Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[NH:22][CH2:23][CH2:24][C:25](O)=[O:26])=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.[CH3:41][C:42]1([CH3:50])[O:47][C:46](=[O:48])[CH2:45][C:44](=[O:49])[O:43]1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:22][CH2:23][CH2:24][C:25]([CH:45]2[C:46](=[O:48])[O:47][C:42]([CH3:50])([CH3:41])[O:43][C:44]2=[O:49])=[O:26])=[O:28])=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCC(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCC(=O)C3C(=O)OC(C)(C)OC3=O)cc2)C1
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)propanoic acid (200 mg, 0.47 mmol, 1.00 equiv) in dichloromethane (20 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (136 mg, 0.71 mmol, 1.50 equiv) and 4-dimethylaminopyridine (115 mg, 0.94 mmol, 1.99 equiv). This was followed by the addition of a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (102 mg, 0.71 mmol, 1.49 equiv) in dichloromethane (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was washed with KHSO4 (2×10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 240 mg (92%) of 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropyl)urea as a yellow solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C1(C)C=CC=CC=1>[CH3:1][O:22][C:21]([C:14]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1(c2ccccc2)CCCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccccc2)CCCCCC1

Procedure:
A 2.0 M solution of trimethylsilyl diazomethane (29.2 mL) was added dropwise to a solution of 1-phenyl-cycloheptanecarboxylic acid (Example 14c) (9.8 g) in methanol (85 mL) and toluene (300 mL) under an atmosphere of nitrogen.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.C(O[CH:14](OCC)[CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)C.Cl>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18]
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: NCCc1c[nH]c2c(Cl)cccc12

Procedure:
A 10.0 g sample of 2-chlorophenylhydrazine hydrochloride and 17.9 g of 4-phthalimidobutyraldehyde diethyl acetal were stirred in 200 mL ethanol with 1 mL 5N HCl. The mixture was concentrated to a residue which was slurried in a small amount of methylene chloride. A yellow solid was collected and vacuum dried at 40° C. The solid was stirred in 500 mL ethanol. Hydrazine hydrate (14 g) was added and the mixture was heated at reflux for 14 hours. A 60 mL sample of 5N HCl was added and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool and was concentrated to a residue. The residue was partitioned between 1N NaOH and chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined extracts were dried (Na2SO4) and concentrated to an oil. The oil was chromatographed on silica gel using a gradient of 0-10% methanol in chloroform containing 0.2% ammonium hydroxide. Fractions containing product were concentrated to an oil which was taken up in a small amount of methanol and added to ethereal HCl. A solid was collected, washed with diethyl ether, and vacuum dried at 50° C.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH-].[K+].C(CN)O.CC1C=CC(CCl)=CC=1>O.C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][CH2:2][CH2:3][OH:4])=[CH:8][CH:7]=1
Reactant: Cc1ccc(CN)cc1
Reactant: OCCCl
Agent: Cc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: NCCO
Product: Cc1ccc(CNCCO)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
The procedure of Example 7 was repeated using 2-chloroethanol (20.9 g, 0.26 mol, Kodak), 4-methylbenzylamine (32.7 g, 0.27 mol, Aldrich), water (25 mL) and KOH (14.6 g, 0.26 mol). A white solid was crystallized from the concentrated solution. The crystallized product was collected by suction filtration and recrystallized from hexanes. The filtrate was concentrated under reduced pressure and the residue was fractionally distilled using a 7.5 inch vigreux column. The fraction boiling at 140-144° C./9 mm pressure was collected. Total yield 15 g (35% yield). 1H NMR (δ, 360 MHz, CDCl3): 2.32 (s, 3H), 2.51 (broad s, 2H), 2.74 (t, 2H), 3.61 (t, 2H), 3.72 (s, 2H) and 7.142 (m, 4H). 13C NMR (δ, 90 MHz, {1H}, CDCl3): 21.0 (--CH3), 50.5 (--NCH2CH2O--) 53.2 (--NCH2CH2O--), 60.7 (--NCH2Ph), 128.1, 129.1 and 143.0 (--CH2Ph). mp 61-62° C. uncorrected. The title compound was also prepared using the following procedure. In a 2L three-neck flask (equipped with a mechanical stirrer and an addition funnel) ethanolamine (91.6 g, 1.5 mol, Aldrich) and 100 mL of toluene were placed. To this solution was added dropwise 4-methylbenzyl chloride (70.3 g, 0.5 mol, Aldrich). The mixture was stirred for 10 hours at room temperature. Crushed KOH (30.0 g, 0.5 mol) was added and stirring was continued for another 3 hours. Water (300 mL) was added to dissolve all solid. The mixture was poured into a separatory funnel and the toluene layer was separated. The aqueous layer was extracted with 50 mL portions of methylene chloride three times. The combined extracts were dried on anhydrous sodium sulfate and rotovaped to remove the solvents. A white solid was crystallized from the concentrated solution. The crystallized product (34 g) was collected by suction filtration and washed with several mL of toluene. The filtrate was concentrated under reduced pressure and the residue was fractionally distilled using a 7.5 inch vigreux column. The fraction boiling at 140-144° C./9 mm pressure was collected. Total yield isolated 46.5 g (57% yield).
Reaction SMILES: Cl[C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH2:19]>O.C(Cl)Cl>[CH3:13][C:14]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH:19][C:2]1[C:7]([S:8][CH3:9])=[C:6]([CH2:10][S:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CSCc1ncnc(Cl)c1SC
Reactant: Cc1ccc(OCCN)c(C)c1
Solvent: ClCCl
Solvent: O
Product: CSCc1ncnc(NCCOc2ccc(C)cc2C)c1SC
Yield: 47.2 %

