Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2].[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:39]3[C:33]4[O:32][C:31]5[CH:30]=[CH:29][CH:28]=[CH:27][C:35]=5[C:34]=4[CH:36]=[CH:37][CH:38]=3)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of [5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.417 g, 1.0 mmol) and 4-dibenzofuranboronic acid (0.233 g, 1.1 mmol) in toluene (15 mL, X M) was treated with 2 N aq K2CO3 (1.5 mL, xx mmol) and Pd[PPh3]4 (0.058 g, 0.05 mmol). The resulting solution was heated to reflux for 2 h, cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (10% ethyl acetate in heptane) provided [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.394 g, 78%) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH3:6].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl>[C:23]([O:7][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:4][CH2:3][C:2]([F:14])([F:15])[F:1])[CH3:6])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)(CCC(F)(F)F)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C)(CCC(F)(F)F)c1ccccc1
Reaction time: 12 h
Yield: 72 %

Procedure:
21 g of 5,5,5-trifluoro-2-phenylpentan-2-ol (5) and 11.6 g of triethylamine dissolved in 40 mL of methylene chloride was slowly charged into flask equipped with magnetic stirrer and 11 ml, of methacryloyl chloride in 100 mL of dichloromethane cooled down to 0° C. The resultant mixture slowly warmed up to room temperature and allowed to stir at this temperature for 12 hours. Upon completion of the reaction as confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 mL of deionized water and extracted further into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered and concentrated in vacuo affording 20 g of 5,5,5-trifluoro-2-phenylpentan-2-yl methacrylate (LG2) (˜72% yield) of as an amber oil. The oil was purified further by passing through a silica gel plug and eluting with a 70:30 mixture of hexanes/methylene chloride to afford 19 g of pure product. 1H NMR (500 MHz, Acetone-d6): δ 7.32 (s, 3H), 7.24 (s, 2H), 6.11 (s, 1H, vinyl), 5.6 (s, 1H, vinyl), 2.45-2.05 (m/m, 5H), 1.92 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39](=[O:40])[NH:30][C:27]1[CH:28]=[N:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and methyl chloroformate (17 μL, 0.222 mmol) are combined and stirred at room temperature. Reaction complete in less than 15 minutes. Concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (39 mg, 42%).
Reaction SMILES: BrC1C=C([Cl:27])C=C2C=1NCCC2[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][C:21]2[CH:23]=[CH:24][S:25][C:20]=2[C:19](=[O:26])[CH:18]=1.C[O-].[Na+].BrC1C=C([Cl:43])C=C2C=1NCCC2=O.C([BH3-])#N.[Na+]>CO>[ClH:27].[ClH:43].[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][C:21]2[CH:23]=[CH:24][S:25][C:20]=2[C:19](=[O:26])[CH:18]=1
Reactant: O=c1cc(NCCCNC2CCNc3c(Br)cc(Cl)cc32)[nH]c2ccsc12
Reactant: O=C1CCNc2c(Br)cc(Cl)cc21
Agent: C[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cl
Product: NCCCNc1cc(=O)c2sccc2[nH]1

Procedure:
A representative example of method E is as follows. Preparation of 5-[3-(8-Bromo-6-chloro-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one: A solution of 5-(3-Amino-propylamino)-4H-thieno[3,2-b]pyridine-7-one di-hydrochloride (XVIII) in methanol (0.08M) was prepared and then treated with sodium methoxide (2 equivalents, 0.5M in methanol). 8-Bromo-6-chloro-2,3-dihydro-1H-quinolin-4-one (1 equivalent) was added as a solid. Sodium cyanoborohydride (3 equivalents) was added as a solid. The mixture was then refluxed for 20 hours, adding an additional equivalent of sodium cyanoborohydride after 16 hours. The reaction mix was poured onto a column of silica gel and the product was eluted with 10% NH3 (sat.)/MeOH and dichloromethane. Solvent was then removed in vacuo. Purification of the crude product was accomplished by flash chromatography, product eluted with a gradient of 0-12% NH3 (sat.)/MeOH and dichloromethane. The resulting solid was triturated with ether, isolated by filtration, and dried to give the title compound as a white solid (formula XIX, X═NH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)CC=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:24]CC1.[CH3:28][C:29]([OH:32])(C)[CH3:30]>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:28][CH:29]([OH:32])[CH2:30][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Reactant: C=CCN(C1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)C1CCCC1
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of 1.1 g (3.7 mmol) of 6-chloro-N-cyclopentyl-N-(prop-2-en-1-yl)pyridine-3-sulfonamide in 15 mL of a mixture (1/1) of tBuOH and water are added, at room temperature, 1.2 g (10.3 mmol) of NMO and 0.52 mL (0.04 mmol) of 2.5% OsO4 in tBuOH. Stirring is continued for 12 hours. The medium is then diluted with 200 mL of water and extracted with Et2O (2×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 0.92 g of 6-chloro-N-cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-3-sulfonamide is obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([O:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][OH:21])[C:13]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(Cl)Cl>[C:36]([O:21][CH2:20][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][O:17][C:14]1[C:13]2[CH:30]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][N:15]=1)(=[O:37])[NH2:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.47 g of 5-tert-butoxycarbonylamino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.21 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. Subsequently, 10 ml of water is added, and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are collected by filtration, to obtain 0.47 g of colorless, crystalline 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole.
