Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCOCCOCc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCC(CO)CCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C6H5—CH2O—CH2CH2OCH2CH2—CH(COOC2H5)2 (5 g) from Step B was dissolved in 200 ml of toluene and 29.5 ml of LiA1H4 (1 M in THF) was added at 0-5° C. After stirring overnight at room temperature, 1 ml of water was added followed by 1.0 ml of 15% NaOH and 3.0 ml of water. The insoluble material was filtered and the filtrate was evaporated to dryness. The product was purified by flash chromatography on a silica gel column eluted with ethyl acetate. Combined fractions were evaporated to dryness. The final product was dried under vacuum overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Br:11])[CH:5]=1.B1([C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)OCCCO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=[C:6]([Br:11])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)cc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 67.6 %

Procedure:
To the solution of Methyl-3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol) in toluene (50 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.24 g, 7.63 mmol), potassium carbonate (8.11 g, 58.7 mmol) and tetrakis(triphenylphoshine)palladium (O) (0.34, 0.29 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 80° C. under argon for 10 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 3% methanol in dichloromethane to isolate Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 67%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:29])[N:14]([CH3:28])[N:15]=[C:16]([CH2:26]Br)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[C-:30]#[N:31].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:29])[N:14]([CH3:28])[N:15]=[C:16]([CH2:26][C:30]#[N:31])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CBr)nn(C)c1=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CC#N)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-bromomethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (675 mg, 1.48 mmol) in DMSO (4 ml) was added sodium cyanide (80 mg, 1.63 mmol), and stirred at room temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 405 mg of Compound (I-30) (yield: 66%) as solid.
Reaction SMILES: [CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1.C(O)C.[OH-].[K+]>O>[CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=CCC(C)(C)c2cc(N(C)c3ccc(C(=O)O)cc3)c(C)cc21
Temperature: 60 °C
Yield: 89.4 %

Procedure:
Following previously described General Procedure E, to a solution of ethyl 4-[methyl-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 40, 0.05 g, 0.14 mmol) and 2 mL of absolute ethyl alcohol was added aqueous 5M KOH (0.3 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as a dark green solid. PNMR (300 MHz, CDCl3) δ—1.24 (s, 6H), 2.12 (s, 3H), 2.14 (s, 3H), 2.22 (d, 2H, J=2.4 Hz), 3.32 (s, 3H), 5.81 (s, 1H), 6.52 (d, 2H, J=7.5 Hz), 7.08 (s, 1H), 7.19 (s, 1H), 7.92 (d, 2H, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O>ClCCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[N:44]=[CH:12]2
Reactant: CC(=O)Nc1ccc(Br)c(F)c1C
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2c(F)c(Br)ccc21
Temperature: 65 °C

Procedure:
N-(4-Bromo-3-fluoro-2-methylphenyl)acetamide (36 mmol) was suspended in 1,2 dichloroethane (150 mL) and acetic anhydride (108 mmol), potassium acetate (74 mmol), 18-Crown-6 (1.4 mmol) and isopentyl nitrite (79 mmol) were added sequentially. The mixture was heated at 65° C. for 24 h, cooled to rt and washed with sat. NaHCO3. The organic layer was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography (0-20% EtOAc/hexanes). 1-(5-Bromo-4-fluoroindazol-1-yl)ethanone was obtained as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([CH3:31])[C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([CH3:31])[C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([NH2:16])=[O:15])[C:7]3=[O:12])=[O:29])=[CH:25][CH:26]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](C(N)=O)n1ccc2c(NC(=O)[C@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanamide (0.2 g, 0.0007 mol), (R)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol) N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.33 g, 0.00088 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a white solid. 1H NMR δ (CDCl3) δ: 8.24 (d, J=8.1 Hz, 1H), 7.99 (t, J=7.2 Hz, 1H), 7.53-7.33 (m, 6H), 7.07 (br, 1H), 6.26 (br, 1H), 6.06-6.03 (m, 1H), 5.31 (br, 1H), 5.14 (d, J=11.4 Hz, 1H), 3.82 (q, J=7.2 Hz, 1H), 2.55-2.48 (m, 1H), 1.62 (d, J=11.1 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H), 0.76 (dd, J=2.1, 6.6 Hz, 3H). MS m/z 426.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2>ClCCl.CN(C=O)C.O>[CH:47]12[CH2:55][CH:51]3[CH2:50][CH:49]([CH2:54][CH:53]([CH2:52]3)[CH:46]1[NH:45][C:12]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)=[O:14])[CH2:48]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cn1ncc(C(=O)O)c1-n1cccn1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1-n1cccn1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
2′-Methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (Intermediate 8, 50 mg, 0.26 mmol) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.23 mL, 1.3 mmol) and TSTU (93 mg, 0.28 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (58 mg, 0.31 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reversed phase prep-HPLC with a gradient of 10-100% acetonitrile/water to give 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid adamantan-2-ylamide (65 mg, 77%). Mass spectrum: m/z: 362.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:19][CH3:20])[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([CH3:23])[CH:3]=1.[CH:24]([O-])([O-])OCC.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([C:15]2[O:16][CH:24]=[N:18][N:17]=2)[O:19][CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(c1nnco1)c1ccccc1COc1ccc(Cl)cc1C
Yield: 13.5 %