Procedure:
4.4 g (0.02 mol) of 4-chloro-5-methylthio-6-methylthiomethylpyrimidine and 7.4 g (0.045 mol) of 2-(2,4-dimethylphenoxy)ethylamine were heated for 2 hours at 100° C. The mixture was worked up using a water/methylene chloride mixture, and the organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel (mobile phase, ethyl acetate/methanol (19:1)). 3.3 g (47.2% of theory) of 4-[2-(2,4-dimethylphenoxy)ethyl amino)-5-methylthio-6-methylthiomethylpyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:38]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[C:16]2[Cl:38])=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2cc3ccc(O)c(Cl)c3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 8 h

Procedure:
To a reaction mixture of 7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (100 mg, 0.201 mmol) in DMF (2 mL) was added N-chlorosuccinimide (32.3 mg, 0.242 mmol) at room temperature. The reaction mixture was stirred overnight then loaded onto an SCX column, washed with MeOH, and eluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated and purified via silica gel flash column chromatography to give the title compound as a light brown solid product (25 mg, 23% yield). MS (M+1)=531.6.
Reaction SMILES: [BrH:1].O[C:3]([CH3:10])([CH2:7][C:8]#[N:9])[CH2:4][C:5]#[N:6].C(=O)([O-])O.[Na+]>>[Br:1][C:5]1[N:6]=[C:8]([NH2:9])[CH:7]=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(O)(CC#N)CC#N
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(N)nc(Br)c1

Procedure:
Hydrogen bromide solution (33 wt. % in acetic acid) (17.8 ml, 98.92 mmol) was added dropwise to 3-hydroxy-3-methyl-pentanedinitrile (3.07 g, 24.73 mmol) with stirring. The reaction was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added until neutralised. The resulting white precipitate was collected by filtration, washed with water and dried under vacuum to give the desired product. Yield 2.55 g, 55%. LCMS MI: 186.89+188.91, RT: 3.16 min, Method: 2.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH:8]([F:10])[F:9])(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:43][C:24]3([CH2:29][CH2:28][N:27]([C:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([CH3:42])[CH:33]=4)=[O:31])[CH2:26][CH2:25]3)[CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:43][C:24]3([CH2:25][CH2:26][N:27]([C:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:40])[CH3:41])=[C:34]([CH3:42])[CH:33]=4)=[O:31])[CH2:28][CH2:29]3)[CH2:23][N:22]([CH2:7][CH:8]([F:10])[F:9])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)F)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Temperature: 70 °C
Yield: 106.5 %

