Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH3:12]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCOCC1>[NH2:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: Brc1cncc2ccccc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cncc2ccccc12
Temperature: 165 °C
Reaction time: 21 h

Procedure:
A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfate pentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and 1,4-dioxane (100 ml) was stirred in a sealed tube at 165° C. for 21 hours. The reaction mixture was cooled to room temperature, the insoluble matters were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (13.2 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[OH:18]O>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:18])=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OB(c2cnc(Br)c(Cl)c2)OC1(C)C
Solvent: CO
Product: Oc1cnc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
To crude 2-bromo-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 238, 8.27 g, 26.0 mmol) was added methanol (100 mL), and the stirred solution cooled in an ice bath. To the solution was added hydrogen peroxide solution (35% in water, 4.25 mL, 43.8 mmol) over 5 minutes. The solution was allowed to warm slowly to room temperature for 18 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (500 mL), with rapid stirring for 15 minutes. The organics were removed in vacuo, and brine (100 mL) was added. The aqueous phase was extracted into ethyl acetate (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to leave an off white solid. The solid was triturated in 4:1 heptene:ethyl acetate and filtered to afford the title compound as a white solid (2.20 g, 41%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.00 g (3.80 ml, 26.3 mmol) 4-trifluoromethoxy-benzaldehyde, 3.10 g (30.0 mmol) malonic acid, 0.26 g (3.0 mmol) piperidine and 15.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 50 g ice and 15 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 5.20 g (85%) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.[OH-].[Na+]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCSc2nc3ccccc3[nH]2)ccnc1CSc1ccncc1
Yield: 83 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-mercaptobenzimidazole in the presence of sodium hydroxide solution gives, after crystallization from dichloromethane/diisopropyl ether, the title compound; m.p. 128-129° C.; yield 83% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]([N:14]=[C:15]=[S:16])(=[O:13])[O:10][CH2:11][CH3:12]>O1CCOCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:9]([NH:14][C:15]([NH:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[S:16])=[O:13])[CH3:12]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc(Cl)ccn1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 4-chloropyridin-2-amine (2.16 g, 16.8 mmol, Eq: 1.00) in dioxane (70 ml) was added O-ethyl carbonisothiocyanatidate (2.2 g, 1.9 ml, 16.8 mmol, Eq: 1.00) at 25° C. The resulting mixture was stirred for 2 hours at 25° C. The mixture was diluted with ethyl acetate and washed with water and brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1-ethoxycarbonyl-3-(4-chloro-pyridin-2-yl)-thiourea (4.02 g/92.1%) as a green waxy solid. MS: m/e=257.9 (M−H+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[N:22]1([CH2:21][C:20]2[C:13]3[O:12]/[C:11](=[CH:10]\[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)/[C:15](=[O:16])[C:14]=3[CH:17]=[CH:18][C:19]=2[OH:36])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCCNCC1
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-1,4-diazepane-1-carboxylate (0.141 g, 0.288 mmol) in methylene chloride (1.5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (1.5 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting solid was washed with methylene chloride to obtain (Z)-7-[(1,4-diazepan-1-yl)methyl]-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.0843 g, 75%).
Reaction SMILES: [ClH:1].C([C:4](=[C:10]([CH3:16])[CH:11]=[CH:12][N:13](C)[CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#N>C(O)C>[Cl:1][C:14]1[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Reactant: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
Hydrogen chloride was introduced to a stirred mixture of 164 g (0.839 mole) of crude ethyl 2-cyano-5-(N,N-dimethylamino)-3-methyl-2,4-pentadienoate (5) in 500 mL ethanol at 20-45° C. The mixture was stirred at ambient temperature overnight, then heated to reflux for 8 hours. The ethanol was removed under reduced pressure and the residue distilled under high vacuum at 84-94° C., to give 47.7 g (30.4%) of a yellow oil, MH+ 200, NMR (CDCl3), ppm: 1.42 (t,3H); 2.36 (s,3H); 4.46 (q,2H); 7.12 (d,lH); 8.28 (d,1H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:18])=[O:5])=[C:10]([C:16]#[CH:17])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#Cc1cc(Cl)ccc1OCC(=O)O
Reaction time: 8 h

