Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH2:20][CH2:21][N:22](CC=C)[CH2:23][CH:24]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1C(=O)CC(=O)N(C)C1=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.ClCCl>[C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCN1CC=C(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: O=c1ccn(C2=CCNCC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A suspension of 3-(1-phenyl-1H-pyrazol-5-yl)-1-(1-prop-2-en-1-yl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4(1H)-one (0.10 g), tetrakis(triphenylphosphine)palladium(0) (50 mg), 1,3-dimethylbarbituric acid (0.13 g) and dichloromethane (5 mL) was heated under reflux for 2 hr under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from 2-propanol/ethyl acetate to give the title compound (32 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[NH:19]
Reactant: Cc1ccc(-c2ccccc2N)cc1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1ccc(-c2ccccc2NC(=N)N(C)C)cc1

Procedure:
A mixture of 2-amino-4'-methylbiphenyl hydrochloride (5.3 g), N,N-dimethylcyanamide (2.55 g) and m-cresol (25 ml) was heated at 90°-95° C. for 10 hours to give N,N-dimethyl-N'-(4'-methyl-2-biphenylyl)guanidine (m.p. 147°-148° C.) which was recrystallised from hexane.
Reaction SMILES: Cl.[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH2:13])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3].[C:33]([N:40]([CH3:46])[C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH:13][C:43](=[O:44])[C@@H:41]([N:40]([CH3:46])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:42])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](N)[C@@H]1C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[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
Solvent: O
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a 0° C. solution of (3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (162 mg, 361 μmol) in DMF (1.2 ml) was added Boc-N-methyl-L-alanine (80.7 mg, 397 μmol), N,N-diisopropylethylamine (250 μl, 1.44 mmol), and HBTU (151 mg, 397 μmol). The reaction was stirred at rt for 30 min, then diluted with H2O and the solids were collected by vacuum filtration, taken up in EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (189 mg, 88%) as a white solid. MS m/z 620 (MNa)+.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-])=[O:8].[C:14]1([C:20]2[N:21]=[CH:22][C:23]3[C:28](=O)[O:27]C(=O)[N:25]([CH2:31][CH2:32][CH3:33])[C:24]=3[N:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH2:12]([O:11][C:5]([C:6]1[C:7](=[O:8])[N:25]([CH2:31][CH2:32][CH3:33])[C:24]2[N:34]=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=[CH:22][C:23]=2[C:28]=1[OH:27])=[O:10])[CH3:13]
Reactant: CCCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
50 ml. of NaOEt (0.24 g.-0.011 mole) was added to 1.7 g. (0.011 mole) of ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution formed and 1.5 g. (0.005 mole) of 7-phenyl-1-propyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and the mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the resulting precipitate filtered off and rinsed with water. Recrystallization from ethyl acetate gave 1.5 g. of the title compound--m.p. 164°-167° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=[O:6])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:13]([C:7]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:5]=[O:6])[CH3:14]
Reactant: CCc1cc(OC)cc(CC)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(O)cc(CC)c1C=O
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 2.50 g (13.0 mmol) 2,6-diethyl-4-methoxy-benzaldehyde in 15 ml dichloromethane at −60° C. was added dropwise 26.0 ml (26.0 mmol) of a 1 M solution of boron tribromide in dichloromethane. After the addition was complete, the reaction mixture was allowed to warm to room temperature and then heated at reflux for 16 h. The reaction mixture was then cooled to room temperature and poured onto an ice-water mixture. The mixture was diluted with dichloromethane, the phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in a 1:1 mixture of ethyl acetate and diethyl ether and extracted with 1 N aqueous sodium hydroxide solution. The phases were separated and the aqueous phase was acidified to pH 1 by addition of concentrated hydrochloric acid and then extracted with ethyl acetate. The phases were separated and the organic phase was washed with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1.48 g (64%) of the title compound as a brown crystalline solid. MS (ISP): 177.4 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH:27]=2)[S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:41])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:27]=2)[S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)OC(C)(C)C)c2)S(=O)(=O)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-{[(3-tert-butoxycarbonylmethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (138 mg, 0.237 mmol) in MeOH (5 mL) was added aqueous NaOH (2N, 0.36 mL, 0.72 mmol). The reaction was heated at 100° C. for 1 h and was cooled to room temperature. The reaction was concentrated in vacuo and was diluted with water and EtOAc. The pH was adjusted to about 5 with 1N HCl. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Sodium chloride was added to the aqueous solution and the solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. The combined title compound (104 mg) was used in the next step without further purification. MS 527 (M+1).