Reaction SMILES: N#N.[CH3:3][C:4]([CH3:22])([O:6][C@H:7]1[C@@:15]2([CH3:16])[C@@H:10]([CH2:11][C:12]([OH:21])=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH2:9][CH2:8]1)[CH3:5].[CH2:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]>C(Cl)Cl>[CH3:5][C:4]([CH3:22])([O:6][C@H:7]1[C@@:15]2([CH3:16])[C@@H:10]([CH2:11][C:12](=[O:21])[C:13]([CH2:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH2:9][CH2:8]1)[CH3:3]
Reactant: COC(=O)C1=C(O)C[C@H]2CC[C@@H](OC(C)(C)C)[C@]2(C)C1
Reactant: C=CCCCC(=O)C=C
Agent: N#N
Solvent: ClCCl
Product: C=CCCCC(=O)CCC1(C(=O)OC)C[C@]2(C)[C@H](CC[C@H]2OC(C)(C)C)CC1=O
Temperature: 180 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
Neutral alumina (15 g) was heated in a flask at 180° C. under high vacuum for 4 h. After cooling down to room temperature, the flask was filled with N2. Compound 31 (7.2 g, 25.5 mmol), 1,7-octadien-3-one (4.3 g, 30 mmol), and CH2Cl2 (30 mL) were added to the anhydrous alumina at room temperature. The mixture was stirred at room temperature for 16 h. The suspension was filtered through Celite® 545 which was washed with CH2Cl2 (100 mL×3). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 32 (9.4 g, 91%). The compound is a mixture of diastereomers at position C-5 in a 3 to 1 ratio. The major diastereomer had: 1H NMR (CDCl3) δ 5.72-5.60 (m, 1H), 4.95-4.86 (m, 2H), 3.64 (s, 3H), 3.35 (t, J=7.1 Hz, 1H), 1.05 (s, 9H), 0.75 (s, 3H); 13C NMR (CDCl3) δ 209.5, 208.0, 173.7, 137.8, 115.0, 79.9, 72.4, 56.2, 52.2, 46.9, 45.5, 42.4, 42.1, 41.7, 38.1, 32.9, 31.3, 30.5, 28.6, 28.4, 25.5, 22.6; IR νmax 1714, 1641, 1435 cm−1. Anal. Calcd for (C24H38O5): C, 70.90; H, 9.42. Found: C, 71.16; H, 9.70.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][NH:21][CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc(Nc2ccc3c(c2)OCO3)c2c3c([nH]c2n1)CCNC3
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)OCO5)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Benzo[1,3]dioxol-5-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (50 mg, 0.16 mmol), acetic anhydride (18 μL, 0.19 mmol), and triethylamine (67 μL, 0.49 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 56 (25 mg, 44% yield) as a tan powder. LC-MS (M+H=351, obsd.=351).