Procedure:
2,2-difluoroethyl trifluoromethanesulfonate (17 mg, 0.08 mmol) was added to a solution of [10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (22 mg, 0.05 mmol) and NaHCO3 (13 mg, 0.15 mmol) in anhydrous ethanol (0.3 mL) at room temperature. The reaction mixture was purged with argon, sealed with a cap and heated at 70° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with MeOH to 1 mL, microfiltered and purified by Waters mass directed LC/MS: (10-99% ACN/H2O (5 mM HCl)) to yield [10-(4-chlorophenyl)-8-(2,2-difluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (27 mg, 100%). ESI-MS m/z calc. 506.21478. found 507.2 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[C:17]([CH3:18])=[N:16][CH:15]=[N:14]1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>CN(C=O)C>[CH2:19]([O:22][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[C:17]([CH3:18])=[N:16][CH:15]=[N:14]1)[CH:20]=[CH2:21]
Reactant: C=CCO
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1ncnc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A suspension of NaH (0.675 g, 16.88 mmol, 60% dispersion in mineral oil) in DMF (25 mL) was cooled to 0° C. A solution 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (2.50 g, 11.25 mmol) was added dropwise. Allyl alcohol (0.784 g, 13.5 mmol) was added via syringe over 5 min. The reaction mixture was allowed to warm up to room temperature. After 30 min, TLC showed completion of reaction. It was slowly quenched with water (10 mL), diluted with brine (100 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (20-80% EtOAc/hexane, linear gradient). Pure fractions were concentrated under reduced pressure to afford 1-(2-(allyloxy)-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (1.5 g 51% yield) as a yellow-brown colored solid. LC-MS (M+H)+=261.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.02-7.94 (m, 3H), 7.58 (d, 1H, J=8.4 Hz), 5.98-5.89 (m, 1H), 5.37-5.32 (m, 2 H), 4.69-4.70 (m, 2H), 2.403 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[CH3:21][S:22]([C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:30]([C:28]2[S:29][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[O:31])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Product: CS(=O)(=O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)s1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065 g). Title compound obtained as white solid (0.039 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH3:1])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOCOc1ccc(OC)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium carbonate (14.3 g, 103 mmol) was added to 3a (2.50 g, 10.3 mmol) in N,N-dimethylformamide (103 mL). After 10 minutes, methyl iodide (6.43 mL, 103 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×50 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, 4:1 Hexane:EtOAc) to afford 4a as a yellow oil (2.40 g, 91%): 1H NMR (CDCl3, 500 MHz) δ 6.87 (d, J=2.8 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.60 (dd, J=13.3, 1.7 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 3.72-3.69 (m, 2H), 3.68-3.63 (m, 2H), 1.17-1.13 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.7, 146.2, 143.9, 111.2, 107.9, 105.8, 93.2, 93.0, 63.3, 63.0, 55.4, 14.1, 14.0; IR (film) νmax 2976, 2932, 2899, 2835, 1595, 1508, 1393, 1227, 1153, 1103, 1080, 1009, 847 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C13H20O5, 279.1208. found, 279.1181.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:15][CH2:14]2
Reactant: CCOC(=O)C1CCc2cccc(OC)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2c1OC(C(=O)O)CC2
Reaction time: 24 h
Yield: 106.3 %

