Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[Br:26]N1C(=O)CCC1=O>>[Br:26][C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:13]([Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 27 b], 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with tert-butyldimethylsilyl chloride and subsequently with N-bromosuccinimide to obtain 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole as brown solid.
Reaction SMILES: O[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.O(Br)[Br:19].[P].CN([CH:25]=[O:26])C>ClCCCl>[Br:19][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: BrOBr
Agent: [P]
Solvent: ClCCCl
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1C=O
Temperature: 90 °C

Procedure:
To a solution of ethyl 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate (6.47 g, 27.52 mmol) in DCE (70 mL) is added phosphorus oxy bromide (13.86 g, 48.16 mmol) and DMF (4 mL, 51.46 mmol). The reaction mixture is refluxed at 90° C. for 3 h. Phosphorus oxy bromide (34.8 g, 121.38 mmol) is added again and the reaction mixture is refluxed at 90° C. for 20 h. The reaction mixture is poured over ice and extracted with DCM twice. The organic layer is dried over Na2SO4 and concentrated. The crude is purified by column chromatography to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 10.30 (s, 1H), 7.63-7.61 (m, 5H), 4.38 (q, J=3.6 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H). MS (ESI+): 325.0, HPLC (max plot) 97.37%, Rt 4.42 min.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH:15]([CH3:16])[CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CC(C)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.3 mmol) in DMF (10 mL) was added sodium hydride (276 mg, 6.9 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (473 mg, 3.5 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether-hexane to yield 2-(pyridin-4-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (DMSO, HCl salt) d (ppm): 8.62 (d, 2H), 8.10 (d, 2H), 7.18 (s, 1H), 6.90 (m, 1H), 6.80 (m, 1H), 4.62 (m, 2H), 4.40 (m, 3H), 4.05 (m, 1H), 3.80 (m, 1H), 3.05 (s, 3H), 2.38 (s, 3H), 1.75 (d, 3H), 1.70-1.50 (m, 3H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C=CC1C=CC=CC=1.[C:16]([O:20]O)([CH3:19])(C)C>O>[C:1]([O:6][CH2:7][CH:16]1[O:20][CH2:19]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(C)OO
Reactant: C=C(C)C(=O)OC
Solvent: O
Solvent: C=Cc1ccccc1
Product: C=C(C)C(=O)OCC1CO1

Procedure:
An amount of 1155 g of an aqueous latex of a core polymer mainly comprising a styrene-butadiene rubber (containing 375 g of styrene-butadiene rubber particles) as obtained using the procedure described in Example 2 was charged into a 3 L glass vessel followed by addition of 440 g of pure water. A monomer mixture composed of 62 g of methyl methacrylate, 38 g of styrene and 0.1 g of t-butyl hydroperoxide as a monomer mixture that is not the shell forming monomers (A) was added thereto over the course of 120 minutes while stirring at 60° C. in a nitrogen atmosphere to carry out graft polymerization. Following completion of the addition of the monomer mixture, stirring was further continued for 2 hours to complete the reaction. The polymerization conversion rate was 99%. The volume average particle size of the resulting minute polymer particles (CS-1C) in the form of an aqueous latex was 0.1 μm, and a sharp, monodisperse particle size distribution similar to CS-2 of Example 2 was shown.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=[C:25]1[CH:23]1[CH2:22][NH:21][CH2:24]1
Reactant: c1ccc(C(c2ccccc2)N2CC(c3cc4ccccc4o3)C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: c1ccc2oc(C3CNC3)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122.2 %

Procedure:
1-Chloroethyl chloroformate (36 μL, 0.33 mmol) was added to a solution of 1-benzhydryl-3-(benzofuran-2-yl)azetidine (108 mg, 0.32 mmol) in dichloromethane (3 mL) at 0° C. The reaction mixture was stirred for 2 hours at 0° C. and for 1 hour at room temperature. Ethanol (3 mL) was added at 0° C. and the reaction mixture was stirred for 2 hours at 0° C., for 19 hours at room temperature and for 4 hours at 40° C. After concentration to dryness, the crude mixture was triturated in n-pentane (2×4 mL) to afford the title compound as a pink solid (82 mg, 123%) which was used without further purification.
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15]CC)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6]CCC.[F-].C([Si](C)(C)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[CH:42]([C:43]4[CH:57]=[CH:56][C:46]([O:47]CCN5CCCCC5)=[CH:45][CH:44]=4)[O:41][C:40]4[CH:39]=[C:38]([O:58][Si](C(C)(C)C)(C)C)[CH:37]=[CH:36][C:35]=4[C:30]=3[CH2:31][O:32][C:33]=2[CH:34]=1)(C)(C)C.[CH3:68][C:69]([CH3:74])([CH3:73])[C:70](Cl)=[O:71]>C1COCC1.C(OCC)(=O)C>[OH:24][C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[CH:42]([C:43]4[CH:44]=[CH:45][C:46]([O:47][CH2:15][CH2:14][N:5]5[CH2:6][CH2:13][CH2:12][CH2:11][CH2:10]5)=[CH:56][CH:57]=4)[O:41][C:40]4[CH:39]=[C:38]([O:58][C:70](=[O:71])[C:69]([CH3:74])([CH3:73])[CH3:68])[CH:37]=[CH:36][C:35]=4[C:30]=3[CH2:31][O:32][C:33]=2[CH:34]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)C1=C2COc2cc(O)ccc21
Reaction time: 0.25 h

Procedure:
TBAF (1 M in THF, 850 μL, 0.85 mmol, 3 eq.) was added drop-wise into a solution of 1-(2-{4-[2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-phenoxy}-ethyl)-piperidine (200 mg, 0.285 mmol) in THF (10 mL) at −10° C. The reaction mixture was stirred for 15 minutes. To the reaction mixture was then added 2,2-dimethylpropionic acid chloride (714 μL, 0.285 mmol, 1 eq). The reaction mixture was diluted with ethyl acetate and washed with 5% sodium bicarbonate and then with brine. The organic layer, was dried over anhydrous Na2SO4, and concentrated to yield a crude oil, which was purified by HPLC (using Luna C18 column, 1% TFA in acetonitrile (ACN) and 1% TFA in H2O as gradient solvent system). Two peak were collected separately and evaporated to dryness in vacuum to yield 2,2-Dimethyl-propionic acid 8-hydroxy-11-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester as peak one
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>CO.[OH-].[Na+].O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNC(=O)N1N=C(c2ccc(N)cc2)c2cc(SC)ccc2C1C
Yield: 87 %

Procedure:
The solution of acetyl amide 9 in methanol and NaOH (2 N) was refluxing until there is no more starting material left monitored by TLC. The solution was diluted with water, and extracted with DCM three times. Removal of the solvent afforded the crude product, which was purified by using a silica gel column, gave the desired products 12 (Yield: 87%). 1HNMR (CDCl3): 7.45 (d, J=8.6 Hz, 2H), 7.35-7.25 (m, 4H), 6.78 (d, J=8.6 Hz, 2H), 6.53 (br, 1H), 5.60 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH3:24])[C:21]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:25]([OH:27])=[O:26])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:31][C:29](=[O:30])[CH2:28][C:21]1([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH:22]([CH3:24])[CH2:23][N:19]([C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:20]1)([CH3:34])([CH3:33])[CH3:35]
Reactant: BrCc1ccccc1
Reactant: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 5 °C
Yield: 98.2 %

Procedure:
Benzyl bromide (4.48 ml, 37.7 mmol) was added to a mixture of (3RS,4SR)-1-[(benzyloxy)carbonyl]-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1b (14.5 g, 38.5 mmol), potassium carbonate (10.6 g, 77 mmol) and N,N-dimethylformamide (50 ml) with stirring under ice-cooling (internal temperature: 3 to 7° C.), and the mixture was stirred for one hour, returned to mom temperature and stirred overnight. Water was added to the reaction liquid, which was extracted with ethyl acetate three times. The organic layers were combined, sequentially washed with a saturated aqueous ammonium chloride solution (five times), water (twice) and brine, and then dried over sodium sulfate, filtered and concentrated to give the title compound (17.67 g, yield: 98.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18](I)=[CH:17][N:16]=1>>[Br:14][C:15]1[N:16]=[CH:17][C:18]([NH:1][C:2]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:19][C:20]=1[CH3:21]
Reactant: CCOC(=O)c1cc(C)ccc1N
Reactant: Cc1cc(I)cnc1Br
Product: CCOC(=O)c1cc(C)ccc1Nc1cnc(Br)c(C)c1
Yield: 25 %

Procedure:
Obtained (0.050 g, yield 25%) following the procedure described in Intermediate 16 starting with ethyl 2-amino-5-methylbenzoate (0.56 mmol, 0.100 g) and 2-bromo-5-iodo-3-methylpyridine (1.0 mmol, 0.166 g).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:44])[CH:40]=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:44][C:1]([NH:23][CH:20]4[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][O:14][CH3:13])[CH2:22][CH2:21]4)=[O:12])[CH:40]=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: COCCN1CCC(N)CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COCCN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=460.7 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN[O:18][CH3:19].[CH3:20][N:21]1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:21][CH2:20][O:18][CH3:19])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CN1CCOCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCNC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (8.0 g, 39 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.6 g, 47 mmol) in methylene chloride (80 mL) is added N-methylmorpholine (5.2 mL, 47 mmol), HOBT (6.4 g, 47 mmol) and EDCl (9.1 g, 47 mmol). The mixture is stirred at RT for 18 h then is washed sequentially with 10% citric acid (2×), sat. NaHCO3 (2×) and brine. The organic solution is dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting oil is purified by flash chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OCC)C.[Cl:22][CH2:23][C:24]([O:26][CH2:27]/[CH:28]=[C:29](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])\[CH3:30])=[O:25].ClCC([O-])=O>CCCCC>[Cl-:22].[CH3:16][N+:14]([CH3:15])([CH2:23][C:24]([O:26][CH2:27]/[CH:28]=[C:29](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])\[CH3:30])=[O:25])[CH2:13][CH2:12][CH2:11][NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)NCCCN(C)C
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCl
Agent: O=C([O-])CCl
Solvent: CCOCC
Solvent: CCCCC
Product: CCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Product: [Cl-]
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A 22.84 g (0.100 mol) portion of N-octanoyl-N′,N′-dimethyl-1,3-diaminopropane and 250 ml of diethyl ether were put into a flask, and 24.23 g (0.105 mol) of geranyl chloroacetate was added thereto at 0 to 5° C. spending 10 minutes. The reaction mixture was stirred at 5 to 25° C. for 24 hours, and disappearance of the most part of chloroacetate was confirmed by 1H-NMR. Next, the reaction mixture was slowly added dropwise to 650 ml of pentane which was ice-cooled and vigorously stirred, spending 10 minutes, to effect precipitation of the product as a white solid. Thereafter, in the same manner as described in Inventive Example 1, the title compound (to be referred to as betaine ester (4) hereinafter) was obtained as a light yellow viscous oil. Yield 38.2 g (0.0832 mol; yield 83.2%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O>ClCCl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1nc(-c2ccccc2)oc1-c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of (2-phenyl-5-(pyridin-3-yl)oxazol-4-yl)methanol (210 mg, 832 μmol) and triethylamine (253 mg, 348 μL, 2.5 mmol) in dichloromethane (4 mL) was added at 0-5° C. methanesulfonyl chloride (191 mg, 130 μL, 1.66 mmol). The ice bath was removed after 10 min and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give the product as light brown solid (197 mg, 728 μmol, 87.4%) which was used without further purification for the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH2:30])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=[O:3])[CH3:2].Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CN(C)[C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2N(C)C)C=CC=1.[I-].[Na+]>CN(C=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:30]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[CH2:32][C:33](=[O:34])[O:35][CH2:45][C:54]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(NC(C)=O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC(C)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 16 %