Procedure:
To 0.50 g (1.5 mmol) of 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide was added 1.5 ml of ethyl orthoformate, stirred under reflux for 3 hours, and thereafter concentrated under reduced pressure. To the residue thus obtained, 4.5 ml of benzene and 0.03 g (0.15 mmol) of p-toluenesulfonic acid monohydrate were added and stirred under reflux for an hour. After completion of the reaction, 100 ml of water was added and extracted twice with 50 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-methoxybenzyl]-1,3,4-oxadiazole (0.07 g, 13.5%) as colorless crystals. mp. 68-70° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH:12]([O:15][C:16]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:14])[CH3:13]>CN(C)C=O>[CH:12]([O:15][C:16]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:17]=1[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 0.14 mmol 4-cyanophenol in 1 ml N,N-dimethylformamide was added 0.19 mmol sodium hydride (60% suspension in oil) and the mixture was stirred at room temperature for 30 min. 0.12 mmol methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperidin-4-yl ester was then added, and the reaction mixture was stirred at 60° C. for 2 h and then at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude material was purified by reversed phase HPLC (acetonitrile/water) to afford the title compound as a white crystalline solid (yield 21%). MS (m/e): 443.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH3:18])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH2:19](O)[CH:20](C)[CH3:21].CS(O)(=O)=O.[Cl-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH2:18][CH:20]([CH3:21])[CH3:19])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COCN(C(=O)CCl)c1c(OC)cccc1OC
Reactant: CC(C)CO
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cccc(OC)c1N(COCC(C)C)C(=O)CCl
Yield: 88 %

Procedure:
A mixture containing alpha-chloro-N-[methoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (4.9 g; 0.018 mole), 20 ml. of isobutanol and 0.2 ml. of methanesulfonic acid in 150 ml. of xylene was heated at reflux temperature for 2 hours under a soxhlet extractor containing 20 g. of activated 3A molecular sieves. The reaction mixture was then cooled to 26° C. after which time a 2.5% sodium chloride solution was added to the reaction mixture. The layers were separated and the organic layer was dried, filtered and concentrated to yield a yellow solid. The yellow solid was recrystallized from heptane to yield alpha-chloro-N-[2-methylpropoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (5.0 g; 88% yield) as white crystals having a melting point of 107°-110° C. and the following analysis:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1I)=[O:29])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:31]4[N:30]([C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:29])[CH:34]=[CH:33][N:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)C(=O)n1ccnc1I
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(C#Cc3nccn3C(=O)C(C)(C)C)CCC(=O)CC2)cc1OC1CCCC1
Yield: 43.2 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.28g, 0.9 mmol) and 1-tert.-butylcarbonyl-2-iodoimidazole (0.29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.042 g, 4%), copper(I) iodide (0.005 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-tert-butylcarbonylimidazol-2-ylethynyl)cyclohexan-1-one (0.18 g, 4%), as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.85 (m, 1H), 3.84 (s, 3H), 3.18 (m, 2H), 2.44 (m, 4H), 2.22 (m, 2H), 1.8-2.0 (m, 6H), 1.6 (m, 11H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14](=[N:19][OH:20])[NH2:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(OCC#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCc1ccc(OCC(N)=NO)cc1
Yield: 99.8 %

Procedure:
30.6 g (0.13 mol) of 4-n-heptyl-phenoxy-acetonitrile, 18.1 g (0.26 mol) of hydroxylamine hydrochloride and 27.6 g (0.26 mol) of sodium carbonate are stirred at reflux temperature in 100 ml of ethanol and 200 ml of water until the reaction is complete (approximately 24 hours). The entire reaction batch is subsequently introduced into water, and the mixture is extracted using methylene chloride. 34.3 g (99.8% of theory) of 4-n-heptyl-phenoxy-acetamide oxime are obtained.
Reaction SMILES: ClC1N=C(Cl)C2CCN(CC3C=CC(OC)=CC=3)C=2N=1.[CH:21]([C:33]([O:35]CC)=O)([C:28]([O:30]CC)=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH2:38][C:39]([NH2:41])=[O:40]>>[OH:40][C:39]1[N:41]=[C:28]([OH:30])[C:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:33]([OH:35])[N:38]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: COc1ccc(CN2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CCOC(=O)Cc1c(O)nc(O)nc1O
Yield: 52.4 %

