Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 g, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 87 (M+1)
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:41][CH:42]=3)(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 186-188° C.; MS m/e 559 (M-H)+;
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:36]2[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]2=[O:37])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
5-Phenylpentan-1-ol (0.50 g, 3 mmol), triphenylphosphine (0.45 g, 3 mmol), and phthalimide (0.80 g, 3 mmol) were vigorously stirred in dry THE (5 mL) while cooling to 0° C. A solution of DEAD (0.62 g, 3 mmol) in 5 mL of dry THF was added dropwise to the cooled mixture. After stirring at room temperature for 12 his, the solvent was removed by reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 90:10) to afford the title compound (0.68 g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (m, 2H), 1.49-1.69 (m, 4H), 2.52-2.58 (m, 2H), 3.56 (t, J=7.06 Hz, 2H), 7.06-7.27 (m, 5H), 7.75-7.95 (m, 4H). MS (ESI) m/z: 334 [M-H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:16]([O:32][CH3:36])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13.4 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-3-oxo-5-pyridin-4-yl-2,3-dihydro-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.135 g, 0.3 mmol) in dry DMF (2 mL) was cooled to 0° C. and added lithium hydride (0.0035 g, 0.45 mmol). After stirring for 5 minutes, iodomethane (0.037 mL, 0.6 mmol) was added and the reaction was allowed to gradually warmed to room temperature and stirred for 20 hours. The reaction was diluted with ethyl acetate and washed with water; the aqueous layer was back-washed with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% methanol/methylene chloride afforded 18.8 mg (13%) of a monomethylated product. MS (ES+): 469.2 (M+H)+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: OC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To 3.5 g of N,N-dimethylformamide were added 2.00 g of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85° C. for 10 minutes. The solvent and the like were distilled off under reduced pressure. After adding 10 ml. of ethanol to the residue, the mixture was heated under reflux for 10 minutes and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 2.10 g of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@H:6]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C@@:6]3([CH3:24])[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@@]2(C)CO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (124 mg, crude) was added iodomethane (0.25 mL, 4 mmol) and DMSO (2 mL). The mixture was cooled to 0° C. and then −78° C. and sodium 2-methylpropan-2-olate (0.154 g, 1.6 mmol) was added, followed by more DMSO (0.7 mL). The cooling bath was removed and the mixture was stirred at room temperature for 14 hours and then diluted with EtOAc and water, extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] found 323.3.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]2)=[O:7])[CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1.[H-].[Na+]>CS(C)=O.CCOC(C)=O>[CH3:32][C:28]1[N:29]=[CH:30][C:31]([O:1][CH:2]2[CH2:3][N:4]([C:6]([CH:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:10][CH2:9]3)=[O:7])[CH2:5]2)=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(C(=O)N2CC(O)C2)CC1
Reactant: Cc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(OC2CN(C(=O)C3CCCN(C(=O)OCc4ccccc4)CC3)C2)cn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of benzyl 4-[(3-hydroxyazetidin-1-yl)carbonyl]azepane-1-carboxylate (97 mg, 0.29 mmol) and 4-chloro-2-methylpyridine (52 μl, 0.46 mmol) in DMSO (2 ml) was added NaH (37 mg of a 60% dispersion in mineral oil, 0.93 mmol). The mixture was stirred at room temperature for 12 hours, 50° C. for 3 hours and a further 12 hours at room temperature. The reaction was then diluted with EtOAc (20 ml) and washed with water (3×10 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1:1 to 95:5:1 DCM/MeOH/2M NH3 in MeOH) to give the title product as colourless oil (35 mg, 29%).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C.O>[C:1]1([CH:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[O:24][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:25])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C(=O)NCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 14 h