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH3:13])[CH:7]=1.O.[NH2:17]N>C(O)(=O)C>[CH3:13][S:12][C:8]1[CH:7]=[C:6]([C:5]2[N:4]=[CH:3][NH:2][N:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CSc1cccc(C(=O)N=CN(C)C)c1
Solvent: O
Solvent: CC(=O)O
Product: CSc1cccc(-c2nc[nH]n2)c1
Temperature: 90 °C

Procedure:
8 g of N-[1-dimethylaminomethylidene]-3-methylsulfanyl-benzamide were dissolved in 80 ml of glacial acetic acid. 2 ml of hydrazine hydrate were added and the mixture was heated to 90° C. for 2 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography (300 g of silica gel; DCM/MOH, gradient from 100:0 to 95:5). 4.5 g of the title compound were obtained as an oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[H][H]>[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#[N:2]
Reactant: [H][H]
Reactant: N#CCCC1CCCCC(=O)O1
Agent: [Pd]
Product: N#CCCCCCCCC(=O)O

Procedure:
In a reactor with a catalyst composed of palladium on carbon at 5% deposited on the walls, 167 g of 7-cyanoethyl-2-oxepanone are heated to 500° C. in a hydrogen atmosphere, collecting 1 g/minute of liquid condensed product mainly formed by 8-cyanooctanoic acid with 95% lactone conversion and 80% selectivity.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[OH:15])[CH2:13][CH2:12]1
Reactant: O=C(C1CC1)C1CC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1nccs1)(C1CC1)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.953 mL, 2.38 mmol) was added to a stirred, cooled −78° C. mixture of thiazole (0.169 mL, 2.383 mmol) in THF (5.0 mL) and the mixture was stirred at −78° C. for 15 min. A solution of the dicyclopropylmethanone (250 mg, 2.27 mmol) in THF (3.0 mL) was added dropwise and the mixture was stirred 30 mill at −78° C. and then the temperature was allowed to reach room temperature. The reaction was quenched by addition of water and the mixture was extracted with ethyl acetate (3×). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give dicyclopropyl(1,3-thiazol-2-yl)methanol (412 mg, 2.110 mmol, 93% yield). MS APCI: [M-OH]+ m/z 179.0.
Reaction SMILES: COC(=O)N=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]([O:29][CH3:30])=[C:22]([O:31][CH3:32])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:36]([C:38]1[N:43]=[CH:42]C=[CH:40][N:39]=1)[NH2:37].C(N(CC)CC)C.[CH3:51][N:52]([CH:54]=[O:55])C>>[CH3:32][O:31][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[CH:40]=[N:39][C:38]([N:36]3[C:54](=[O:55])[NH:52][CH:51]=[N:37]3)=[N:43][CH:42]=2)[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]=1[O:29][CH3:30]
Reactant: NNc1ncccn1
Reactant: CN(C)C=O
Reactant: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Solvent: CCN(CC)CC
Product: COCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cnc(-n3nc[nH]c3=O)nc2)cc(OC)c1OC
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 169 mg of [2-(3,4-dimethoxy-5-methoxymethylphenyl) -2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 40 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(3,4-dimethoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (89 mg) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:38][C:39]1([CH3:53])[C:43]([CH3:45])([CH3:44])[O:42][B:41]([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)[O:40]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH:50][C:49]3[CH:48]=[CH:47][C:46]([B:41]4[O:42][C:43]([CH3:45])([CH3:44])[C:39]([CH3:53])([CH3:38])[O:40]4)=[CH:52][CH:51]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of (R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.6 mmol) and EDC (140 mg, 0.75 mmol) and HOAt (100 mg, 0.75 mmol) dissolved in DMF (4.6 mL) was stirred for 30 min and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.62 mmol) and N,N-diisopropylethylamine (130 μL, 0.75 mmol) were added. The reaction mixture was stirred at RT overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-70% ethyl acetate:hexanes) to provide the title intermediate (250 mg, 80% yield). (m/z): [M+H]+ calcd for C28H39BN4O5 523.30. found 523.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[N:5](C(OCC)=O)[CH2:6]2>Cl>[CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CCN(C)C2C1C
Agent: Cl
Product: CC1NCC2CCN(C)C21

Procedure:
