Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]4[CH2:20][CH2:19][CH2:18][O:17][CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]5[CH2:20][CH2:19][CH2:18][O:17][CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(Br)ccc3ncc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(-c4ccc(F)nc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
Pd(Ph3P)4 (0.160 g, 0.14 mmol) was added to 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (1 g, 2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59 mmol) and Cs2CO3 (1.799 g, 5.52 mmol) in 1,4-dioxane (23 mL) and water (3 mL) under nitrogen. The resulting mixture was stirred at 100° C. for 3 h then allowed to cool and the solvent removed under reduced pressure. The crude product was purified by FCC, elution gradient 0 to 7% MeOH in DCM to give the desired material (0.905 g, 87%) as a yellow solid. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.83-1.86 (2H, m), 2.15-2.19 (1H, m), 2.49-2.64 (1H, m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.15-4.26 (2H, m), 4.91-5.10 (1H, m), 7.42 (1H, dd), 7.96 (1H, dd), 8.13 (1H, d), 8.38 (1H, s), 8.44 (1H, td), 8.72 (1H, d), 8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.1.
Reaction SMILES: [CH2:1]([N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([C:24]1[CH:29]=[C:28]([SH:30])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:23])([CH3:22])[CH3:21]>C(N(CC)CC)C>[CH2:1]([N:13]1[C:14](=[O:19])[CH2:15][CH:16]([S:30][C:28]2[CH:27]=[C:26]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:25]([OH:35])=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:29]=2)[C:17]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCN1C(=O)CC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 39.7 %

Procedure:
The procedure of Example 1 is repeated using 13.27 grams N-dodecylmaleimide, 11.92 grams 2,6-di-tert-butyl-4-mercaptophenol, and 0.5 grams triethylamine. The sample is purified by dry column chromatography to give 10.0 grams of a clear syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]#[N:32])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCC#N)CC2)cn3-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCc4nnn[nH]4)CC2)cn3-c2ccc(F)cc2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-[5-(2-methyltetrazol-5-yl)-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl]propionitril 15a, (3.5 g), sodium azide (2.5 g), and triethylamine hydrochloride (4.5 g) in DME (25 mL) was boiled at reflux for 16 hours. The solvent was evaporated and water (25 mL) and ethyl acetate (1-2 mL) were added after stirring for 0.5 hours the precipitated title compound 16a, was filtered off and dried. Yield 3.2 g, mp 131-132° C.
Reaction SMILES: [N+](=C)=[N-].N(N(C)[C:7](N)=O)=O.[OH-].[K+].[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:24])=[CH2:23])=[CH:18][C:17]=1[CH3:25].CC=CC1C=CC=CC=1.COC(=O)C1C=CC=CC=1C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2([CH3:7])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: C=C(C)c1ccc(C(=O)OC)c(C)c1
Reactant: CN(N=O)C(N)=O
Agent: [Pd+2]
Agent: C=[N+]=[N-]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(C)CC2)cc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 87.1 %

Procedure:
Formation of Diazomethane: N-Nitroso-N-methylurea (9.1 g, 61.8 mmol) was added under stirring in portions to a two phase mixture of 50 ml potassium hydroxide solution (23.9 g in 50 ml water) and 50 ml diethyl ether at 0° C. The color of the organic phase changed from colorless to yellow. The two phase mixture was vigorously stirred for 40 min at 0° C. The organic layer that contains diazomethane was separated. Cyclopropanation by adding diazomethane solution to methyl styrene: 4-Isopropenyl-2-methyl-benzoic acid methyl ester (2.94 g, 15.45 mmol) was dissolved in 15 ml diethyl ether and cooled to 0° C. Palladium (II) acetate (0.173 g, 0.773 mmol) was added. The yellow organic phase (containing diazomethane) was added dropwise. In total 20 ml of the organic phase (approximately 4 eq. of diazomethane) was added until the reaction was done. You observe releasing nitrogen by adding diazomethane to the methyl styrene intermediate. The reaction mixture was filtered over cellulose; washed with diethyl ether; concentrated; The residue (brown liquid) was purified by 40 g silica gel chromatography (gradient elution 0-100% ethyl acetate in hexane for 15 min) 2.9 g of a crude light yellow liquid was obtained. NMR shows 8% 2-methylbenzoic acid methyl ester. The crude residue was purified again by 110 g flash chromatography (gradient elution 0-20% EtOAc in Hex for 30 min) to give 2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid methyl ester (2.75 g, 13.46 mmol) MS (ESI) 268.9 (M+Na++ACN)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[CH:13][C:12]([O:23]CC2C=CC=CC=2)=[CH:11][N:10]=1)=[O:8])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[CH:13][C:12]([OH:23])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNC(=O)c1ncc(O)cc1O
Temperature: 13 °C
Yield: 97.7 %