Reaction SMILES: [F:1][C:2]([C:7]1[S:8][C:9]([NH2:12])=[N:10][N:11]=1)([F:6])[CH:3]([Cl:5])[Cl:4].[C:13](Cl)(Cl)=[O:14]>ClC1C=CC=CC=1>[F:1][C:2]([C:7]1[S:8][C:9]([N:12]=[C:13]=[O:14])=[N:10][N:11]=1)([F:6])[CH:3]([Cl:4])[Cl:5]
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C(F)(F)C(Cl)Cl)s1
Solvent: Clc1ccccc1
Product: O=C=Nc1nnc(C(F)(F)C(Cl)Cl)s1
Yield: 73.1 %

Procedure:
21.7 g (0.1 mol) of 2-(1',1'-difluoro-2',2'-dichloroethyl)-5-amino-1,3,4-thiadiazole were suspended at room temperature in 500 ml of chlorobenzene, and a solution of 30 g of phosgene in 200 ml of chlorobenzene was rapidly added with agitation. With further agitation and feeding-in of gaseous phosgene, the temperature was raised by 15°C per hour until 110°C were attained (a clear solution was obtained from 60°C onward). The solution was then allowed to cool, nitrogen was passed through the solution to remove the residual phosgene, and the solution was concentrated. A brittle mass remained which became pulverulent on trituration with petroleum ether (boiling point 80°-110°C). By suction-filtration and drying, 19 g (73 %) of 2-(1',1'-difluoro-2',2'-dichloro-ethyl)-5-isocyanato-1,3,4-thiadiazole were obtained. Decomposition temperature: 200°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH2:12])=[O:11])=[N:4][NH:5][C:6]=1[CH:7]([CH3:9])[CH3:8].N[C:14](N)=[O:15].C(O)(=O)C>[OH-].[Na+]>[OH:15][C:14]1[N:12]=[C:10]([OH:11])[C:3]2[NH:4][N:5]=[C:6]([CH:7]([CH3:9])[CH3:8])[C:2]=2[N:1]=1
Reactant: CC(C)c1[nH]nc(C(N)=O)c1N
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)c1n[nH]c2c(O)nc(O)nc12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Mixture of 4-amino-5-isopropylpyrazole-3-carboxamide (770 mg, 4.58 mmol) and urea (1.4 g, 4.58 mmol) was fused at 180° C. for 30 min. After cooling, the solid was dissolved in 2.3 mL of 2 M sodium hydroxide. The boiling solution was acidified with glacial acetic acid and the warm solution was filtered. This solution was cooled to 5° C. and the product started to precipitate after a few minutes. The crude product (1.3 g) was recrystallized twice from a hot water. Yield 78.5%; mp=295-298° C. 1H NMR (300 MHz, DMSO): 1.21 d (6H, J=6.6 Hz), 3.17 sept (1H, J=6.6 Hz). MS (EI): 194(94; C8H10N4O2); 179(100; C7H7N4O2); 162(51; C7H4N3O2); 136(15); 123(7); 95(8); 81(13); 54(26); 43(23).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:41]([C:45](O)=[O:46])=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]1=[O:48])[CH3:31].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:45]([C:41]1[C:42]2[CH2:43][CH2:44][N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:36](=[O:48])[C:37]=2[CH:38]=[CH:39][CH:40]=1)=[O:46])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCOCCN1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 29.5 %

Procedure:
Poured into a suspension of 255 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 113.5 mg of 2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 9 mg of hydroxybenzotriazole, 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7.6 cm3 of dichloromethane is 0.3 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed once with 5 cm3 of dichloromethane, twice with 5 cm3 of diisopropyl ether, then dried under vacuum. 82 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].C(N(CC)CC)C>C(O)C.ClCCl>[CH3:18][C@@H:19]([CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[CH2:20][OH:21]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: C[C@H](CO)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](CO)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-trifluoromethyl-phenyl)-piperazine (52.0 g; 221 mmol); (R)-3-bromo-2-methyl-propan-1-ol (36.0 g; 226 mmol) and triethylamine (61.7 mL; 443 mmol) in ethanol (350 mL) is heated at 95° C. for 45 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue obtained is diluted with dichloromethane (500 mL) and the organic layer is washed with water (500 mL); with brine (500 mL) and the solvent is removed under reduced pressure. The crude residue obtained is re-crystallized from ethanol (200 mL), the re-crystallized product is washed with cold ethanol (100 mL). The mother liquor is concentrated under reduced pressure and is crystallized from ethanol (100 mL). The precipitate obtained is washed with cold ethanol (50 mL). The combined fractions are dried overnight at 40° C. under 3 mbar to deliver the enantiopure product (53.7 g; 178 mmol).
Reaction SMILES: I[CH:2]([CH2:5][C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][OH:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:23][C:6]([F:24])([C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:14])[F:13])[CH2:5][CH2:2][CH2:3][OH:4]
Reactant: OCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
2-iodo-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononan-1-ol 19 (15 g, 29.8 mmol) was slowly added to a solution of lithium aluminum hydride (1.14 g, 30.1 mmol) in THF (60 mL). After stirring at room temperature overnight, the reaction mixture was quenched with ethylacetate (5 mL). Water (150 mL) was added to the mixture and extracted with ether (3×75 mL). Ether layers were combined, washed with water and brine solution. The ether layer was then concentrated and distilled to get 20 (8.66 g, 77%) bp 90-92° C. at aspirator pressure; 1H NMR (CDCl3) δ3.75 (t, J=6.1 Hz, 2H), δ2.31-2.13 (mn, 2H), δ1.92-1.83 (mn, 2H)
Reaction SMILES: [CH3:1][N:2]([CH2:40][C@@H:41]1[CH2:43][C@H:42]1[CH3:44])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:33]=1)[C:6]([NH:8][NH:9][C:10]([C@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=O)=[O:7].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.Cl>ClCCCl.CCOC(C)=O>[CH3:39][N:34]([C:32]1[CH:31]=[C:5]([C:6]2[O:7][C:10]([C@H:12]3[C@@H:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][N:8]=2)[CH:4]=[C:3]([N:2]([CH3:1])[CH2:40][C@@H:41]2[CH2:43][C@H:42]2[CH3:44])[N:33]=1)[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NNC(=O)[C@H]2[C@@H](c3ccccc3)CCCN2C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H]1CN(C)c1cc(-c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)cc(N(C)S(C)(=O)=O)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl cis-2-[(2-{2-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)carbonyl]-3-phenylpiperidine-1-carboxylate (93.7 mg, 0.15 mmol) in 1,2-dichloroethane (1.5 ml) was added Burgess reagent (162 mg, 0.60 mmol). The reaction vessel was sealed and heated to 120° C. for 10 min in an Emry's Optimizer microwave reactor. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield the cyclodehydration product. A solution of the material in EtOAc (15 ml) at 0° C. was saturated with HCl gas and allowed to stir for 1 h. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield title example N-methyl-N-(6-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-4-[5-(cis-3-phenylpiperidin-2-yl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl)methanesulfonamide. HRMS (ES, M+H), cal'd for C26H34N6O3S: 511.2486. found: 511.2475. 1H NMR (400 MHz, CD3OD) δ 7.32 (m, 3H), 7.19 (d, J=7.3 Hz, 2H), 6.78 (m, 1H), 6.55 (m, 1H), 5.45 (d, J=5.1 Hz, 1H), 3.99 (m, 1H), 3.62 (m, 1H), 3.54 (m, 2H), 3.38 (m, 1H), 3.34 (s, 3H), 3.14 (s, 3H), 3.10 (s, 3H), 2.43-2.27 (m, 2H), 2.03 (m, 2H), 1.04 (d, J=5.7 Hz, 3H), 0.73 (m, 2H), 0.46 (m, 1H), 0.26 (m, 1H).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:28][CH2:29][O:30]C)[CH:4]=[CH:5]2.[C:32](O)(=O)C>O>[C:29]([O:28][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH:11]=[CH:10][C@@H:9]35)(=[O:30])[CH3:32]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OCC4CCCCO4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](OCC4CCCCO4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-ene (2.17 g, 5.08 mmol) is dissolved in water (65 ml) and glacial acetic acid (65 ml) and then stirred for 6 hours at 100° C. The volatile components are eliminated using the Rotavapor. The residue thus obtained is purified by flash chromatography (130 g of silica gel; mobile phase: methylene chloride/methanol=9:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised. Yield: 1.55 g 4,5α-epoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-en-3-ol acetate (68.