Procedure:
To a suspension of N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-3-hydroxybenzamide (60.0 mg) and K2CO3 (58.6 mg) in DMF (1.8 mL) was added dropwise ethyl bromoacetate (18.8 μL) at ambient temperature and the mixture was stirred at the same temperature for 14 hours. The resulting mixture was diluted with water (5.0 mL) and the aqueous solution was extracted with EtOAc (10.0 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=98:2) to give ethyl {3-[({2-[5-(diphenylmethyl)-2-oxo-1(2H) -pyridinyl]ethyl}amino)carbonyl]phenoxy}acetate (70 mg) as a colorless syrup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:37][NH2:38]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:37]/[NH2:38])/[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/N)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (2 g, 2.05 mmol) in THF (350 mL) was added hydrazine monohydrate (645 μl, 20.51 mmol) to give a yellow solution. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble black particles and concentrated to dryness under reduced pressure. The resulting yellow solid was used directly in the following step as crude without any further purification. LCMS (Method D): RT=1.04 min, M+1=486.
Reaction SMILES: C(SCCCC)CCC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Li].[C:17]([O:21][C:22](=[O:36])[CH:23]=[CH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([O:21][C:22](=[O:36])[CH2:23][CH:24]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([CH3:35])[CH:34]=1)[NH:31][N:30]=[CH:29]2)([CH3:19])([CH3:20])[CH3:18]
Reactant: Cc1cc(CC=CC(=O)OC(C)(C)C)cc2cn[nH]c12
Reactant: [Li]c1ccccn1
Solvent: CCOCC
Solvent: CCCCSCCCC
Product: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ccccn2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 50-mL oven-dried flask was added di-n-butylsulfide (261 mg, 1.781 mmol, 6.4 equiv) and cuprous iodide (170 mg, 0.891 mmol, 3.2 equiv) under nitrogen. Anhydrous ether (1 mL) was added and the suspension was cooled to 0° C. before the solution of 2-pyridinyl lithium was added via canuula. A yellowish brown precipitate was formed. After stirring at 0° C. for 15 min, the cooling bath was removed and 4-(7-methyl-1H-indazol-5-yl)-but-2-enoic acid tert-butyl ester (75.8 mg, 0.278 mmol, 1.0 equiv) in anhydrous ether (1 mL) was added via syringe. The dark solution was stirred at room temperature for 40 min. LCMS indicated the formation of the desired product. The reaction mixture was then partitioned between an aqueous ammonium hydroxide/ammonium chloride solution and ethyl acetate (upon shaking, the solids gradually dissolved to a blue aqueous solution). The layers were separated and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to an oil. Careful flash column chromatography (5% methanol in methylene chloride) afforded the desired product (10.4 mg, 11%) which was carried on without farther purification. MS (ESI) 352 (M H)+, 296 (M-tBu)+.
Reaction SMILES: I[C:2]1[S:6][CH:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[OH:8][CH2:7][C:4]1[CH:3]=[C:2]([C:9]#[N:10])[S:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: OCc1csc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)cs1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (5-iodothiophene-3-yl)methanol (42 g, 176 mmol) in 150 mL of DMF is added Zn(CN)2 (12.4 g, 106 mmol) and Pd(PPh3)4 (8.13 g, 7.04 mmol). The solution is heated to 80° C. After 6 hours, the solution is diluted with 3 L of EtOAc. The resulting solution is washed with 1 N NH4OH, H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (10 g, 72 mmol) as a clear oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>CC#N>[Cl:15][C:7]1[CH:6]=[C:5]([N:2]([CH3:3])[CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CNC
Solvent: CC#N
Product: COC(=O)c1cnc(Cl)cc1N(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Dimethylamine (1.23 mL, 9.71 mmol) was slowly added to a stirred solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in MeCN (6 mL) at room temperature. The solution was stirred at room temperature for 18 hours then concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-(dimethylamino)nicotinate (335 mg, 1.56 mmol, 80% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:49]=[N+:50]=[N-:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 98.0 mg of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in N,N-dimethylformamide are added 94 mg of sodium azide and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture is diluted with water, extracted with tert-butyl methyl ether, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.47 (EtOAc-heptane 1:1); Rt=5.65.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[CH3:38][C:39]([CH3:45])([CH3:44])[CH2:40][C:41](Cl)=[O:42]>N1C=CC=CC=1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[C@@H:10]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:41](=[O:42])[CH2:40][C:39]([CH3:45])([CH3:44])[CH3:38])[CH3:30]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)CC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt.TFA (33.0 mg) obtained in Example 51-(1) in pyridine (0.5 ml) was added 3,3-dimethylbutyryl chloride (12.8 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 10 min, quenched with water (0.1 ml), and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=15/1 for development to give the product (21.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OC(=O)[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=1)(C)C>C(#N)C.Cl.O>[ClH:30].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[N:24]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Agent: Cl
Solvent: O
Solvent: CC#N
Product: NCCCNc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Yield: 74.3 %

Procedure:
To a solution of 4-aminobenzenesulfonamide (190 mg) in acetonitrile (20 mL), hydrochloric acid solution (4M in dioxane, 0.3 mL) and water (0.3 mL) was added (3-((5-bromo-2-chloro-4-pyrimidinyl)amino)propyl)-carbamic acid-1,1-dimethylethyl ester (360 mg). The resulting mixture was refluxed overnight. The precipitate was collected and washed with acetonitrile and methanol to afford the title compound (320 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C1COCC1.[C:14]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>CCN(CC)CC>[C:14]([C:16]1[CH:17]=[C:18]([NH:22][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: O=C(Cl)c1cccs1
Reactant: C#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(=O)c2cccs2)c1
Temperature: 55 °C
Yield: 85 %

Procedure:
A dry 25 mL flask was charged with thiophene-2-carbonyl chloride and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and extracted with EtOAc (˜10 mL), 1M HCl (˜10 mL), followed by brine (˜10 mL). The combined organic extracts were combined and dried over anhydrous Na2SO4(s) and the concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 50%). The product containing fractions were concentrated to give the title compound as a tan solid (0.33 mg, 1.45 mmol, 85%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: On1cccn1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1cccn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxypyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (79%, oil which slowly crystallizes). HPLC-MS m/z=218.1 (M+1), Rt: 2.82 min. Mp 63-67° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[OH:26]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[O:26][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).