Procedure:
To a 20 L round-bottomed flask was charged nitrogen and palladium on carbon (10% Pd/C) (100 g, 60% wet paste) and ethanol (12 L), followed by the addition of [(3,5-bis-benzyloxypyridine-2-carbonyl)-amino]-acetic acid ethyl ester, 1, (1000 g, 2.378 mol). The resulting mixture was subjected to a vacuum-nitrogen purge cycle three times and a vacuum-hydrogen purge cycle three times. A hydrogen atmosphere was introduced and the reaction mixture was stirred at 1-25° C. until the completion of the reaction by TLC analysis. The reaction typically lasted 2 to 3 hours and a vigorous stirring was important to complete the reaction. The reaction system was then subjected to a vacuum-nitrogen purge cycle to remove hydrogen from the system. The reaction mixture was filtered and the filter-cake was washed with ethanol (2 L). The combined filtrate was concentrated on a rotary evaporator at up to 45° C. bath temperature to a constant weight to provide 558 g (97.7% yield) of the desired product as an off-white solid. MP: 138-140° C.; MS (ESI+): m/z 241 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.79 (s, 1H), 9.09-9.05 (t, J=6 Hz, 1H), 7.76-7.71 (d, J=2.4 Hz, 1H), 6.68-6.67 (d, J=2.1 Hz, 1H), 4.15-4.08 (q, J=6.9 Hz, 2H), 4.02-4.00 (d, J=6.3 Hz, 2H), 1.22-1.17 (t, J=6.9 Hz, 2H).
Reaction SMILES: C([O:3][CH:4]([C:28](=[O:50])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:5](=[O:27])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.[OH-].[K+]>CCO>[C:28]([CH:4]([C:5](=[O:27])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:3])(=[O:50])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)C(OC=O)C(=O)C=CC=CC=CC=CC=CC=CCCCCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)C(O)C(=O)C=CC=CC=CC=CC=CC=CCCCCCCCCC

