Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[OH-:13].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)(=[O:13])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of 5-cyanooxindole (1.2 g, 7.6 mmol), (Tet. Let., 1987, 28, 4027), in 85% sulphuric acid (8 ml) was heated at 80° C. for 6 hours. The mixture was allowed to cool, poured into ice/water and the mixture was adjusted to pH5 with 2M sodium hydroxide solution. The solid product was collected by filtration, washed with water, and dried under vacuum at 60° C. over phosphorus pentoxide to give 5-carbamoyloxindole (1.02 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ncnc2c1cnn2-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
Title compound 10B, 1-(3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (1.0 g, 3.9 mmol) was added to 10% w/w palladium on carbon (0.1 g, 10% w/w) suspended in ethanol (300 ml). This was stirred for 42 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered to remove the palladium residues and the filtrate was concentrated to dryness in vacuo. The resultant residue was purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as an off-white solid. (0.63 g, 2.8 mmol, 71%). LCMS: [M+H]+=227, Rt=0.71 min, 100% purity.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2([C:45](N3CC[C@@]4(C5C=CC=CC=5C(=O)O4)C3)=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2([C:45]([OH:46])=[O:17])[CH2:43][CH2:44]2)=[CH:38][CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OCc5ccccc5)nc4)CC3)C2)c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(O)C1(c2ccc(OCc3ccccc3)nc2)CC1

Procedure:
Following the BOP coupling the desired product, (1R)-1′-({1-[6-(benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one, was purified by prep-HPLC. LC/MS: 441.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:22]COC)=[C:6]([O:20][CH3:21])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].Cl.O>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:22])=[C:6]([O:20][CH3:21])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1cc(OC)c(O)c2c(CC)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1.3 g of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)propenoate in ethanol (10 ml) was added 1 ml of concentrated hydrochloric acid and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation, hexane was added for crystallization to obtain 0.76 g of the titled compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N12CCCN=C1CCCC[CH2:13]2.IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo[5,4,0]undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, iodomethane (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1,8-Diazabicyclo[5,4,0]undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50° C. for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1% ethyl acetate in hexanes. The resulting solid 3-fluoro-4-nitroanisole (72 g, 88%) was collected and air-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:31][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:32]
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-])=O.[N:22]1([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([C:28]2[CH:35]=[CH:34][C:31]([C:32]3[NH:19][C:18]4[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:15])[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:30][CH:29]=2)[CH2:23][CH2:24]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccccc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccccc1