Procedure:
The mixture of 100.7 g (0.43 mol) 8-methoxy-2-chromancarboxylic acid ethyl ester and 20.1 g (0.50 mol) sodium hydroxide in 800 ml ethanol was stirred for 24 h at 20°. After evaporation the residue was treated with water and extracted with diethyl ether. The aqueous phase was acidified and then extracted with diethylether. Usual work-up yielded 95.2 g of crystalline 8-methoxychroman-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CC#N)ccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CC#N)cc1O
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(3-methoxy-4-methylphenyl)acetonitrile (5 g, 31 mmol) in dry CH2Cl2 (20 ml) was added drop wise BBr3 (1M in CH2Cl2, 10.02 g, 40 mmol) at −78° C. under argon. The reaction mixture was stirred at the same temperature for 2 hours and then at 0° C. for 5 hours or until all the starting material is consumed, quenched with ice, extracted with EtOAc (30 ml×3), the combined organic layer was washed carefully with sat NaHCO3, brine and dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1→CH2Cl2:hex 1:1) to give the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10].[Br:11]C1C=NC=CC=1Cl>CN(C=O)C>[Br:11][C:7]1[C:2]([Cl:1])=[C:3]([CH:9]=[O:10])[CH:4]=[N:5][CH:6]=1
Reactant: O=Cc1cncc(Cl)c1Cl
Reactant: Clc1ccncc1Br
Solvent: CN(C)C=O
Product: O=Cc1cncc(Br)c1Cl
Yield: 73 %

Procedure:
Following the procedure described for 4,5-dichloropyridine-3-carbaldehyde, 3-bromo-4-chloropyridine and DMF were reacted to afford the title compound as a white solid (3.74 g, 73% yield). 1H NMR (300 MHz, CDCl3): δ 10.48 (d, J=0.4 Hz, 1H), 8.95-8.92 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9]Cl)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: ClCc1ccccc1CCl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1ccccc1CCl
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of α,α′-dichloro-o-xylene (3.5 g, 18 mmol) in DMF (20 mL) is added sodium methanesulfinate (0.612 g, 6.0 mmol) and the mixture is stirred at 65° C. for 4 h. Ice/water and EtOAc are added, the phases are separated and the organic phase is washed with water and brine, dried over Na2SO4/MgSO4, filtered and concentrated. The resulting residue is chromatographed on silica gel, eluting with a gradient of hexane/EtOAc to afford 1-chloromethyl-2-methanesulfonylmethylbenzene as a white solid: MS (M+NH4)+=236.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1

Procedure:
96 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-phenylpiperazine (0.050 mL, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:33])[N:14]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:10]([O:12][C:13](=[O:33])[N:14]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][N:2]([CH3:9])[CH3:1])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:11]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CN(C)Cc1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nc(CN(C)C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using dimethyl-oxazol-4-ylmethyl-amine (128 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (71 mg), giving the product (99 mg) as a yellow gum.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:55][C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][C:61]=1[F:62]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15]([C:59]4[CH:58]=[CH:57][C:56]([F:55])=[C:61]([F:62])[CH:60]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Yield: 47 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 36 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (47%).
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH2:5][C@@H:4]([NH:15]C(=O)OCC2C=CC=CC=2)[C:3]1=[O:26]>[OH-].[OH-].[Pd+2].CCO>[NH2:15][C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:2]([CH3:1])[C:3]1=[O:26]
Reactant: CN1C(=O)[C@H](NC(=O)OCc2ccccc2)CC=C[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)[C@H](N)CCC[C@H]1c1ccccc1
Reaction time: 6 h

Procedure:
A mixture of benzyl [(3R,7S)-1-methyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (3c) (310 mg) and Pearlman's catalyst (62 mg) in EtOH (8 mL) was hydrogenated at 45 psi for 6 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and concentrated to a viscous oil. The aqueous layer was extracted with DCM (3×). The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to a viscous oil. (166 mg, 86%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[N:7]=[C:6]([NH:16][C@H:17]([CH2:19][CH3:20])[CH3:18])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:17]([NH:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[N:14]=2)[N:7]=1)[C:3]([OH:21])=[O:2])([CH2:19][CH3:20])[CH3:18]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nnn(C)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(-c2nnn(C)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2-methyl-2H-tetrazol-5-yl)-isonicotinic acid methyl ester (250 mg, 0.86 mmol) in methanol (5 mL) with 2 N NaOH (0.64 mL, 1.29 mmol). Stir at room temperature overnight, acidify the reaction to about pH=3 using 1 N HCl. Extract the reaction mixture with ethyl acetate (3×25 mL). Wash the combined organic layers with saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound.