Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C>O1CCOCC1>[CH2:35]([NH:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2NCc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 2-amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (170 mg, 0.379 mmol) in anhydrous dioxane (3 mL) was added a 1 M solution of potassium t-butoxide (0.42 mL, 0.42 mmol). The reaction mixture was stirred at room temperature for 10 minutes and benzyl bromide (130 mg, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 2-benzylamino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-bromopyrazine 112 (165 mg, 0.307 mmol).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Br[C:12]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:22]>O>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:13](=[O:22])[N:14]2[CH2:2][C:3](=[O:4])[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:19][CH:18]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1ccc(Cl)cc1
Solvent: O
Product: O=C(CN1C(=O)C(Cc2ccc(Cl)cc2)(NC2CCCCC2)c2ccc(Cl)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 2-chloro-1-piperidin-1-yl-ethanone (41 mg, 31 mmol) and KI (43 mg, 0.26 mmol) in dimethylformide (5 mL) was added rac-3-bromo-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.26 mmol) prepared in example 76c. After stirring at room temperature for 2 h, water (10 mL) was added and the crude was extracted with ethyl acetate (3×20 mL). The combined organic solution was concentrated in vacuo. The residue was purified with preparative HPLC to give rac-6-chloro-3-(4-chloro-benzyl)-3-cyclohexylamino-1-(2-oxo-2-piperidin-1-yl-ethyl)-1,3-dihydro-indol-2-one as a white solid. MS: 514 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]3=[C:20]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH:21]=2)[N:16]=[CH:15]1)(C)(C)C.Cl>CO>[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]3=[C:20]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH:21]=2)[N:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1n1cnc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c1=O
Agent: Cl
Solvent: CO
Product: N[C@H]1CCCC[C@@H]1n1cnc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c1=O
Temperature: 60 °C

Procedure:
To a solution of tert-butyl{(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamate (0.080 g, 0.15 mmol) in 2 mL of methanol was added hydrochloric acid (0.15 mL, 6 N aqueous, 0.92 mmol). The reaction was heated at 60° C. for 2 h, cooled to ambient temperature and concentrated in vacuo. The residue was concentrated twice with toluene. The residue was purified via preparative reverse phase HPLC to provide 3-[(1S,2S)-2-aminocyclohexyl]-6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 419.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.10-9.08 (m, 1H), 8.56 (br s, 1H), 8.27 (s, 1H), 8.14-8.12 (m, 1H), 8.04 (s, 1H), 7.80-7.75 (m, 3H), 7.43-7.36 (m, 1H), 4.60 (s, 2H), 2.31-2.24 (m, 2H), 2.12-1.94 (m, 4H), 1.70-1.56 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl.[CH3:11]O>>[Br:8][C:7]1[C:2]2[N:1]=[CH:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(O)cccc1Br
Reactant: CO
Agent: Cl
Product: Brc1cccc2ocnc12
Temperature: 90 °C
Yield: 65 %

