, CDCl3): δ 187.28 (CH), 143.18 (CH), 133.29 (CH), 130.67 (CH), 130.28 (C), 109.60 (C), 99.78 (C).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(N(CC)CC)C.[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:23](=[O:24])[C:22]([Br:21])([CH3:27])[CH3:26])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 91.2 %

Procedure:
2,4-Dinitrophenol (9.6 gm, 52 mmol) in 80 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (5.80 g, 57 mmol) followed by the dropwise addition of bromoisobutyryl bromide (15.6 g, 67 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 4 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 15.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([NH2:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[N:12]=2)=[CH:6][CH:5]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][C:27](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]3[N:17]=[C:27]2[CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][N:22]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1nccs1
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCCl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c2nc(CCc3nccs3)n(-c3ccc(CCCl)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of N2-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine (step 2, 276 mg, 1.0 mmol) and 3-(1,3-thiazol-2-yl)propanoic acid (157 mg, 1.0 mmol) in dichloromethane (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (192 mg, 1.0 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene (20 mL) and heated at 150° C. for 5 h. The reaction mixture was poured into water (50 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 210 mg (53%) of the title compound: MS (EI) m/z 396 (M+); 1H-NMR (CDCl3) δ 7.63 (1H, d, J=3.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.15 (1H, d, J=3.4 Hz), 6.93 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.69-3.50 (2H, m), 3.39-3.20 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.66 (3H, s), 2.53 (3H, s).
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:34][CH:33]=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2>CN(C=O)C>[Br-:8].[CH2:1]([N+:16]12[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:34][CH:33]=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3C[N+]4(Cc5ccccc5)CCC3CC4)oc12
Product: [Br-]
Reaction time: 20 h

Procedure:
288 μl (2.42 mmol) of benzyl bromide and 502 mg (3.63 mmol) of potassium carbonate are added to a solution of 500 mg (1.21 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102) in 12.5 ml of DMF. After 20 h at 50° C., the reaction mixture is purified by preparative HPLC. The product fractions are concentrated and, after addition of 50% strength hydrobromic acid, again concentrated and dried under high vacuum. Recrystallization from cyclohexane/acetone affords 537 mg (77% of theory) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].ClC1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([N:33]=[C:34]=S)[N:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1.C([N:39]=C=NC(C)C)(C)C>CN(C)C=O>[N:39]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][N:30]=[C:31]([NH:33][C:34]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[CH:32]=2)=[CH:23][CH:22]=1
Reactant: S=C=Nc1cc(-c2ccc(Cl)cc2)ncn1
Reactant: CC(C)N=C=NC(C)C
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cc(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.298 g, 1.300 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (1.059 g, 3.25 mmol) and 4-(4-chlorophenyl)-6-isothiocyanatopyrimidine (0.322 g, 1.300 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.608 mL, 3.90 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.104 g, 0.276 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.54 (1H, br. s.), 8.83 (1H, d), 7.89-8.04 (2H, m), 7.41-7.54 (2H, m), 7.33 (1H, br. s.), 4.02 (1H, d), 3.71 (1H, d), 3.42 (1H, d), 2.73-3.15 (5H, m), 2.10-2.31 (2H, m), 1.46-1.89 (3H, m). LCMS R.T.=1.92; [M]+=370.35.