Procedure:
A solution of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3; 500 mg; 1.87 mmol) in DCM (2.5 ml) was treated with a 4 N solution of HCl in dioxane (14 ml; 56 mmol) and stirred overnight. The solvents were removed under reduced pressure, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.[I-].[K+].[CH3:18][NH:19][CH2:20][CH3:21]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][N:19]([CH2:20][CH3:21])[CH3:18])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Reactant: CCNC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C)CC(=O)N1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A suspension of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (1 g, 3.47 mmol) and potassium iodide (0.115 g, 0.693 mmol) in 10 mL THF was treated with N-methylethanamine (1.786 mL, 20.79 mmol). The mixture was stirred at room temperature for 2 hours then heated at 65° C. for 1 hour. The mixture was concentrated and partitioned between CH2Cl2 (100 mL) and saturated sodium bicarbonate (25 mL). After extraction, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a light brown residue. This residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a light brown residue (1.06 g, 98%). 1H-NMR (CDCl3) δ 7.52-7.40 (br s, 1H), 7.30-7.27 (m, 2H), 3.80 (t, J=6.0 Hz, 2H), 3.28 (s, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.50 (quart, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.96 (quint, J=6.6 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). MS (ESI): 311.1 and 313.1 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1.O.NN>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccncc2)o1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccncc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of (2-methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (1 g, 3.39 mmol) in ethanol (50 mL) was treated with 10% Pd/C (120 mg) and hydrazine hydrate (3.50 mL, 112.5 mmol) was added drop wise over 10 min. The reaction mixture was stirred at room temperature for 30 min and then refluxed for 2 h. The hot solution was filtered through a short pad of Celite, and the catalyst was washed with hot ethanol. The filtrates were concentrated under reduced vacuum to give the crude product. This was silica gel column chromatographed (dichloromethane/ethanol: 97/3). 720 mg (80%) of (2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine was obtained as pale yellow powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:22])[C:18]([O:20]C)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:22])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)=CCc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=CCc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Yield: 49 %

Procedure:
A mixture of 615 mg of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-butenoate, 6.2 ml of ethanol, 0.6 ml of water and 0.4 ml of a concentrated aqueous solution of potassium hydroxide was refluxed for 1 hour and then was evaporated to dryness under reduced pressure. The residue was taken up in water and the solution was treated with activated carbon, filtered and acidified to a pH of 1 with 2 N hydrochloric acid. The solution was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel with 90-10 ether-methylene chloride eluant to obtain 287 mg of 4-(m-benzoyl-phenyl)-2-methyl-2-butenoic acid in the form of an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][CH:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22]>>[C:3]([C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([CH:20]([F:19])[C:21]([F:23])([F:24])[F:22])=[CH:33][CH:32]=1)([CH3:18])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)C(F)(F)F)cc1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (35 mg, described in Example 39) and 4-(1,2,2,2-tetrafluoroethyl)benzoyl chloride, the title compound was isolated as a solid (6.2 mg, 11%). MS (ES): M/Z [M+H]=508. NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H), 5.20 (d, J=13.8 Hz, 1H), 5.53 (d, J=13.8 Hz, 1H), 5.69 (dq, J=44.3 Hz, 5.9 Hz, 1H), 7.54 (br.s, 1H), 7.58 (s, 1H), 7.60 (d, J=8.1 Hz, 2H) and 7.98 (d, J=8.2 Hz, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −197.6-−197.1 (m, 1F), −79.0 (q, J=5.9 Hz, 3F).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.[H-].[Na+]>>[CH3:1][Si:2]([CH3:17])([CH3:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]2[CH2:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1
Reactant: ClCc1nccs1
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1nccs1
Yield: 66.5 %

