Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:67]=[CH:66][C:51]2[C:52]([C:55]([N:57]3[CH:63]4[CH2:64][CH2:65][N:60]([CH2:61][CH2:62]4)[CH2:59][CH2:58]3)=[O:56])=[N:53][S:54][C:50]=2[CH:49]=1.[CH:68]([N:71]1[CH2:75][CH2:74][NH:73][C:72]1=[O:76])([CH3:70])[CH3:69].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N:60]12[CH2:65][CH2:64][CH:63]([CH2:62][CH2:61]1)[N:57]([C:55]([C:52]1[C:51]3[CH:66]=[CH:67][C:48]([N:73]4[CH2:74][CH2:75][N:71]([CH:68]([CH3:70])[CH3:69])[C:72]4=[O:76])=[CH:49][C:50]=3[S:54][N:53]=1)=[O:56])[CH2:58][CH2:59]2
Reactant: O=C(c1nsc2cc(Br)ccc12)N1CCN2CCC1CC2
Reactant: CC(C)N1CCNC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2ccc3c(C(=O)N4CCN5CCC4CC5)nsc3c2)C1=O
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of toluene (8 mL) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.2 mmol) was degassed with nitrogen for 4 minutes, then heated at 80° C. until the (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl dissolved completely. The solution was allowed to cool to rt and palladium acetate (0.09 mmol) was added. The mixture was stirred until the palladium acetate completely dissolved. The resultant yellow solution was added to a mixture of 6-bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole (0.33 mmol), 1-isopropylimidazolidin-2-one (0.5 mmol) and cesium carbonate (0.39 mmol) under a nitrogen atmosphere. The reaction mixture was subjected to microwave radiation at 150° C. for 360 s. The inorganic precipitates were removed by filtration, and the filtrate was concentrated. The residue was purified by preparative HPLC to provide the product in 75% yield. 1H NMR (CD3OD) δ 8.17 (s, 1H), 8.03-7.93 (m, 2H), 4.30-4.05 (m, 2H), 3.92 (t, J=7.14, 2H), 3.70 (t, J=5.7, 2H), 3.54 (t, J=7.1, 2H), 3.20-3.00 (m, 6H), 1.22 (d, J=6.78, 3 6H); LC/MS (EI) tR3.10 min, m/z 415 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.C(N[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)C>>[CH2:34]([NH:33][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[C:35]1[CH:30]=[CH:31][CH:32]=[CH:37][CH:36]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CCNCCc1ccccn1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)NCc1ccccc1)CC2

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethyl-(2-pyridin-2-yl-ethyl)-amine. MS (ESI): 484.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])[CH3:2].C(Cl)(=O)[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:12]=[C:17]=[O:18])(=[O:13])=[O:14])=[O:15])[CH3:2]
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 95 °C

Procedure:
At 85° C., 68.76 g (0.3 mol) 2-sulfamylbenzoic acid ethylester are added to 57.9 g (0.45 mol) oxalylchloride and 0.4 g diazadicyclo(2,2,2,)octane in 500 ml absolute toluene. The reaction mixture is heated yet three hours to an interior temperature of 95° C., until no gas development is observed.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)nc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 6-bromopyridin-3-ol (10 g, 57.80 mmol) in DMF (60 mL) was added 4-fluorobenzonitrile (6.99 g, 57.8 mmol) and K2CO3 (11.9 g, 86.70 mmol) and the reaction mixture was stirred at 80° C. for 16 hours (h). The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh) to obtain the title compound as an off-white solid (10 g, 63%): mp 113° C.; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=2.9 Hz, 1H), 7.70-7.63 (m, 2H), 7.56-7.51 (m, 1H), 7.28 (dd, J=8.5, 2.9 Hz, 1H), 7.10-7.02 (m, 2H); EIMS m/z 275.
Reaction SMILES: CC1NC([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=C(C)N=1.I[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[CH3:30].IC1NC(C)=NC=1C>>[CH3:18][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[CH3:30]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Reactant: Cc1nc(C2(C)COC2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 301 (M+H)+.
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
2.0 mol/L Sodium hydroxide aqueous solution 0.92 mL was added to a mixed solution of methanol 2.0 mL and tetrahydrofuran 2.0 mL of methyl 2-(4-fluoroanilino)-4-(phenoxymethyl)benzoate 0.22 g, and it was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, water was added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. Solid matter was filtrated to give 2-(4-fluoroanilino)-4-(phenoxymethyl)benzoic acid 0.14 g of white solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Product: Cc1cnc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(5-methyl-thiazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N+:19]([O-:21])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:28]=1>C(O)(C)C>[C:1]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N+:19]([O-:21])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:28]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)NCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
A mixture of 5 ml. of acetic anhydride and 0.3 g. of 5-aminomethyl-2-nitro-3-phenylbenzofuran hydrochloride (from Example 17) is heated on a steam bath for about 30 minutes. The mixture is then partially evaporated to provide a residue which is treated with aqueous isopropanol to form yellow crystals of 5-acetamidomethyl-2-nitro-3-phenylbenzofuran, m.p. 201°-203° C., having the structure
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[OH:8].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:9]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[C:7]=1[OH:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1c(Br)cncc1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1c(Br)cncc1Cc1ccccc1
Yield: 1.1 %