Reaction SMILES: [CH3:1][I:2].[S:3]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4]1>CC(C)=O>[I-:2].[S:3]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N+:10]([CH3:1])[CH:11]=[CH:12][CH:13]=2)=[N:4]1
Reactant: c1cncc(-c2cnsn2)c1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2cnsn2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(1,2,5-thiadiazol-3-yl)pyridine (6 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 1.2 g (74%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl.Cl[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCn1cnc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCn3cnc4ccccc43)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
At room temperature (about 20° C.) and under a nitrogen blanket, 13.95 g of p-phenoxyphenol in 100 ml of anhydrous dimethylformamide is dripped into 6.75 g of 80% strength sodium hydride in 50 ml of anhydrous dimethylformamide. Upon completion of hydrogen evolution, the mixture is stirred for 4 hours at 60° C. At 10° C., 15.22 g of 1-chloromethylbenzimidazole hydrochloride is then added. The mixture is stirred for 8 hours at 120° C. After concentration under reduced pressure, the residue is taken up in ethyl acetate, and washed three times with water and three times with 5% strength aqueous sodium hydroxide solution. The combined organic phases are dried over sodium sulfate and concentrated. The residue is recrystallized from diethyl ether. There is obtained 11.8 g of 1-[(p-phenoxyphenoxy)-methyl]-benzimidazole of m.p. 112° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:13][CH2:14][N:15]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:16][CH2:17]2)=[C:6]([F:18])[CH:5]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 10% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (27 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.67 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.31-7.20 (m, 2H), 7.12-7.06 (m, 2H), 6.49-6.45 (m, 1H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 3.86 (s, 0.9H), 3.85 (s, 2.1; H), 3.81-3.75 (m, 4H), 3.15-3.08 (m, 4H); LC/MS m/z (M+H)+ 470.4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[F:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:31]2[CH2:32][CH2:33][C@H:29]([F:28])[CH2:30]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: F[C@H]1CCNC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (135 mg, 0.477 mmol) in MeOH (4768 μL) was added DIPEA (208 μL, 1.192 mmol), then (S)-3-fluoropyrrolidine (46.7 mg, 0.524 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solvent was removed and the residue applied to Silica gel and eluted with an EtOAc/Hex gradient to afford two diasteriomers (Hp1 and Hp2). Hp1: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.13 (2H, m), 6.93-7.00 (2H, m), 5.32 (1H, td, J=52.57, 3.17 Hz), 4.17 (1H, dd, J=9.16, 5.49 Hz), 4.06-4.14 (1H, m), 3.98-4.06 (1H, m), 3.76-3.90 (2H, m), 3.25 (1H, ddd, J=15.11, 8.55, 6.26 Hz), 3.08-3.16 (1H, m), 2.51-2.60 (1H, m, J=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1H, m), 2.00-2.17 (2H, m). Hp2: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.14 (2H, m), 6.94-7.02 (2H, m), 5.25-5.40 (1H, m), 3.99-4.24 (3H, m), 3.75-3.92 (2H, m), 3.19-3.28 (1H, m), 3.10-3.19 (1H, m), 2.57 (1H, dddd, J=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1H, m), 1.94-2.17 (2H, m)
Reaction SMILES: [OH-:1].[K+].O.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH2:28][CH2:27][CH:26](C(OCC)=O)[CH2:25][C:24]1=C.Cl.[CH2:36]([OH:38])[CH3:37]>>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH2:28][CH2:27][C:26](=[CH:37][C:36]([OH:1])=[O:38])[CH2:25][CH2:24]1
Reactant: [OH-]
Reactant: C=C1CC(C(=O)OCC)CCN1c1cc(C)nc2c(-c3ccc(Cl)cc3Cl)cccc12
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc(N2CCC(=CC(=O)O)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 0.5 h