Procedure:
The above didocosahexaenoylmethyl formate (III, 1.38 g, 2.1 mmol) and KOH (300 mg) were stirred in 90% EtOH (70 mL) at room temperature under nitrogen for 90 min. Upon completion of the reaction, most of the solvent was evaporated. The resulting mixture was treated with 60 mL of 2M HCl solution. The aqueous phase was extracted with ether (2×75 mL). The combined ether extract was washed with water (2×50 mL), brine (50 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave 1.18 g of crude IV as yellowish oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 50 mL) eluted with 0-6% ethyl acetate gradient in hexanes. This gave 1.0 g of didocosahexaenoyl methanol (IV) as colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15](Br)[CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23]CC1C=CC=CC=1)(=[O:22])[CH:20]=[CH2:21].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C.N#N>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15](/[CH:21]=[CH:20]/[C:19]([OH:23])=[O:22])[CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOc2cc(/C=C/C(=O)O)cnc21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-7-bromo-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (1.27 g, 4.03 mmole), benzyl acrylate (7.85 mg, 4.84 mmole), Pd(OAc)2 (45 mg, 0.20 mmole), P(o-tolyl)3 (122 mg, 0.4 mmole), and (i-Pr)2NEt (1.76 mL, 10.1 mmole) in propionitrile (20 mL) was degassed (3×N2/vacuum) then heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. Flash chromatography on silica gel (25% EtOAc/hexanes) gave the title compound (1.17 g, 73%) as a yellow oil: MS (ES) m/e 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]=[C:7](OCC)[C:6]1=[O:15].[F:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:26]=1>C(O)CCC>[Cl:1][C:2]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:29]([C:28]3[CH:33]=[CH:34][C:25]([F:24])=[CH:26][CH:27]=3)=[N:31][N:32]=[C:7]2[C:6]1=[O:15]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CCOC1=NC[C@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2ccc(F)cc2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-3-ethoxy-6-methyl-5,6-dihydropyrazin-2(1H)-one (216 mg, 0.62 mmol) and 4-fluorobenzohydrazide (105 mg, 0.68 mmol) in 1-butanol (6.2 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; 0-10% IPA/EtOAc) afforded the desired product as a white solid (158 mg, 58%). MS (ESI): mass calcd. for C20H15ClF4N4O, 438.1; m/z found, 439.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77-7.70 (m, 3H), 7.68-7.59 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.25-7.15 (m, 2H), 5.33 (d, J=15.7 Hz, 1H), 4.66 (dd, J=13.0, 4.5 Hz, 1H), 4.55 (d, J=15.7 Hz, 1H), 4.23 (dd, J=13.0, 2.0 Hz, 1H), 4.11 (dt, J=14.3, 4.8 Hz, 1H), 1.27-1.24 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10](OCC)(OCC)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1)[CH3:2].Cl.[C:20](=[NH:26])(OCC)[CH2:21][CH3:22]>C(O)C>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:26]=[C:20]([CH2:21][CH3:22])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOC(=N)CC
Reactant: CCNc1cc(C(CN)(OCC)OCC)ccn1
Agent: Cl
Solvent: CCO
Product: CCNc1cc(-c2c[nH]c(CC)n2)ccn1
Yield: 33 %

Procedure:
The procedure of Example XB was employed, starting with 2.0 g. (8 mmoles) of 2-(2-ethylamino-4-pyridyl)-2,2-diethoxyethylamine and 1.16 g. (8.3 mmoles) of ethyl propionimidate hydrochloride in 30 ml. of ethanol, to give 605 g. (33%) of the title compound as a white solid, 190°-193° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][O:17][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(C)CCC(N(C(=O)C(C)(C)COS(C)(=O)=O)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (300 mg, 0.76 mmol) prepared in Step B of Example A8 in DCM was added TEA (192 mg, 1.9 mmol), slowly added dropwise methanesulfonylchloride (104 mg, 0.91 mmol) at 0° C., and the solution was heated to rt, and stirred for 1 h. After the reaction finished, the solvent was concentrated in vacuo, and washed with water and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl){2,2-dimethyl-3-[(methylsulfonyl)oxy]propanoyl}amino]pyrrolidine (250 mg, 75%). A solution of this compound (200 mg, 0.42 mmol) in THF was added dropwise TBAF (in THF, 1.0M 0.5 ml, 0.5 mmol), and the solution was stirred at 80° C. for 3 h. After the reaction finished, the solvent was concentrated in vacuo, and extracted with 1N-HCl and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/4) to give the title compound (147 mg, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O1CCOCC1.O.[Cl-].[Na+].O>[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Method J10) To the solution of 6-aminocaproic acid (2h) (0.982 g, 7.5 mmol) in water/dioxane (1:1) mixture (30 ml) NaOH (0.8 g, 20 mmol) in H2O (2 ml) and benzoyl chloride (1/67) (1.16 ml, 10 mmol) were added. The mixture was stirred for 6 h at room temperature and diluted with brine (150 ml). The mixture was washed with diethyl ether (2×25 ml), acidified with conc. HCl to pH 4, and extracted with ethyl acetate (4×25 ml). The organic solution was washed with brine (3×25 ml), dried (Na2SO4) and evaporated. The crude title compound (1.589 g, 90%) was purified by column chromatography on silica gel with chloroform-ethyl acetate (1:2) as eluent. 1H NMR (CDCl3, HMDS) δ: 1.18-1.85 (m, 6H); 2.34 (t, J=7.0 Hz, 2H); 3.45 (q, J=6.0 Hz, 2H); 6.27 (bs, 1H); 7.29-7.52 (m, 3H); 7.61-7.85 (m, 2H); 10.41 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>CCOCC>[CH3:18][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(-c3ccccc3)ccnc2c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: Cc1ccc2c(-c3ccccc3)ccnc2c1