Procedure:
Following a literature procedure (Org. Prep. & Proc. Int. 22(5), 613 (1990)), a solution of 2-amino-3-bromophenol (800 mg, 4.25 mmol) and trimethylformate (0.685 mL, 6.25 mmol) in methanol (1.25 mL) was treated with concentrated hydrochloric acid (0.01 mL). The flask was fitted with a short path distillation apparatus. The temperature of the solution was slowly raised to 90° C. and maintained until the methanol had finished distilling. Upon cooling, the residue crystallized and was dissolved in diethyl ether (70 mL). This solution was successively washed with 5% sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. After filtering, the solvents were removed by rotoevaporation and the residue was purified by flash column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to yield the title compound (550 mg, 65% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:24]([O:42][CH:43]1[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:46][CH:45]([C:87](O)=[O:88])[CH2:44]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH:1][C:87]([CH:45]2[CH2:46][CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:43]([O:42][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:44]2)=[O:88])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(C(=O)OC)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Methyl 4-amino-2-methoxybenzoate (79 mg, 0.44 mmol) was dissolved in chloroform (1 ml), and HOBt (7 mg, 0.05 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (201 mg, 0.22 mmol) were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml), and then purified by silica gel column chromatography (chloroform/ethyl acetate=10:1) to give N-(3-methoxy-4-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol, yield 27%).
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][CH2:16][CH:17]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:26](=[O:30])[NH:25][C:24]([NH2:31])=[N:23][C:22]1=2)[CH2:18][OH:19])([O:11]CC)=[O:10])C>CN(C)C=O>[OH:19][CH2:18][CH:17]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:26](=[O:30])[NH:25][C:24]([NH2:31])=[N:23][C:22]1=2)[CH2:16][O:15][CH2:14][P:9]([OH:10])([OH:11])=[O:8]
Reactant: CCOP(=O)(COCC(CO)On1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OC(CO)COCP(=O)(O)O)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
Bromotrimethylsilane (290 mg, 0.25 ml, 1.9 mmol) was added to a solution of 9-(1-diethoxyphosphorylmethoxy-3-hydroxyprop-2-oxy)guanine (74 mg, 0.19 mmol) in N,N-dimethylformamide (5 ml) and stirred for 4 hours at 20° C. After evaporation of the solvent, the residue was chromatographed using reverse-phase silica and eluted with water. The correct fractions were evaporated and the residue recrystallised from water-ethanol affording 9-(1-hydroxy-3-phosphonomethoxyprop-2-oxy)guanine (36 mg, 57%) as a white solid, m.p. >300° C.; λmax (H2O) 2.53 (ε13,100)nm; νmax (KBr) 3870, 1710, 1650, 1600, 1380, 1160, 1050 and 940 cm-1 ; δH [(CD3)2SO] 2.75-4.25(3H, v. br.s, D2O exchangeable, 3×OH), 3.61(2H, d, J4.7 Hz, CH2OH), 3.62(2H, d, J8.5 Hz, CH 2 P), 3.76(2H, d, J4.7 Hz, CH2OCH2P), 6.61(2H, br.s, D2O exchangeable, NH2), 7.89(1H, s, H-8), 10.65(1H, br.s, D2O exchangeable, NH); m/z (FAB+veIon) 3.36(MH+, 61%), 358(MNa+, 71%); Found C,31.11; H,4.47; N,20.76%; C9H14N5O7P.0.5H2O requires C,31.40; H,4.39; N,20.37%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>O1CCCC1>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([B:16]([OH:21])[OH:17])[CH:3]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1B(O)O
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
A stirred solution of 5.8 grams (0.026 mole) of 3-bromo-4-methoxychlorobenzene in 150 mL of tetrahydrofuran was cooled to -80° C., and 11.5 mL of n-butyllithium in hexanes (2.5 Molar-0.029 mole) was added dropwise during a 15 minute period, while maintaining the reaction mixture temperature at about -70° C. The initial reaction was very exothermic, which required cooling the reaction mixture to about -100° C. Upon completion of the addition, the reaction mixture was stirred at -80° C. for 15 minutes. After this time, 17.5 mL (0.076 mole) triisopropyl borate was added during a 1 minute period. The reaction mixture was then allowed to warm slowly to ambient temperature during a 3 hour period, where it was stirred for an additional 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to a volume of about 50 mL. The concentrate was then poured into 500 mL of ice-water. The mixture was then made acidic with about 26 mL of aqueous 2N hydrochloric acid. The mixture was then filtered to collect a solid, which was dried, yielding 3.9 grams of 5-chloro-2-methoxyphenylboronic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([CH3:34])[CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:37])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([CH3:34])[CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:37])[CH:21]=1)[CH2:9]/[C:10](=[N:39]\[OH:40])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: CN1CCC(N(C)C(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC(N(C)C(=O)c2ccc(C(C/C(=N\O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=539.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH:6](=[N:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)CN
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)CN=Cc1ccccc1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred solution of isobutylamine (49.7 ml, 500 mmol) in dry benzene (50 ml) was added benzaldehyde (50.8 ml, 500 mmol) over a period of 20 minutes. After three hours, the water layer was separated and the stirring of the benzene solution continued overnight. Again the separated water layer was discarded. The benzene layer after further dilution with dry benzene (150 ml) was dried over a minimum amount of magnesium sulfate. After concentrating the dried benzene solution, the residue was distilled in vacuo, yielding 72.1 g of compound, boiling point 46°-48° C. at 0.1 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cncc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
5-Bromo-pyridine-3-carbaldehyde (0.190g, 1 mmol), NaB(OAc)3H (0.320 g, 1.50 mmol) and piperidine (0.090 g, 1.05 mmol) were suspended in DCM (8 mL) and the reaction mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 M NaOH solution (5 mL) and the mixture was stirred for 1 h. The reaction mixture was extracted with DCM (3×15 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield a crude oily product (0.18 g, 71%). This crude product was carried to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>C(OCC)(=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2ccc3ccc(N)nc3n2)c1
Temperature: 4 °C
Yield: 35.8 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 3-methylphenol (43.2 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (21.6 g; m.p. 148° C.) is dissolved in boiling ethyl acetate (200 cc). After 18 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethyl acetate (10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-amino-7-(3-methylphenoxy)-1,8-naphthyridine (9 g) is produced, m.p. 152° C. EXAMPLE 41
Reaction SMILES: C[O:2][C:3]([C:5]1[S:26][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:25])[NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:4].O>C1COCC1>[CH2:18]([NH:17][C:16]([C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[S:26][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:27][CH2:28][C:29]([OH:31])=[O:30])[C:7]=3[S:15][C:14]=2[CH:13]=1)=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Yield: 56.6 %