Procedure:
A mixture of 3-bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol (2.55 g, 91 mmol), TFA (16 mL) and Et3SiH in CH2Cl2 (30 mL) at rt for 10 h. It was concentrated in vacuo and the residue was purified by flash column on silica gel eluting with hexane/EtOAc/MeOH//600:300:50 followed by hexane/EtOAc/MeOH//400:400:50:10 to obtain an impure product which was triturated with a small amount of MeOH and Et2O to obtain the desired product (255 mg, 10%) as a white solid. 1H NMR (DMSO-d6) δ 11.75 (br s, 1H), 8.13 (s, 1H), 7.54 (s, 1H), 7.26-7.14 (m, 5H), 2.49 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](=O)(O)[O-].[Na+]>CO>[CH3:11][O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:10]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)c1
Reaction time: 0.67 h

Procedure:
2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspended in methanol (175 ml) and anhydrous hydrogen chloride gas was slowly bubbled through the reaction mixture while cooling in a methanol/water (20/80) dry ice bath. Bubbling was continued for 40 min. during which time the suspension cleared to a partial solution. Ice bath was removed and the reaction mixture was heated to reflux under anhydrous conditions for 30 min. to give a clear yellow solution. The solution was cooled in an ice bath and saturated sodium bicarbonate was slowly added with stirring till the pH was neutral. The, organics were removed in vacuo and the product was extracted into ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-chloropyridine-4-carboxylic acid methyl ester as a brown liquid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN(C=O)C.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of NaH (60% in mineral oil) (0.13 g, 3.25 mmol) in DMF (5 ml) was added commercially available 4-bromophenol (0.50 g, 2.89 mmol) and the reaction was stirred at room temperature for 10 minutes. Then, 4-chloro-2-picoline (0.30 g, 2.40 mmol) was added and the resulting reaction mixture was then microwaved at 150° C. for 10 minutes. After cooling, the mixture was diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (DCM) to yield intermediate 25 (0.52 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
To a mixture of 2-(4-bromophenyl)pyrrolidine (231.9 mg, 1.026 mmol) and potassium carbonate (216.6 mg, 1.567 mmol) was added N,N-dimethylformamide (4.0 mL, 52 mmol) and methyl iodide (77 uL, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 days and then methyl iodide (39.0 uL, 0.626 mmol) was added. After stirring at room temperature for an additional two hours, the reaction mixture was poured into ethyl acetate and washed three times with 2M aqueous Na2CO3. The ethyl acetate layer was then dried over MgSO4, filtered, and evaporated in vacuo to yield 108.9 mg (44%) of 2-(4-bromophenyl)-1-methylpyrrolidine. LCMS (ESI): M+H=240.2.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>C(OCC)C>[P:1]([O:8][Si:17]([CH3:19])([CH3:18])[CH3:16])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOP(OCC)O[Si](C)(C)C
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a mixture of diethyl phosphite (2.8 mL, 0.0217 mol) and triethylamine (9. mL, 0.065 mol, 3.0 equiv.) in dry diethyl ether (250 mL) at 0° C. was slowly added freshly distilled trimethylsilyl chloride (3.3 mL, 0.0260 mol, 1.2 equiv.) via syringe. The resulting slurry was allowed to slowly warm to room temperature, and was then warmed to 45° C. for 14 h. Volatiles were removed by distillation using a 55° C. oil bath. The resulting mixture was diluted with pentane (150 mL), filtered to remove triethylammonium salts, and concentrated at atmospheric pressure using a 55° C. oil bath. Distillation of the resulting oil gave diethyl trimethylsilyl phosphite as a colorless oil (3.64 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:29])[O-:28])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1.[ClH:31].[CH3:32][CH2:33][O:34][CH2:35]C>C(Cl)Cl>[ClH:31].[CH3:35][O:34][CH2:33][CH2:32][N:26]([CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:18]=2)[CH2:20]1)[C:27](=[O:28])[OH:29]
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)[O-])C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: COCCN(C[C@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1)C(=O)O
Reaction time: 0.04 h

