Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[Li]CCCC.[F:15][CH2:16][C:17](OCC)=[O:18]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:17](=[O:18])[CH2:16][F:15])[CH:3]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: CCOC(=O)CF
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CF)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 4-bromo-1-fluoro-2-iodobenzene (5.0 g, 116 mmol, (1), Aldrich) in THF (60 ml) under nitrogen atmosphere was cooled to −78° C. A solution of n-BuLi (2.5M in hexanes; 7.31 ml, 18.28 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. Ethyl monofluoroacetate (2.1 g, 19.94 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. The reaction was quenched with aqueous saturated ammonium chloride solution and allowed to warm to RT. The reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-20% EtOAc in Hexanes to afford the title compound as an off white solid. (2.45 g, 10.42 mmol, 63% yield). MS m/z=234.9 M+. Calculated for C8H5BrF2O: 235.03
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]2([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC1(C(=O)O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25.7 %

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (101 mg, 0.318 mmol), 1-aminomethyl-cyclopropanecarboxylic acid (110 mg, 0.955 mmol, prepared according to literature: Ohno, Mitsuru et al Synlett 1991, 919-920), and NaOMe in MeOH (1.6 mL, 0.5 M solution) was microwaved at 120° C. for 1 h, the reaction mixture was cooled, diluted with water and acidified with 2 M HCl aqueous solution, the resulted solids were collected via filtration, water-washed and air-dried to give solids, which were further column purified to give the desired product (33 mg). LC MS ESI+: 404 (M+1)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>ClCCl.CN(C)C=O>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (2.04 mmol) and Boc-p-amino-L-phenylalanine (1.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 4:1 dichloro-methane/dimethylformamide reaction solvent, washed with base only). The product was purified by chromatography on silica gel eluted with 50, 60, 70 and 100% ethyl acetate in hexanes. Yield 226 mg, 42%; HPLC (70/30) 2.45 minutes (100%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([C:14](OCC)=[O:15])[CH2:12][N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:10][C@@H:9]1[C:28](OCC)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:13]([CH2:14][OH:15])[CH2:12][N:11]([S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:10][CH:9]1[CH2:28][OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1CN(S(=O)(=O)c2ccccc2)C[C@@H](C(=O)OCC)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CC(CO)N(Cc2ccccc2)C(CO)C1
Yield: 80.1 %

Procedure:
1 M solution of LiAIH4 in THF (70 ml; 70 mmol) was added dropwise under cooling and stirring to 112c (10.7 g; 23.2 mmol) in THF (275 ml). The reaction mixture was refluxed for 20 min, poured on a saturated solution of Na2CO3 and extracted with TBME three times. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield a colorless solid, which was washed with TBME to yield 112d as white crystals (7 g, 80%). MS: [M+H]+: 377
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.O=S(Cl)[Cl:35]>>[Cl:35][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:32])[CH:21]=2)=[N:25][CH:26]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CO)cn4)sc23)c(F)c1)NC1CC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500 mL round-bottom flask containing 64 (5.34 g, 11.85 mmol) was added slowly SOCl2 (30 mL, 411 mmol). The yellow solution was stirred at RT for 2 h and cooled to 0° C. The reaction mixture was quenched by addition of ice (150 g) and water (100 mL), and the yellow suspension was shaken at RT for 1 h. The solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was triturated with AcOEt to afford the title compound 65 (5.55 g, purity ˜40% by HPLC, contaminated with the des-cyclopropyl side-product) as a yellow solid. MS (m/z): 469.1 (M+H). The material was used in the next step with no additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[K+]>C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:19]=[N+:20]=[N-:21])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1Cl
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
A stirred suspension of 4-(4-chlorobenzoyl)-3-chlorobenzyl bromide (1.60 g, 4.65 mmol) and potassium azide (0.715 g, 8.81 mmol) in ethanol (15 ml) was refluxed 5 hours, cooled to ambient temperature, and stirred 16 hours. The solids were filtered and washed twice with ethanol. The combined filtrate and washes were evaporated under vacuum, diluted with diethyl ether (40 ml), filtered, and evaporated under vacuum to provide 1.51 g (106% of theory) of 4-(4-chlorobenzoyl)-3-chlorobenzyl azide, m.p. 33°-33.5° C., suitable for subsequent reaction.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[N:7]=1.[C:15]1([CH:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C.[Cl-].[Na+]>CN(C)C=O>[C:33]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=4)[N:7]=3)[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1nc2ccc(Cl)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
0.92 g of methyl 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylate and 1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of N,N-dimethylformamide; 1.49 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing at 80° C. for 15 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the residue was recrystallized from ethanol-ethyl acetate (1:2) to yield 639 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11](O)[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(Cl)C(=O)C([Cl:55])=C(Cl)C(=O)C=1Cl.O>C(#N)C>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([Cl:55])[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(Cl)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
0.50 g (1.2 mmol) of 3-[4-chloro-2-(1-hydroxyethyl)-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil and 0.64 g (2.5 mmol) of triphenylphosphine were dissolved in 20 ml of acetonitrile, and 0.60 g (2.5 mmol) of chloranil was added thereto at room temperature. After stirring at room temperature for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a 5% potassium carbonate aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 96.2%) of the desired product as a pale brown glassy substance. Refractive index: 1.5639 (20° C.).
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH:15]2[N:19]([C:20](=[O:23])[CH2:21]Cl)[CH2:18][CH2:17][S:16]2)=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH:15]2[N:19]([C:20](=[O:23])[CH2:21][S:6][CH2:4][CH3:5])[CH2:18][CH2:17][S:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(OCC2SCCN2C(=O)CCl)cc1
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(=O)N1CCSC1COc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.56 g of sodium methylate is MeOH (5 ml), cooled at 0° C., was treated with 0,71 ml of ethanethiol (CH3CH2SH). After 10 minutes, a solution of 3 g of 2-(4-methoxyphenoxymethyl)-3-α-chloroacetyl-1,3-thiazolidine in 10 ml MeOH was dropped into the mixture. After 30 minutes, the solvent was removed under reduced pressure and the residue was partitioned between 30% NaH2PO4 and ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness to yield 2,9 g of 2-(4-methoxyphenoxymethyl)-3-ethylmercaptoacetyl- 1,3-thiazolidine after crystallization from isopropyl ether, m.p. 98°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1>>[C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:15]2[N:20]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:18]([CH3:22])=[CH:17][N:16]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccccc1-c1ccccc1
Product: Cc1cnc(Nc2ccccc2-c2ccccc2)nc1Nc1ccccc1-c1ccccc1