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([NH:21][C:22](=[O:43])[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:25][C:24]=4[NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:55]([O:57][CH2:58][CH3:59])=[O:56]>C1COCC1.O>[CH2:58]([O:57][C:55]([N:18]1[C:15]2[CH2:16][CH2:17][N:12]([S:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][C:14]=2[C:20]([NH:21][C:22](=[O:43])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[NH:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:19]1)=[O:56])[CH3:59]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)CC4)c(NC3CCOCC3)c2)CC1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2NC2CCOCC2)c2c1CCN(S(=O)(=O)c1cc(F)cc(F)c1)C2
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
To a solution of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (1.38 g, 2.24 mmol) in anhydrous THF (150 mL), cooled to −40° C., under argon, was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.35 mL, 2.35 mmol). The mixture was stirred for 5 min. then ethyl chloroformate (0.225 mL, 2.35 mmol) was added. The reaction was stirred at −40° C. for 1 h, then was poured in water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried with sodium sulfate. After filtration and evaporation the crude was triturated with ether to give the title compound as white solid (1.32 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:20].I[CH:23]1[CH2:26][O:25][CH2:24]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C.CCOC(C)=O.O.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:8][CH:9]=2)[N:4]([CH:23]2[CH2:26][O:25][CH2:24]2)[C:3]1=[O:20]
Reactant: CC1(C)C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: IC1COC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(C2COC2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (56 mg, 0.20 mmol) and 3-iodooxetane (85 μL, 0.98 mmol) in DMF (1 mL) was added a THF solution of NaHMDS (1.0 M, 0.21 mL, 0.21 mmol). After 1.5 h, the reaction mixture was heated to 70° C. After an additional 1.5 h, the reaction mixture was cooled to r.t. and additional 3-iodooxetane (30 μL, 0.34 mmol) and NaHMDS solution (0.1 mL, 0.1 mmol) were added. The reaction mixture was heated to 70° C. and was stirred an additional 16 h. The reaction mixture was cooled and diluted with EtOAc, water, and brine, and the layers were separated. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide 3,3-dimethyl-1-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (7.43). LCMS-ESI+ (m/z): [M+H]+ calcd for C19H27BNO4: 344.20; found: 316.25.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[CH:6]([OH:10])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH2:18](O)[C:19]([CH3:22])([CH3:21])[CH3:20]>OS(O)(=O)=O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[CH:6]([OH:10])[C:7]([O:9][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)CO
Agent: O=S(=O)(O)O
Product: CC(C)(C)COC(=O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
2,6-dinitromandelic acid (4.00 g, 16.5 mmol) was added to an excess of neopentyl alcohol (20.0 g, 227 mmol) melted in a round bottom flask. To this solution was added 5 drops of H2SO4 and it was heated to reflux for 3 hours. The excess neopentyl alcohol was removed under reduced pressure, and the residue was purified by column chromatography over silica gel (60-200 mesh) using methylene chloride/hexane (1:1) as the eluant. The yield after two recrystallizations from CHCl3 /petroleum ether was 3.8 g (74%).