Procedure:
According to General Protocol I, 2,4-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was prepared from triethyl ethane-1,1,2-tricarboxylate (10 g, 41 mmol) and urea (2.44 g, 41 mmol), and isolated as a pale-yellow solid (4.6 g, yield 35%).
Reaction SMILES: [NH4+:1].[Cl-].C.C[O:5][C:6]([C@@H:8]1[C@H:12]([CH2:13][N:14]=[N+:15]=[N-:16])[CH2:11][CH2:10][N:9]1[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=O>C1(C)C=CC=CC=1.C[Al](C)C>[N:14]([CH2:13][C@@H:12]1[CH2:11][CH2:10][N:9]([C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[C@@H:8]1[C:6]([NH2:1])=[O:5])=[N+:15]=[N-:16]
Reactant: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Reactant: [NH4+]
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](CN=[N+]=[N-])[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum in toluene (2 M, 15.95 mmol) was added dropwise to a mixture of NH4Cl (15.95 mmol) in toluene (2 mL) at 0° C. with the formation of methane gas. The reaction mixture was allowed to warm to rt, stirred for a further 15 min and then slowly treated with a solution of (2S,3S)-3-azidomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Stage 36.4) (7.98 mmol) in toluene (8 mL). Additional reagent prepared from NH4Cl (15.95 mmol) in toluene (2 mL) and trimethylaluminum in toluene (2 M, 15.95 mmol) at 0° C. was added after 18 h. After stirring for 44 h, the mixture was cooled to 0° C., quenched with 1M HCl and then washed with CH2Cl2 (3×). The aqueous phase was basified with a 1:1 saturated solution of NaHCO3/saturated solution of Rochelle's salt and extracted with THF (10×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow oil. HPLC: tR=2.50 min (method G); ESI-MS: [M+H]+ 274; TLC: Rf=0.26 (3:1 Hex/EtOAc).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)CCC(=O)O
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (97 mg, 91%), MS (ISP) m/z=429.4 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[F:26][C:27]1([F:35])[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH:30]4[CH2:31][CH2:32][C:27]([F:35])([F:26])[CH2:28][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCC1CCC(F)(F)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCC(F)(F)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4,4-difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.25 (m, 2H) 1.60-1.82 (m, 5H) 1.95 (d, J=8.1 Hz, 2H) 2.37 (s, 3H) 3.15 (t, J=6.3 Hz, 2H) 7.59 (d, J=7.6 Hz, 1H) 7.67 (s, 1H) 8.36 (br. s., 1H) 8.70 (br. s., 1H) 8.82-8.88 (m, 1H) 13.16 (br. s., 1H). MS m/z [M+H]+ 452.5.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH:14]=[C:15]([O:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[C:7]1=2)C.Cl>C(O)(=O)C>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:34])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCCNC(=O)OC(C)(C)C)c21
Agent: Cl
Solvent: CC(=O)O
Product: NCCOc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Yield: 64.2 %

Procedure:
A solution of [4-(2-tert-butoxycarbonylamino-ethoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (47 mg) in acetic acid (4 mL) was treated with 1N HCl (1 mL) at 100° C. 2 h. The reaction was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (22 mg) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 8.34-8.33 (m, 1H), 8.17-8.15 (m, 1H), 7.08 (d, J=1.8 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 5.76-5.72 (m, 1H), 4.35-4.32 (m, 2H), 3.47-3.44 (m, 2H), 3.31-3.25 (m, 1H), 2.57-2.49 (m, 1H). MS calcd for (C15H16BN3O6+H)+: 346.2. MS found: (M+H)+=346.2.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[O:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23].[ClH:28]>O1CCOCC1>[ClH:28].[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[O:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23]
Reactant: COCOc1ccccc1CCc1ccccc1OCCC1CCCN1C
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1CCOc1ccccc1CCc1ccccc1O
Reaction time: 0.5 h
Yield: 86 %

Procedure:
0.660 g of 2-(2-{2-[2-(2-methoxymethoxyphenyl)ethyl]phenoxy}ethyl)-1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 5 ml of dioxane, and 5 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then allowed to stand at room temperature for 30 minutes, after which it was concentrated by distillation under reduced pressure. The resulting colorless solid was dissolved in a small amount of a mixture of methylene chloride and methanol, and about 30 ml of ethyl acetate were added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.555 g (yield 86%) of the title compound as colorless crystals, melting at 168.5°-171° C.