Procedure:
In like manner to the preparation of 5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine were reacted to provide N2,N4-bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret. time: 30.47 min.; purity: 91%; MS (m/e): 429 (MH|).
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([C:11]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([O:20]CC)=[O:19])[CH:14]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=3)=[O:12])=[CH:23][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C

Procedure:
Ethyl 5-(4-phenylbenzoyl)pyrrole-3-carboxylate (3.1 g.) was boiled in an open flask with 100 ml. of methanol and 70 ml. of 1N sodium hydroxide for 1 hour by which time most of the methanol was removed by evaporation. The solution was cooled to room temperature, and product which had precipitated as the sodium salt recovered by filtration. The salt was stirred with 75 ml. of 1N hydrochloric acid and 5-(4-phenylbenzoyl)pyrrole-3-carboxylic acid (1 g., m.p.>280° C.) recovered by filtration.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCC=Cc1cccc(Br)c1
Reactant: BrCCCCCOCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1cccc(CCCCCOCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
At -78° C., 27.8 ml of t-butyl lithium (1.7M) in hexane are added to 5.30 gm of 3-bromo-(1-hexenyl)benzene in 75 mls of tetrahydrofuran. The reaction is stirred for 10 minutes, and then 1.1 ml of Li2CuCl3 (0.20M/THF) is added followed dropwise by 5.78 grams of 1-bromo-5-benzyloxy pentane. After allowing the reaction mixture to come to ambient temperature over 5 hours and stirring for an additional 24 hours, silica gel is added; and the mixture is concentrated and then chromatographed (HPLC) to yield pure 3-(5-benzyloxypentyl)-1-(1-hexenyl)benzene.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:2]2.C(O)(=[O:30])C>OO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH+:9]([O-:30])[C:10](=[O:27])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[CH2:2]2
Reactant: CC(=O)O
Reactant: CC(=O)Nc1cc(OCC2CC2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Agent: OO
Product: CC(=O)Nc1cc(OCC2CC2)c(C(=O)[NH+]([O-])C2CN3CCC2CC3)cc1Cl
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide (2.6 g; 0.007 moles) in acetic acid (20 ml), 30% hydrogen peroxide (1.8 ml) was added and the resulting solution was stirred at 80° C. for 15 hours. The solvent was removed in vacuo, the residue was treated with water, alcalinized with sodium hydroxyde aqueous solution, saturated with sodium chloride and extracted with methylene chloride. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residual yellow solid treated with diethyl ether and collected. After washing with acetonitrile and diethyl ether, N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide N-oxide was obtained as a white solid, which was dried at 50° C. to give 1.4 g; m.p. 234°-236° C. (d).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][CH2:13][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1NCCc2ccccc21
Reactant: OCCCBr
Product: O=C1c2ccccc2CCN1CCCO

Procedure:
from 3,4-dihydroisoquinolin-1(2H)-one and 3-bromopropanol
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1[CH2:50][CH2:49][CH2:48][C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][C@@H:36]([CH3:37])[C:49]([CH3:48])([CH3:50])[CH3:2])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@@H](C)C(C)(C)C)c4)cc23)CC1
Yield: 34.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.8 mg of the title compound (34.7%).
Reaction SMILES: C([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])=[C:15]2[C:10]([N:11]=[C:12]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[N:13]([CH3:26])[C:14]2=[O:25])=[N:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:16]1[NH:8][N:9]=[C:10]2[C:15]=1[C:14](=[O:25])[N:13]([CH3:26])[C:12]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[N:11]2
Reactant: CCCN(CCC)c1nc2nn(Cc3ccccc3)c(-c3ccc(C)cc3C)c2c(=O)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)c1nc2n[nH]c(-c3ccc(C)cc3C)c2c(=O)n1C
Yield: 84 %

