Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([OH:6])[CH3:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([N:16]1[CH2:22][C:21]2[N:23]=[CH:24][C:25](Cl)=[N:26][C:20]=2[O:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([N:16]1[CH2:22][C:21]2[N:23]=[CH:24][C:25]([O:6][C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])=[N:26][C:20]=2[O:19][CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H](O)C1CC1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](Oc1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of (1R)-1-cyclopropylethanol (130 mg) in toluene (3 mL) was added sodium hydride (120 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. A mixture of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (415 mg), BINAP (41 mg), Pd2(dba)3 (28 mg) and toluene (3 ml) was added, and the mixture was stirred under an argon atmosphere at 100° C. for 3 hr. Water was added to the reaction solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (329 mg, 67%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.I[CH2:26][C:27]#[N:28].[CH2:29]([O:36][C:37](=[O:69])[NH:38][C:39]1[N:68]=[C:42]2[N:43]([C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=3)[C:44]([CH3:57])=[C:45]([C:55]#[N:56])[C@@H:46]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=3)[N:41]2[N:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:69])[N:38]([C:39]1[N:68]=[C:42]2[N:43]([C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:65])[F:66])[CH:59]=3)[C:44]([CH3:57])=[C:45]([C:55]#[N:56])[C@@H:46]([C:47]3[CH:48]=[CH:49][C:50]([C:53]#[N:54])=[CH:51][CH:52]=3)[N:41]2[N:40]=1)[CH2:26][C:27]#[N:28])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: N#CCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC#N)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 mmol, 2.1 eq.), 18-crown-6 (30 mg, 113 mmol, 2.1 eq.) and iodoacetonitrile (19 mg, 113 mmol, 2.1 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 mmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 78% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
As in Example 115, (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid (21.0 g) and 4-nitrophenol (11.2 g) in dichloromethane (300 mL) was treated with 1,3-dicyclohexylcarbodiimide (14 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature overnight. After the usual work up, the crude product was crystallized from ether-hexane to give 24.7 g of (E)-5,5-bis (4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 121°-123° C. Recrystallization of the material from 2-propanol afforded the purified ester, mp 125°-126° C. Anal. Calculated for C25H21NO6 : C, 69.60; H, 4.91; N, 3.23 Found: C, 69.19; H, 4.94; N, 3.25
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15]3)[CH2:8]1.COCCO[AlH2-]OCCOC.[Na+].C(OCC)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (4.02 g, 9.16 mmol, 1 eq) was dissolved in dry toluene (40.2 mL), degassed with nitrogen and heated to 60° C. Red-Al (11.3 mL, 36.6 mmol, 4 eq) was added slowly and the reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled to 0° C. and 49 mL of ethyl acetate was added followed slowly by 19.1 mL of a 10M aqueous NaOH solution (190 mmol, 7.6 g NaOH) and 19 mL of water. The reaction mixture was then transferred to a separatory funnel, diluted with brine and extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (200 g column; 50 mL/min; 10% MeOH in CH2Cl2 to 5% 7N NH3 in MeOH:90% CH2Cl2), which yielded 1.81 g (69%) of the title compound as a light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CC1CCCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.87 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[C:25]([CH3:34])[C:24]=2[CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10].[Li+].[OH-]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[C:25]([CH3:34])[C:24]=2[CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:10])=[O:11]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(NS(=O)(=O)c3ccc(Cl)cc3Cl)c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an N2 atmosphere, methyl 2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-2,3-dimethylphenyl)acetate (0.194 g, 0.354 mmol) was dissolved in tetrahydrofuran (2.5 mL) and 1N LiOH (aq) was added. The reaction was allowed to stir at room temperature for 2.5 h. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was made acidic with citric acid to pH 4 and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 8% methanol in dichloromethane, afforded the title compound. LC-MS EST (neg.) m/z: 531.1 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 10.94 (s, 1H); 9.75 (s, 1H); 7.53 (d, J=8.5 Hz, 1H); 7.48 (d, J=2.0 Hz, 1H); 7.20 (dd, J=8.5 Hz and 2.0 Hz, 1H); 7.07 (d, J=8.6 Hz, 1H); 6.72 (d, J=8.4 Hz, 1H); 6.27 (d, J=8.4 Hz, 1H); 6.13 (s, 1H); 5.99 (d, J=8.4 Hz, 1H); 3.50 (s, 2H); 2.35 (s, 3H); 2.09 (s, 3H); 1.92 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CS([O-])(=O)=O.[C:21]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:29](O)[CH:28]=[CH:27]2)(=[NH:23])[NH2:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C.N1C=CC=CC=1>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21](=[NH:22])[NH2:23])[CH:25]=3)[C:30]=2[CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:12])=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1c(O)ccc2cc(C(=N)N)ccc12
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1c(OC(=O)c2ccc(NC3=NCCN3)cc2)ccc2cc(C(=N)N)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
60 Milliliters of 20% hydrous pyridine was added to 2.8 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.methanesulfonate, 3.0 g of 6-amidino-1-methoxycarbonylmethyl-2-naphthol.methanesulfonate, 4.19 g of DCC and 103.4 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 48 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of DMF. The solution was added dropwise to a mixed liquid of 500 ml of acetone and 300 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 40 ml of methanol and 0.83 ml of methanesulfonic acid. The resulting solution was added dropwise to 400 ml of acetone, followed by stirring for 30 minutes under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.4 g of the desired product.
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH:15]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(C2=NC(Cc3ccccc3C)C(=O)N(C)c3ccc(Cl)cc32)cc1
Yield: 84.1 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of (Z)-7-chloro-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.50 g, 1.59 mmol) in THF (8 mL) was slowly added 1 M KOtBu (2.4 mL, 2.4 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 2-methylbenzyl bromide (0.46 g, 2.5 mmol, 1.5 eq) in THF (2 mL). After stirring another ˜35 min at −78° C., the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 20-40% EtOAc/heptane gave 0.56 g (yield of 84%) of the title product [Note: when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature]. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.41 (s, 3H), 3.5-3.65 (m, 2H), 3.74 (dd, 1H), 3.84 (s, 3H), 6.89 (dt, 2H), 7.05-7.15 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.5 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].C1COCC1.[OH-].[Na+].Cl>O.CO>[C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)c[nH]c(=O)c32)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
To a solution of methyl 4-(4-cyano-3-cyclopentyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (18 mg) in a mixed solvent of THF (1 mL), methanol (1 mL) and water (1 mL) was added 1N aqueous sodium hydroxide solution (0.195 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1N hydrochloric acid (0.195 mL), and the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting solid was washed with water and hexane to give the title compound (17 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:28]([O:31][C:32]1[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:34](O)=[O:35])(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1>C(#N)C.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[O:31][C:28](=[O:30])[CH3:29])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCN
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNC(=O)c1ccccc1OC(C)=O
Yield: 62.6 %

Procedure:
0.27 g (0.66 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-methoxyphenylacetamide obtained in Step 5 of Example 3, 0.17 g (0.94 mmol) of acetylsalicylic acid and 0.10 g (0.74 mmol) of 1-hydroxylbenzotriazole were dissolved in 15 ml of a mixture of acetonitrile and dimethylformamide(1:2). 0.19 g (0.92 mmol) of dicyclohexanecarbodiimide was added thereto and the resultant mixture was stirred at a room temperature for 2 days. White precipitates were removed and the remaining solution was diluted with 30 ml of dichloromethane, which was washed with water and dried. After removing the solvent under a reduced pressure, the residue was subjected to silica gel chromatography to obtain 0.22 g of the title compound (yield: 63%).