Procedure:
Compound 259 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-benzoylaniline and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C24H22N4O2: 399.18; found: 398.99.
Reaction SMILES: CS(Cl)(=O)=O.C(N(CC)CC)C.O[C@H:14]1[CH2:23][C@@H:22]2[N:17]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21]2)[C@H:16]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=2)[CH2:15]1>C(Cl)Cl>[F:31][C:29]1[CH:30]=[C:25]([C@@H:16]2[CH:15]=[CH:14][CH2:23][C@@H:22]3[N:17]2[C:18](=[O:24])[CH2:19][CH2:20][CH2:21]3)[CH:26]=[C:27]([F:33])[C:28]=1[F:32]
Reactant: O=C1CCC[C@@H]2C[C@H](O)C[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC[C@@H]2CC=C[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Methanesulfonyl chloride (776 μL) and triethylamine (2.79 mL) were added to a solution of (6S*,8S*,9aR*)-8-hydroxy-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one (1.0 g) in methylene chloride (20 mL) under ice-cooling, and the reaction solution was stirred at room temperature for two hours. The solvent was removed by an evaporator. Then, sodium methoxide (28% solution in methanol, 3.22 g) was added to a mixed solution of the resulting residue in THF-ethanol (17 mL), and the reaction solution was stirred at room temperature for four hours. To make the starting material disappear, sodium methoxide (28% solution in methanol, 5.0 mL) was added to the reaction solution, which was then stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 681 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH2:14][OH:15])[CH:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1c(C=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Following a procedure similar to that described in Example 49(i), but using 1-(4-fluorophenyl)-4-hydroxymethyl-5-methyl-2-(4-methylsulfonylphenyl) pyrrole (prepared as described in Example 47) and manganese dioxide as starting materials, the title compound was obtained as a white powder (yield 98%), melting at 167-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]2([CH3:26])[CH2:12]OS(=O)(=O)[N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH:7]=1.CN(C)C(N(C)C)=N.[SH:36][CH2:37][C:38]#[N:39]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]([NH:9][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])([CH3:26])[CH2:12][S:36][CH2:37][C:38]#[N:39])[CH:7]=1
Reactant: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Reactant: N#CCS
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN[C@@](C)(CSCC#N)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a solution of (R)-4-(5-Bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (5.1 g, 11.1 mmol, Eq: 1.00) and 1,1,3,3-tetramethylguanidine (1.91 g, 2.09 ml, 16.6 mmol, Eq: 1.5) in DMF (77.3 ml) was added at 23° C. 2-mercaptoacetonitrile (1.22 g, 16.6 mmol, Eq: 1.5) dropwise. The reaction mixture was stirred at 23° C. for 16 hours. All volatiles were was evaporated at high vacuum and the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours. Sat. NaHCO3 solution was slowly added (pH=8), then extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetonitrile (5.2 g, 10.9 mmol, 98.3% yield) as a light brown oil. MS (ISP): m/z=453.0 [M+H]+ and 455.2 [M+2+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:20])[CH2:16][N:17]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:20])[CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCCCCc1ccccc1
Yield: 77 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 4.5 g of 3-(6-phenylhexyloxy)-2-hydroxypropylazide (prepared as described in Preparation 62), 1.23 g of lithium aluminum hydride and 150 ml of anhydrous tetrahydrofuran were used, to give 3.14 g of the title compound as a pale yellow oil having an Rf value of 0.12 (on silica gel thin layer chromatography, using a 5:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:22][C:11]3=[N:12][C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([I:16])[CH:15]=[C:10]3[C:9]=2[C:23]([NH:25][CH3:26])=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].CN(C=O)C>O>[CH3:26][NH:25][C:23]([C:9]1[C:10]2[C:11](=[N:12][C:13]([N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])=[C:14]([I:16])[CH:15]=2)[O:22][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:24]
Reactant: C=CCCCBr
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (440 mg), Cs2CO3 (322 mg, 1.1 eq.), 5-bromopent-1-ene (402 mg, 3 eq.) and dry DMF (4.5 ml) was stirred in a microwave reactor at 150° C. for 15 min and cooled to rt. Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with 2× water. Silica gel flash chromatography using 0-11% ether-methylene chloride yielded the title compound (250 mg, 55%). MS (ESI) m/z 558.1 (M+1). Retention time=1.33 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH2:35][CH3:36]
Reactant: CCI
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(O)c(Cl)cc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2cc(-c3ccccc3)n(Cc3cccc(C(=O)OC)n3)c2cc1Cl

Procedure:
To a solution of methyl 6-(6-chloro-5-hydroxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxylate (100 mg) in N,N-dimethylformamide (1 mL) were added, potassium carbonate (70.4 mg) and ethyl iodide (0.031 mL) and the mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (83.9 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH2:14]([C@H:18]1[CH2:22][O:21][CH:20]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:19]1)[CH:15]([CH3:17])[CH3:16].[Cl-].[NH4+]>C1COCC1>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([C@H:20]([NH:19][C@@H:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:22][OH:21])[C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])=[CH:7][CH:2]=1
Reactant: CC(C)C[C@H]1COC(C(F)(F)C(F)(F)F)N1
Reactant: Brc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of dibromobenzene (9.85 g, 41.8 mmol) in 100 mL of THF was added nBuLi (16.5 mL of 2.5M hexanes solution, 41.2 mmol) giving a thick suspension. After stirring 10 min, a solution of (4S)-4-isobutyl-2-(pentafluoroethyl)-1,3-oxazolidine (3.3 g, 13 mmol) in 3 mL THF was added giving a dark brown solution. The solution was allowed to warm to room temperature, then was poured into saturated aqueous ammonium chloride and extracted with ether. Purification by silica gel chromatography (10% to 40% ethyl acetate/hexanes gradient) gave the title compound as a single diastereomer.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])#[N:2].[OH-].[Na+:19]>O>[C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11](=[O:17])[C:12]([O-:14])=[O:13])#[N:2].[Na+:19]
Reactant: CCOC(=O)C(=O)Nc1sc(C)c(C)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1sc(NC(=O)C(=O)[O-])c(C#N)c1C
Temperature: 25 °C