Procedure:
To a solution of ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (352 mg, 0.75 mmol) in CH2Cl2 (3 mL) was added dropwise a 2.0 M HCl solution in ether (0.375 mL, 0.75 mmol) under an N2 atmosphere. It was followed by the addition of 20 mL ether which lead to the precipitation of 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (350 mg, 92%) which was then filtered and dried. LC/MS: m/z 469.5 (M+H)+ at 2.29 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.45 (m, 3H), 6.89 (d, J=8.3 Hz, 1H), 6.82 (t, J=9.5 Hz, 1H), 4.54 (s, 1H), 4.03 (d, J=2.7 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.24 (s, 3H), 2.99 (m, 2H), 2.54 (s, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.38 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=O.C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[NH2:15][C:10]1[C:9](=[O:18])[N:8]([CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:21]
Reactant: C=O
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1ccn(Cc2ccc(OC)cc2)c(=O)c1N
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:24])=[CH:4][C:3]=1[O:25][CH3:26].[CH2:27]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:28]#[CH:29].C(N(CC)CC)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:10]3[C:9](=[O:24])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]#[C:28][CH2:27][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[C:3]([O:25][CH3:26])[CH:4]=4)[CH2:13][CH2:12][C:11]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1Br
Reactant: C#CCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1C#CCN1CCCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 11.2 %

Procedure:
Treat a suspension of 5-(4-bromo-3-methoxy-phenyl)-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.25 mg, 0.56 mmol), 1-prop-2-ynyl-pyrrolidine (0.12 g, 1.10 mmol), dichlorobis(triphenylphosphine)palladium (II) (12.0 mg, 0.02 mmol), triethylamine (0.5 mL) in DMF with CuI (4.0 mg, 0.02 mmol). Stir at 80° C. under nitrogen for 2 days. Dilute the reaction with water and extract with CH2Cl2 (2×). Dry, filter, and concentrate the organic solution and purify the crude material by flash chromatography, using a gradient of 0-10% MeOH in CH2Cl2 to give the title compound (30.0 mg, 12%). MS (ES+) 478.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (m, 3H), 6.95 (d, 1H, J=2.2 Hz), 6.82 (dd, 1H, J=8.1, 2.0 Hz), 4.10 (t, 2H, J=6.8 Hz), 3.84 (m, 5H), 3.26 (t, 2H, J=6.8 Hz), 2.88 (m, 4H), 1.89 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31]([NH:33][NH2:34])=O)=[CH:24][C:23]=1[Cl:35]>>[Cl:35][C:23]1[CH:24]=[C:25]([C:31]2[O:15][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:12][CH2:11]3)=[N:34][N:33]=2)[C:26]2[O:30][CH2:29][CH2:28][C:27]=2[C:22]=1[NH2:21]
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(C3CCN(C4CCOCC4)CC3)o2)c2c1CCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To 1-(tetrahydro pyran-4-yl) piperidine-4-carboxylic acid (168.2 mg, 0.58 mmol) was added phosphoryl chloride (1.76 mL). The mixture was stirred for 15 minutes and 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid hydrazide (101.2 mg, 0.0.44 mmol, obtained in preparation 3) was added. The reaction mixture was gradually heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The residual mass was purified by silica gel column to obtain 5-chloro-7-{5-[1-(tetrahydro pyran-4-yl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-2,3-dihydro benzofuran-4-yl amine (23.5 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2OCC[O:15]2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([C:8]1[N:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(C3OCCO3)cn2)cc1
Agent: Cl
Product: O=Cc1ccc(Cc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
2-Benzyl-5-[1,3]dioxolan-2-yl-pyridine (7.3 g, 30 mmol) described in Manufacturing Example 210-1-3 and 2 N hydrochloric acid (100 mL) were stirred for 15 minutes at 100° C. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and a 5 N sodium hydroxide solution (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.7 g, 79%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C(O)CCC>O1CCCC1.O.C(O)(=O)C.C(O)C>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CCNCCc2ccc(OC)c(OC)c2)cc1OC
Temperature: 10 °C
Yield: 75 %

Procedure:
37.7 g of sodium borohydride are suspended in 1500 cc of anhydrous tetrahydrofuran in an inert atmosphere of nitrogen. To the suspension are added 36 g of amide prepared in part (b), while the mixture is stirred and cooled to 10° C., and there is added also 58 cc of glacial acetic acid. The mixture is warmed under reflux for four hours. At the end of this period, the solvent is evaporated under reduced pressure and the residue is treated with water and then with dilute hydrochloric acid to a full acidity. To the mixture is then added a solution of sodium hydroxide until the pH is alkaline and the material is extracted four times with 300 cc each time of dichloromethane. The organic phase is extracted with dilute hydrochloric acid, the acetic solution is washed with dichloromethane. It is then cooled and made alkaline with potassium carbonate and finally extracted again with four portions of dichloromethane, using 200 cc each time. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. The residue is the crude amine which is recrystallized from ethanol thus giving a pure product, 28.5 g, yield 75%; m.p. 56°-58° C. A single spot is obtained on T.L.C. (eluent: n-butanol, ethanol, acetic acid, water 60:20:40:10).