Procedure:
This compound was prepared according to a process similar to that described in step 20.2, by reacting 570 mg (2.18 mmol) of ethyl 6-trimethylsilyl-1H-indole-2-carboxylate with 440 mg (3.27 mmol) of 2-(chloromethyl)thiazole in the presence of 0.14 g (3.27 mmol) of sodium hydride (55%). The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate, to give 520 mg of the expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[CH3:12].C[Mg]Cl.CC([Li])CC.CN(C)[CH:23]=[O:24].Cl>C1COCC1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:12])=[N:6][NH:7]2)=[CH:3][C:2]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1n[nH]c2cc(F)c(Br)cc12
Agent: C[Mg]Cl
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(F)c(C=O)cc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 30 g (131 mmol) 5-bromo-6-fluoro-3-methyl-1H-indazole [preparation described in WO 2005/085227-A1, Example 104c); also commercially available, CAS Reg.-No. 864773-66-0] in THF (525 ml) was cooled to −45° C. A solution of methylmagnesium chloride in THF (3 M; 50.2 ml, 151 mmol) was added dropwise at −45° C., and the resulting solution was stirred for 40 min at this temperature. Using a dosing pump, 253 ml (354 mmol) of 2-butyllithium solution (1.4 M in cyclohexane) were added so that the temperature did not exceed −40° C. The resulting mixture was stirred for 30 min at −40° C., and then 30.2 ml (393 mmol) N,N-dimethylformamide were added dropwise keeping the temperature at −40° C. The resulting mixture was stirred for 30 min at −40° C., then allowed to warm up to room temperature, and slowly poured into a volume of 2.8 L of 2 N hydrochloric acid cooled to 5° C. (ice-water bath). The mixture was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography on silica gel (eluent: pentane/ethyl acetate 6:4 v/v) to afford 19.6 g (78% of th.) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[NH:10][C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[N:10]([CH3:19])[C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
In 20 ml of dry acetone was dissolved 930 mg (3.3 mmol) of 5-(3,5-dichlorobenzyl)-4-isopropyl-2-methyl-1H-imidazole (54), followed by addition of 1.4 g (10.1 mmol)of anhydrous potassium carbonate, and the mixture was stirred at room temperature. After 5 minutes, 225 μl (3.6 mmol)of methyl iodide was added at room temperature, and the mixture was heated to 80° C. After 5 hours, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate)to give 218 mg of the target compound (Compound I-100)(yield 22%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)[CH3:16]
Reactant: O=C1CCOCC1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(CNC1CCOCC1)OCC
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (10.6 g) was added to a cooled (0° C.) solution of aminoacetaldehyde diethyl acetal (5.8 mL) and tetrahydro-4H-pyran-4-one (3.7 mL) in dichloromethane (100 mL). The reaction was stirred for 18 h, allowing the temperature to warm to ambient conditions. Water (100 mL) was added, followed by portionwise addition of sodium bicarbonate (16.8 g), causing effervescence. The mixture was stirred vigorously for 1 h, and then allowed to partition. The phases were then separated and the aqueous phase extracted with more dichloromethane (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the titled compound as a colourless oil. Yield 8.3 g.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:19][C:14]1[CH:13]=[C:12]([N:7]2[CH2:8][C:9]3[CH:10]=[N:11][C:2]([Cl:1])=[CH:3][C:4]=3[N:5]([CH3:23])[C:6]2=[O:22])[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21

Procedure:
By analogy to Example A24, 6-chloro-4-(methylamino)nicotinaldehyde (from Example A24), 4-fluoro-3-nitroaniline and sodium triacetoxy borohydride are combined in glacial acetic acid to give crude 2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)-N-methylpyridin-4-amine, which is reacted with diphosgene by the procedure of Example A75 to give 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. Zn Dust is reacted with a suspension of 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one and NH4Cl in MeOH/THF (1:1) to provide 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. By analogy to Example A25, 4-methoxybenzylamine and 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one are combined and heated to 180° C. to provide 7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, which is further reacted with trifluoroacetic acid to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:9]1)=O)(C)(C)C>Cl.CCO>[C:22]1([CH:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccccc1OC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1OC(c1ccccc1)C1CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
3-(Phenyl-o-tolyloxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (149 mg, 405 μmol) was dissolved in a solution of HCl in EtOH (1.25M, 3 mL) and stirred at room temperature for 3 hours, and then evaporated to dryness. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH:9/1) to afford the RS/SR mixture of enantiomers of the hydrochloride salt of the title compound as a yellow foam (112 mg, 98% purity).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]1)=[O:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]2)=[O:12])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1O)N1CC[C@@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)N2CC[C@@H](O)C2)c1O
Yield: 62.8 %

Procedure:
A solution of 7.83 g (26 mmol, 1 eq) of (2-hydroxy-3-nitrophenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone at 84% in 100 ml of methanol was stirred at hydrogen atmospheric pressure in the presence of 728 mg (10% by weight) of palladium on carbon at 10% for 16 hours. The reaction medium was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, Spot II) eluted with dichloromethane/methanol (96/4). 3.63 g of (3-amino-2-hydroxyphenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone were obtained in the form of a yellow amorphous solid. Yield=63%. SiO2/CH2Cl2 90: MeOH 10, developing with KMnO4.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26]([N:11]2[CH2:12][C@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]2[C:8](=[O:9])[NH:7][C:4]2([C:2]#[N:3])[CH2:6][CH2:5]2)=[O:27])=[CH:30][CH:31]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)Oc2ccc(F)cc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with 4-fluorophenyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid 4-fluoro-phenyl ester as a colorless oil. MS: 492.1 [M+H]+.