Procedure:
To a solution of 7-chloro-4-phenylquinoline (10.0 g, 41.7 mmol) and Ni(dppp)2Cl2 (2.26 g, 4.17 mmol) in ether (200 mL) was added dropwise 3.0 M MeMgBr (24.3 mL, 73 mmol) and heated at reflux for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ether. The combined organic layer was washed with water and brine and then dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting crude product was used in the next step without further purification. 1H NMR (400 MHz, acetone-d6): δ 8.9 (d, 1H), 7.93 (bs, 1H), 7.82 (d, 1H), 7.52-7.62 (m, 5H), 7.43 (dd, 1H), 7.35 (d, 1H), 2.60 (S, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=3)[N:18]=2)[CH:14]=[CH:13][C:12]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[Cl:3][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[N:18]=[C:17]([C:15]3[CH:14]=[CH:13][C:12]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:11]([F:10])[CH:16]=3)[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Temperature: 80 °C

Procedure:
Thionyl chloride (20 mL, 0.274 mol) and N,N-dimethylformamide (2 mL) are added to a stirred solution of 4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]phenylmethanol (32 g, 0.092 mol) in dichloromethane (150 mL) at 0° C. The reaction mixture is heated at 80° C. for 1 hour and then concentrated under reduced pressure. The residue is neutralized with a saturated aqueous sodium bicarbonate solution (150 mL) to furnish a solid which is filtered and washed with n-hexane (150 mL) to give 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole.
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:32])=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C(=O)[O-])(C)C.C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C>[NH2:5][CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:32])=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][C:27]=2[Br:40])[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nncc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN(C(=O)[O-])C(C)(C)C)sc1Cl
Solvent: CN(C)C=O
Product: Cn1nnc(Br)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Yield: 10.6 %

Procedure:
A solution of 1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclohexylpropyl]carbamate (140 mg, 0.29 mmol, prepared in Example 280) and NBS (103 mg, 0.58 mmol) in 2 mL of DMF was heated at 100° C. for 2 hours. The reaction mixture was purified by reverse phase HPLC (5-65% acetonitrile in H2O with 1% TFA) to give the title compound 14.1 mg (8%) as a white solid. LCMS (ES) m/z 462.0 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) ppm 7.75 (s, 1H), 4.43 (m, 1H), 4.05 (s, 3H), 3.17 (m 1H), 3.05 (m, 1H), 2.00-0.90 (m, 13H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])[C:11]=2[CH:10]=[CH:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,γ,γ,γ-pentafluoropropyloxypyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 3 in the Example 59 to obtain 610 mg of desired compound as solid in 94% of yield.
Reaction SMILES: [F-].[K+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.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]>[S:12]1[CH:16]=[CH:15][C:14]([C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]#[N:11])=[CH:13]1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccsc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cccnc1-c1ccsc1
Temperature: 90 °C
Yield: 56 %

Procedure:
To an oven-dried, N2-purged, 50 mL, round-bottomed flask containing a magnetic stir bar were added potassium fluoride (767 mg, 13.2 mmol), bis(tri-t-butylphosphine)palladium (51.0 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2-chloro-3-cyanopyridine (559 mg, 4.00 mmol), and 3-thiopheneboronic acid (819 mg, 6.4 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporation to give a brown oil. The product was purified by recrystallization from ethyl acetate/hexanes to give 417 mg (56%) of the title compound. MS (ESI−) m/z 186.9 (M+H)+; 1H NMR (CDCl3) δ 7.30 (7.8, 4.7 Hz, 1H), 7.44 (dd, J=5.3, 2.9 Hz, 1H), 7.88 (dd, J=5.1, 1.4 Hz, 1H), 8.03 (dd, J=8.0, 1.9 Hz, 1H), 8.29 (dd, J=3.0, 1.4 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 62.7 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.080 g, 0.334 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.090 g; 0.368 mmol), HATU (0.127 g; 0.334 mmol) and N,N-diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (5 mL), was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and a solution of sodium hydrogen sulfate. The organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.090 g (62%) of the title compound as a pink solid.