16.9 g (79.6 mol) of ethyl 2,8-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate together with 130 ml of concentrated hydrochloric acid are refluxed overnight. The mixture is concentrated, the concentrate is taken up in 50 ml of water, and this mixture is rendered alkaline using potassium carbonate and extracted five times using 50 ml portions of chloroform. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+]>O1CCOCC1.O>[OH:17][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 3′-aminobiphenyl-2-carbonitrile (10.9 g, 56 mmol) in 1,4-dioxane (30 ml) was treated with a solution of 25% aqueous sulfuric acid (150 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 10 minutes with a solution of sodium nitrite (4.6 g, 67 mmol) in water (10 ml). After stirring at 0° C. for 30 minutes the reaction was poured into hot (70° C.) water (500 ml). On cooling to ambient temperature the product was extracted into ethyl acetate (500 ml), the organic layer was washed with water (300 ml), brine (300 ml) and dried (Na2SO4). Filtration and concentration in vacuo afforded 7.1 g (65%) of 3′-hydroxybiphenyl-2-carbonitrile as a dark oil: 1H NMR (400 MHz, CDCl3) δ 5.40 (1H, br), 6.92 (1H, ddd, J 8, 3, 1 Hz), 7.04 (1H, dd, J 3, 3 Hz), 7.11 (1H, ddd, J 8, 3, 1 Hz), 7.35 (1H, dd, J 8, 8 Hz), 7.44 (1H, ddd, J 8, 8, 1 Hz), 7.51 (1H, dd, J 8, 1 Hz), 7.64 (1H, ddd, J 8, 8, 1 Hz), 7.75 (1H, dd, J 8, 1 Hz).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[NH4+].N(N(C1C=CC=CC=1)O)=O>N1C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: O=NN(O)c1ccccc1
Agent: [NH4+]
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCC(O)COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a reaction vessel were placed 56 g of glycidyl methacrylate, 48 g of p-hydroxybenzaldehyde, 2 g of pyridine and 1 g of N-nitroso-phenylhydroxylamine ammonium salt and reacted with stirring in a water bath at 80° C. for 8 hrs to obtain p-(3-methacryloxy-2-hydroxypropyloxy)benzaldehyde.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:5]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[BH4-]>C1COCC1.CCOC(C)=O.CCCCCCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C@H:4]([CH2:3][OH:2])[CH:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:11][C:12]([F:14])([F:13])[F:15])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(N[C@H](CO)C(CC(F)(F)F)CC(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.8 %

Procedure:
To a solution of (2S)-2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic acid methyl ester (2.924 g, 6.6 mmol) in THF (30 mL) was added LiBH4 (9.9 mL of 2M THF solution, 19.8 mmol) over 10 minutes at 4-6° C. The reaction mixture was stirred at 25° C. for 4 days. Additional LiBH4 (6.6 mL of 2M THF solution, 13.2 mmol) was added, and the reaction mixture was stirred at 25° C. for an additional 24 hours. The reaction mixture was cooled to 0° C. and quenched by slow addition of 30 mL of 2N HCl (vigorous gas evolution). The mixture was partially concentrated in vacuum and extracted with EtOAc. The organic fraction was washed with brine, dried over Na2SO4, and concentrated to afford 2.66 g of crude product. The crude product was dissolved in a mixture of EtOAc (10 mL) and heptane (3 mL) at 55° C., cooled to 25° C., and the resultant suspension was aged for 48 hours. Heptane (27 mL) was added and the mixture was stirred at 25° C. for additional 48 hours. The precipitate was filtered and washed with heptane to afford 1.962 g of the title compound (72% yield), mp: 186-187° C. Chiral HPLC: 97% ee (the Chiralcel® AD column 0.46×25 cm, 10% EtOH in hexanes). HRMS calc. (for M+H): 414.0360. Found: 414.0359.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of p-methoxybenzoyl chloride (37.8 g, .222 mol) in CH2Cl2 (200 ml) at 0°, is added triethylamine (22.5 g, .222 mol) followed by the slow addition of 3-phenylpropylamine (20 g,.148 mol) dissolved in CH2Cl2 (100 ml). The reaction is allowed to warm to room temperature over several hours. The solvent is removed in vacuo, and the residue is dissolved in EtOAc (500 ml) and 2N HCl (500 ml). The EtOAc is separated, washed with 2NHCl (350 ml), H2O (350 ml), saturated NaHCO3 solution (350 ml), and saturated NaCl solution (350 ml); dried over MgSO4 ; and evaporated. The resulting light brown solid is purified by chromatography (SiO2 ;1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) yielding N-(3-phenylpropyl)-4-methoxybenzamide as creamy solid.