Procedure:
In a mixed solvent of 85% potassium hydroxide (1.3 g) and water (1.4 mL)-ethanol (8 mL), 8-(2,4-dichlorophenyl)-2-methyl-4-(4-ethoxycarbonyl-methylidenepiperidin-1-yl)quinoline (2.3 g) was stirred at 80° C. for 1 hour. The reaction mixture was neutralized with 3 M hydrochloric acid under ice-cooling and stirred under ice-cooling for 2 hours and then at room temperature for 30 minutes. The solid precipitated was collected by filtration to obtain a mixture (1.5 g) of 2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-piperidin-4-ylidene}acetic acid and 2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridin-4-yl}acetic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH3:7]OC(OC)OC.[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>CC(O)C>[NH:3]1[C:2]([NH:1][CH:7]=[N:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]([O:23][CH3:24])=[O:22])=[N:6][N:5]=[N:4]1
Reactant: COC(=O)c1ccccc1N
Reactant: Nc1nnn[nH]1
Reactant: COC(OC)OC
Solvent: CC(C)O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 80 °C
Reaction time: 0.58 h

Procedure:
A mixture of 5 g of 5-aminotetrazole and 150 ml of 2-propanol was heated to 80° C. under nitrogen. To the resulting heterogeneous mixture was added 7 g of trimethoxymethane and 9.3 g of methyl anthranilate. The mixture was stirred for 35 minutes and then cooled to 30° C. The white crystals which formed were separated by filtration, washed with 2-propanol and vacuum oven dried to give N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine.
Reaction SMILES: [OH:1][C@H:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][O:4][C:3]1=[O:9].C(N(C(C)C)CC)(C)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].Cl>ClCCl.CCOC(C)=O>[CH3:7][C:6]1([CH3:8])[CH2:5][O:4][C:3](=[O:9])[CH:2]1[O:1][C:19](=[O:22])[CH:20]=[CH2:21]
Reactant: CC1(C)COC(=O)[C@H]1O
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC(=O)OC1C(=O)OCC1(C)C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R) was prepared in the following manner: 3-(S)-Hydroxy-4,4-dimethyl-dihydro-furan-2-one (2.60 g, 20 mmol) and diisopropylethylamine (5.2 mL, 30 mmol) in dichloromethane (25 mL) was cooled to −10° C. and treated dropwise with acryloyl chloride (2.03 mL, 25 mmol) and stirred for 2 h. 1M HCl (20 mL) was added and the organic layer was washed with sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-40% EtOAc, hexanes) afforded 2.09 g (57% yield) of the desired acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R) as a clear oil. This substrate was used to prepare the acid chloride of (1R)-4-methyl-cyclohex-3-enecarboxylic acid analogous to the procedure described in Scheme 15 and Scheme 16.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27](O)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.[NH2:41][C@:42]1([C:49]([NH:51][S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[O:50])[CH2:44][C@H:43]1[CH2:45][CH:46]([F:48])[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:14]([CH3:17])([CH3:15])[CH3:16])[C@H:9]([C:27](=[O:28])[NH:41][C@:42]3([C:49](=[O:50])[NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[CH2:44][C@H:43]3[CH2:45][CH:46]([F:47])[F:48])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1CC(F)F
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@H]2CC(F)F)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
To a solution of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (15 mg, 0.026 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-(2,2-difluoroethyl)cyclopropanecarboxamide (8.84 mg, 0.029 mmol), and HATU (15.03 mg, 0.040 mmol) in DMF (1 mL) was added N,N-Diisopropylethylamine (0.014 mL, 0.079 mmol). The formed light yellow solution was stirred at room temperature for 5 h. Diluted with MeOH, purified by prep-HPLC to yield the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (14 mg, 0.015 mmol, 58.3% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 0.83 (t, J=7.17 Hz, 3H), 1.09-1.12 (m, 10H), 1.22-1.45 (m, 7H) 1.47-1.52 (m, 10H), 1.66 (s, 2H), 2.07-2.38 (m, 4H), 2.37-2.51 (m, 1H), 2.76-2.87 (m, 1H), 2.91-3.04 (m, 11H), 3.85-4.06 (m, 2H), 4.51 (d, J=9.77 Hz, 1H), 5.05 (d, J=11.29 Hz, 1H), 5.73-6.09 (m, 1H), 7.37 (t, J=7.02 Hz, 1H), 7.46 (t, J=7.48 Hz, 2H), 7.54-7.64 (m, 4H), 7.68 (d, J=8.24 Hz, 2H). LC-MS (retention time: 3.48 min, method B), MS m/z 819 (M+H).
Reaction SMILES: FC1C=CC2OC(C(N3CCN(CC4C=CC=CC=4)CC3)=O)CC=2C=1.Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH:32]([C:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:43][CH2:42]1)=O)[CH2:33][O:34]2>>[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH:32]([CH2:39][N:41]1[CH2:42][CH2:43][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:46]1)[CH2:33][O:34]2
Reactant: COc1cccc2c1CC(C(=O)N1CCN(Cc3ccccc3)CC1)CO2
Agent: Cl
Agent: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Product: COc1cccc2c1CC(CN1CCN(Cc3ccccc3)CC1)CO2
Yield: 42 %

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl) carbonyl]-4-benzylpiperazine with the hydrochloride of 1-[(5-methoxychroman-3-yl) carbonyl]-4-benzylpiperazine obtained in Stage A, the title product is obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:34].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)(=[O:34])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidine-4-sulfinyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 223 (86 mg, 0.19 mmol) in DCM (7 mL) was added TFA (74 μL, 0.953 mmol) followed by a slow addition of a solution of m-CPBA (43 mg, 0.248 mmol) in DCM (2 mL) and the resulting mixture was stirred for 3 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further column chromatography purification (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 224 as a white solid (69 mg, 77%). LCMS: RT 2.08 min [M+H]+ 467.1. 1H NMR (DMSO, 400 MHz): δ 8.95 (1H, d, J=2.41 Hz), 8.40 (1H, d, J=4.98 Hz), 7.96 (1H, s), 7.80 (1H, s), 7.70 (1H, dd, J=8.62, 2.44 Hz), 7.29 (1H, d, J=8.62 Hz), 7.09 (1H, dd, J=5.05, 1.56 Hz), 4.65-4.55 (4H, m), 3.24-3.15 (1H, m), 2.83 (2H, bd, J=11.14 Hz), 2.70-2.60 (1H, m), 2.41 (3H, s), 2.09 (2H, t, J=11.51 Hz), 1.88 (2H, d, J=12.14 Hz), 1.54-1.41 (2H, m), 0.90 (6H, d, J=6.55 Hz)