Procedure:
Following General Procedure A, 6-benzylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (9 mg, 0.02 mmol) was stirred in THF (1 ml) and water (1 ml) for 17 hr. Work-up yielded 5 mg (63%) of title compounds as a light yellow solid.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:31]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Product: COc1cc(CCc2cnc3[nH]c(-c4cccc(N5CCN(C)CC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. LCMS calculated for C27H32N5O3 (M+H)+: m/z=458.3. Found 458.3.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 6 h
Yield: 61.7 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (350 mg) was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), and then 10% palladium carbon (162 mg) was added, followed by stirring under a hydrogen atmosphere for 6 hrs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (201.4 mg) as pale yellow foam.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:51])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:37]=[C:38]([NH:42][C:43]([C:45]5[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=5)=[O:44])[CH:39]=[CH:40][CH:41]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[OH:51][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:37]=[C:38]([NH:42][C:43]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[O:44])[CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4cccc(NC(=O)c5cccnc5)c4)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1)Nc1cccc(NC(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of N-(3-{[({3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}amino)carbonyl]amino}-phenyl)pyridine-3-carboxamide (0.109 g) in acetic acid (4 ml) and water (2 ml) was heated to 68° for 30 min. The mixture was cooled to room temperature before concentrating in vacuo to leave a residue that was purified by Biotage. Elution with dichloromethane-EtOH-ammonia (25:8:1) followed by solvent evaporation in vacuo gave the title compound (0.089 g). LCMS RT=2.02 min, ES+ve 672 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1>CO>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:9]=[CH:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Solvent: CO
Product: Fc1ccc(Oc2ccc(N=Cc3cccnc3)cc2)c(F)c1
Temperature: 55 °C

Procedure:
4-(2,4-Difluorophenoxy)aniline (2.21 g, 10.0 mmol) and pyridine-3-carboxaldehyde (1.12 g, 10.5 mmol) were dissolved in anhydrous methanol (35 ml) and the solution was heated at 55° C. for three hours. The solution was cooled and concentrated in vacuo to a residual oil, which was maintained under a 90 μm Hg vacuum for twenty-four hours. N-(4-(2,4-Difluorophenoxy)phenyl)pyrid-3-ylmethyleneamine was obtained in quantitative yield. 1H NMR(400 MHz): 6.83-6.90(1H,m), 6.93-7.00(3H,m), 7.05-7.13(1H,m), 7.21-7.27(2H,m), 7.40(1H,dd, J=8.1, 4.9), 8.27(1H,dd,J=8.1, 1.7), 8.50(1H,s), 8.69(1H,dd,J=4.9, 1.7), 9.00(1H,d,J=1.7); MS(ESI)m/z 311.1([M+H]+,100); Anal. Calcd. for C18H12F2N2O C,69.67; H,3.90; N,9.03. Found: C,69.28; H,3.99; N,8.91.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 12.5 °C
Yield: 84.3 %

Procedure:
Stearyl alcohol (2.7 g, 0.01 mol), and triphosgene (0.99 g, 0.0067 mol) were dissolved in 20 ml methylene chloride, stirred and cooled to 10-15° C. Anhydrous pyridine (0.8 g of, 0.02 mol) was added dropwise into the pre-cooled solution over a 1 hr period. The reaction mixture was stirred for an additional 1 h, then heated in a water bath at 65° C. for 15 min until all the methylene chloride evaporated. The residue was washed 3 times with cold water, dried over Na2SO4 and evaporated to give stearyl chloroformate (1.88 g, 83% yield), also known as octadecyl chloroformate.
Reaction SMILES: [F:1][CH:2]([F:14])[N:3]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[N:4]1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][CH:2]([F:14])[N:3]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[N:4]1
Reactant: C[Si](C)(C)C#Cc1cnn(C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnn(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.9 %

Procedure:
1-(Difluoromethyl)-4-((trimethylsilyl)ethynyl)-1H-pyrazole (Preparation 151, 413 mg, 1.9 mmole) was stirred with methanol (4 mL). Potassium carbonate (17 mg) was added and stirred at room temperature for 50 minutes. The solvent was evaporated and the residue was filtered in dichloromethane through a short pad of silica to afford the title compound (187 mg 1.31 mmole 72%). 1H-NMR (CDCl3, 500 MHz): δ 3.08 (s, 1H), 7.17 (t, J=60.5 Hz, 1H), 7.75 (s, 1H), 7.97 (s, 1H).