Reaction SMILES: C(N(CC)CC)C.C([O:11][C@@H:12]([CH3:16])[C:13](Cl)=[O:14])(=O)C.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:50])[F:49])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:30]=[C:29]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)[N:28]=3)[CH2:19]1.C[O-].[Na+].CO>C(Cl)Cl.CO.C(Cl)Cl.CO>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:29]2[N:28]=[C:27]3[C:32]([N:33]=[C:25]([N:20]4[CH2:21][C@@H:22]([CH3:24])[N:23]([C:13](=[O:14])[CH:12]([OH:11])[CH3:16])[C@@H:18]([CH3:17])[CH2:19]4)[N:26]3[CH2:47][C:48]([F:50])([F:49])[F:51])=[C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[N:30]=2)=[CH:41][N:42]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(O)C(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
Triethylamine (70.2 μl, 0.50 mmol) and (S)-(−)-2-acetoxypropionyl chloride (32.9 μl, 0.25 mmol) were added to a methylene chloride suspension (7.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (112.7 mg, 0.23 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 hours followed by the addition of (S)-(−)-2-acetoxypropionyl chloride (9.0 μl, 0.07 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (7.0 ml) followed by the addition of triethylamine (140.3 μl, 1.01 mmol) and (S)-(−)-2-acetoxypropionyl chloride (65.7 μl, 0.50 mmol) with ice cooling, and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (157.0 μl, 0.69 mmol) was added to a methanol (6.0 ml) solution of the resulting residue, and the resulting mixture was stirred at 50° C. for 22 hours. The resulting mixture was left standing to cool and then the reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (132.6 mg, 96%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[C:22]([C:33]#[N:34])=[N:23][N:24]([CH2:31][CH3:32])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1[N:24]([CH2:31][CH3:32])[N:23]=[C:22]2[C:21]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:2]=[C:33]2[NH2:34]
Reactant: CCn1nc(C#N)c(Br)c1CCCCCl
Reactant: Nc1ccccc1B(O)O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Temperature: 110 °C
Yield: 8 %

Procedure:
2-Aminophenylboronic acid hydrochloride (1.88 g, 10.8 mmol), potassium phosphate (6.9 g, 32 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (186 mg, 0.18 mmol), and bis[(2-diphenylphosphino)phenyl]ether (116 mg, 0.217 mmol) were added to a solution of 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (2.1 g, 7.2 mmol) in toluene (45 mL). Nitrogen was bubbled through the reaction mixture, and then the reaction was heated at 110° C. for 48 hours. The mixture was filtered through a layer of silica gel (eluting with 3:2 chloroform/methanol). The filtrate was concentrated under reduced pressure and dissolved in ethanol (36 mL). Hydrogen chloride (5.4 mL of a 4 M solution in ethanol) was added to the resulting solution, and the reaction was heated at reflux for two hours and allowed to cool to ambient temperature. The solvent was removed under reduced pressure, and the residue was adjusted to pH 11 with the addition of 2 M aqueous sodium carbonate. The mixture was diluted with brine and extracted with chloroform. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with chloroform/CMA in a gradient from 100:0 to 70:30). The resulting dark semi-solid was recrystallized from acetonitrile to provide 175 mg of 1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH3:18][NH:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[F:9][C:8](=[CH:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][CH3:18])[CH:21]=2)=[CH:31][CH:30]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)=Cc1ccc(-c2cccc(NC)c2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.3 %

Procedure:
382 mg (9.5 mmol) of sodium hydride are added to a solution of 1.9 mL (9.5 mmol) of commercial triethyl 2-fluoro-2-phosphonoacetate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 40 minutes. A solution of 803 mg of 3′-methylaminobiphenyl-4-carbaldehyde prepared as described in Example 5b (3.8 mmol) in 8 mL of tetrahydrofuran is then added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the residue (2.2 g) is purified by chromatography on a column of silica eluted with an 85/15 heptane/ethyl acetate mixture. 936 mg (82%) of ethyl 2-fluoro-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:42][CH:34]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41]1)[CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: NCCC(O)CCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCI, m/z): 516 [M+H]+.