Procedure:
A mixture of 1.1 g (2.63 mmol) of 3-(acetylamino)-5-(octadecyloxy)benzenamine, 4.2 ml (26 mmol) of benzyl bromoacetate, 1.4 g (6.6 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.4 g (2.63 mmol) of sodium iodide in 40 ml of acetronitrile and 5 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 0.3 g (16% yield, mp 89°-90°) of N-[3-(acetylamino)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine benzyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[CH2:22]([S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH3:23]>ClCCl.O>[CH2:22]([S:24]([N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[CH3:19])[CH2:31][CH2:32]1)(=[O:26])=[O:25])[CH3:23]
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 1.5 g. (0.0049 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 2.7 g (0.015 mole) of 1-(ethylsulfonyl)-piperazine was heated at 130° for 50 min, allowed to cool and taken up in dichloromethane and water. The organic layer was washed again, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 70 g of silica gel first with ethyl acetate and then with 2% methanol in ethyl acetate. The eluant containing product, Rf(silica--ethyl acetate)=0.05, was concentrated to dryness in vacuo. Recrystallization of the residue from 2-propanol afforded 1.5 g (68%) of the title compound, mp 72°-74°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].[CH2:15]=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C=O
Reactant: CNC
Reactant: Clc1cnc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 8.00 g, 0.0524 mol) in isopropyl alcohol (250.0 mL) were added dimethylamine hydrochloride (4.79 g, 0.0587 mol) and formaldehyde (1.77 g, 0.0589 mol). The reaction was stirred at room temperature overnight, followed by refluxing for 4 hours. The reaction was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (533, 10.0 g, 91%), that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([OH:12])=[O:11]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(F)cc1F
Yield: 89 %

Procedure:
Step AM (1): 2-(2,4-Difluorophenyl)acetic acid (2.5 g, 14.52 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.0 mL, 29.0 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.5 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(2,4-difluorophenyl)hexanoic acid (3.39 g, 89% yield). LC-MS (M−H)− 261.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [Na].C1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9](CC)=[N:8]2)CCCC1.[CH2:18](OC1C=CC=CC=1C(OCC)=O)C=C.O>C(O)C.CCOCC>[N:7]1[C:11]2=[N:12][CH:18]=[N:15][C:13](=[O:14])[C:10]2=[CH:9][N:8]=1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: C=CCOc1ccccc1C(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: O=C1N=CN=C2N=NC=C12

Procedure:
Sodium spheres (207 mg) was dissolved in ethanol (15 ml) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1 g, 45 mmol) was added, followed by ethyl 2-(2-propenyloxy)benzoate (1.85 g, 9 mmol). The reaction mixture was refluxed overnight, cooled, the ethanol was stripped and water was added. The pH was adjusted to about 7 and a solid was isolated by filtration. The solid was taken up in ether, washed with dilute HCl, dried over MgSO4, filtered and the solvent was removed and the solid residue was recrystallized from ether to afford 0.56 g of 1-cyclopentyl-3-ethyl-6-[2-(CH2 =CH--CH2O)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 119-120° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH3:24][O:25][CH2:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:30][CH:28]([CH2:27][CH2:26][O:25][CH3:24])[CH3:29])=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COCCC(C)N
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COCCC(C)NC(=O)c1ccc(-n2ncc(-c3ccnc(OC)c3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 4-methoxybutan-2-amine 1H NMR (400 MHz, methanol-d4) δ ppm 1.28 (d, J=6.32 Hz, 3 H) 1.86 (dd, J=6.95, 5.43 Hz, 2 H) 3.33 (s, 3 H) 3.44-3.57 (m, 2 H) 4.18 (s, 3 H) 4.22-4.34 (m, 1 H) 7.77 (d, J=5.31 Hz, 1 H) 7.86 (s, 1 H) 8.04 (d, J=6.57 Hz, 1 H) 8.44 (br. s., 3 H) 8.68-9.15 (m, 1 H). MS m/z [M+H]+ 398.2.