Procedure:
To a Parr flask was added 0.14 g (0.31 mmol) of 2-benzyl-3-(2,4-dimethylphenyl)-6-dipropylamino-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrmidin-4-one and 30 ml of ethanol, followed by 0.10 g of 20 palladium hydroxide. The flask was purged with hydrogen and pressurized to 50 psig hydrogen and shaken. After complete reaction, the mixture was filtered through GF/F paper and the filtrate concentrated under reduced pressure. The residue was purified via biotage eluting with 50% ethyl acetate/hexanes to afford 0.092 g (82.47%) of product.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccc([N+](=O)[O-])o1
Yield: 28.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.56 g of 5-nitro-2-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.25 g of the title compound was obtained as yellow plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[CH:7]=1)#[N:2].[NH2:27][OH:28].Cl.CCN(CC)CC>CCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[C:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:6]4[CH:7]=[C:3]([C:1]([NH2:2])=[N:27][OH:28])[CH:4]=[N:5]4)[C:12]=3[CH:19]=[N:18]2)=[CH:25][CH:24]=1
Reactant: N#Cc1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
A mixture of 2-(4-cyanopyrazol-1-yl)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.175 g, 0.50 mmol), NH2OH—HCl (0.500 g, 7.2 mmol) and NEt3 (1.00 mL, 7.1 mmol) in EtOH (3 mL) was heated at 90° C. for 5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to obtain 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 60%).
Reaction SMILES: [N+:1]([CH:4]([CH2:9][CH2:10][CH:11]=O)[CH2:5][CH2:6][CH:7]=[O:8])([O-:3])=[O:2].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C(Cl)Cl>[N+:1]([CH:4]1[CH2:5][C:6]([CH:7]=[O:8])=[CH:11][CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: O=CCCC(CCC=O)[N+](=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=CC1=CCCC([N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
To a solution of 4-Nitro-heptanedial (35.2 g, 0.2 mol) in methylene chloride (0.7 L) were added pyrrolidine (2 ml, 0.024 mol) and benzoic acid (1.46 g, 0.012 mol), and the resulting mixture was refluxed for 10 to 15 hours. The reaction mixture was cooled to room temperature, washed with 1N HCl (170 ml), saturated with NaHCO3 (170 ml) and water (170 ml) and concentrated to give brownish oil with a purity of about 80%. The product was carried to the next step without further purification. Yield: 32.2 g, 75%. 1H NMR (400 MHz, CDCl3) δ 2.29-2.34 (m, 2H), 2.46-2.64 (m, 2H), 2.85-2.88 (m, 2H), 4.74 (m, 1H), 6.86 (m, 1H), 9.50 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@@:13]3([CH2:22][C@@:21]3([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:10]=1)[C:5]([O-:7])=[O:6].O[Li].[OH2:36]>CO.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@:21]2([CH:23]([CH3:24])[CH3:25])[C@:13]3([C:14]4[C:19](=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[N:11]([C:9]4[CH:8]=[C:4]([CH:3]=[C:2]([N:11]5[CH2:9][CH2:8][O:36][C:12]5=[O:33])[CH:10]=4)[C:5]([OH:7])=[O:6])[C:12]3=[O:33])[CH2:22]2)=[CH:27][CH:28]=1
Reactant: O
Reactant: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)N(c1cc(Br)cc(C(=O)[O-])c1)c1ccc(F)cc12
Agent: [Li]O
Solvent: CO
Product: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 108 %

Procedure:
To a solution of (1R,2R) and (1S,2S)-3-bromo-5-(2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoate (27.4 mg) in methanol (2 mL) and water (1 mL) was added LiOH.H2O (18 mg, 0.4 mmol) in one portion. The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH˜3. The precipitates was collected by filtration and dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as white solid (15 mg). LC/MS m/e calcd. for C29H24ClFN2O5 534, observed (M+H)+: 545.7. 1H NMR (400 MHz, MeOD-d4) δppm 0.89 (dd, J=20.34, 6.69 Hz, 6 H) 2.21-2.28 (m, 2 H) 2.89-3.01 (m, 1H) 4.22 (t, J=8.08 Hz, 2 H) 4.55 (t, J=8.08 Hz, 2 H) 5.28 (dd, J=8.84, 2.27 Hz, 1 H) 6.65 (dd, J=8.34, 1.77 Hz, 1 H) 6.80-6.89 (m, 2 H) 7.19 (dd, J=8.34, 2.02 Hz, 1 H) 7.45-7.54 (m, 2 H) 7.86 (s, 1 H) 8.09 (s, 1 H) 8.22 (s, 1 H).