Procedure:
Approximately 0.756 g. (0.003 mole) of the purified ethyl (3-cyano-4,5-dimethylthiophen-2-yl)oxamate is suspended in 20 ml. of water and hydrolyzed by the addition of 32 ml. of 0.1N NaOH in a dropwise manner during about twenty minutes. The hydrolysis mixture is stirred for an additional twenty minutes at room temperature. The clear yellow solution (pH 9.2) is adjusted to pH 8.3 with 2 ml. of 0.1N HCl and concentrated in vacuo to recover the sodium salt of (3-cyano-4,5-dimethylthiophen-2-yl)oxamic acid as a yellow solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCN(C3CCC3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(N2CCC(CC3CCNCC3)CC2)C1

Procedure:
1,1-Dimethylethyl 4-[(1-cyclobutyl-4-piperidinyl)methyl]-1-piperidinecarboxylate (may be prepared as described in Description 5) (5.7 g) was stirred in a solution of HCl-Dioxane (100 ml, 4M) for 1 h. The solvent was evaporated and the resultant yellow solid was dissolved in saturated potassium carbonate (25 ml). The solution was extracted into dichloromethane (3×50 ml) and the combined organics dried (MgSO4) and evaporated to give the title compound (D6) as a pale yellow oil which solidified on standing (3.04 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[CH:13][CH:12]=2)=[N:6][CH:5]=1.[CH2:31]([N:33](CC)[CH2:34]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:19](=[O:20])[N:33]([CH3:34])[CH3:31])=[CH:13][CH:12]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)nc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)nc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
The compound 17 (2.2 g, 5.28 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (0.883 mL, 6.33 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 2.5 g, 5.80 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 13.2 mL, 26.4 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 18 (1.3 g, ˜98%). 1H NMR (400 MHz, DMSO-d6): 8.67 (br, 1H), 8.29 (dd, J=8.8 and 2.4 Hz, 1H) 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.57 (m, 1H), 3.85 (s, 3H), 2.93 (s, 3H), 2.85-2.75 (m, 2H), 2.80 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:25]2[N:24]=[N:23][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:26]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.0 mmol) in anhydrous THF at 0° C. may be treated with sodium hydride (60% dispersion in mineral oil) (1.3 mmol). After stirring for 15 min the reaction mixture is allowed to come to room temperature. To the alkoxide solution is added 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.74 mmol). After completion of the addition, the reaction mixture is warmed to 50° C. and is stirred 3 hours. The reaction is concentrated onto SiO2, purification via flash chromatography may be used (20-50% ethyl acetate in hexanes) to provide trans-{-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:11])[S:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])[S:2]1
Reactant: COC(=O)CCCNC(=O)CCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCNC(=O)CCCCC1CCSS1
Yield: 45.2 %

Procedure:
The reaction was effected as described in Example 49, but using 0.65 g of methyl 4-[5-(1,2-dithiolan-3yl)pentanoylamino]butanoate (prepared as described in Example 73), 13 ml of methanol and a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralisation with 2N aqeous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0.28 g of the title compound as yellow crystals, melting at 56 to 58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([P:8](=[O:13])([O:11]C)[O:9]C)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([P:8](=[O:9])([OH:13])[OH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)P(=O)(O)O
Yield: 76 %

Procedure:
To a solution of dimethyl p-chlorobenzoylphosphonate (1 mmol) in dry dioxane (5 ml), BrMe3Si (3 mmol) was added dropwise under magnetic stirring, in nitrogen atmosphere at room temperature. After 5 h the solvent was removed under vacuum and the brown residue was dissolved in MeOH at 0° C. The solvent was evaporated and a solution of NaOH (1 mmol) in MeOH (5 ml) was added in portions. The white solid was filtered and dried under vacuum. Yield: 76%. NMR, 1H: 7.54 (d, 2H), 8.11 (d, 2H); 31P, −1.48 ppm.