Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2nc(OC3CCN(Cc4ccccc4)CC3)sc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(Cc5ccccc5)CC4)sc3c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 14A (0.68 g, 1.686 mmol) in dry THF (9.4 ml) at −78° C. under argon was added dropwise BuLi (0.742 ml, 1.855 mmol). After the completion of addition, the reaction mixture was stirred at −78° C. for 1 h. At the conclusion of this period, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.37 g, 1.855 mmol) in THF (1.9 ml) was transferred to the reaction mixture via cannulation. The resulting mixture was stirred and gradually warmed to −20° C., where it stirred for an additional hour. At the conclusion of this period, the mixture was quenched with aq. NaHCO3 (saturated, 20 mL) and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with H2O (3×10 mL) and brine (10 mL), dried (Na2SO4) and then filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to give Compound 14B′ as a white solid (0.63 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.36 (m, 4H), 7.24-7.29 (m, 1H), 5.21 (tt, J=7.9, 3.9 Hz, 1H), 3.98 (br. s., 2H), 3.54 (s, 2H), 3.25 (br. s., 2H), 2.73 (br. s., 2H), 2.38 (t, J=8.7 Hz, 2H), 2.08-2.18 (m, 2H), 1.85-2.03 (m, 5H), 1.75 (d, J=12.1 Hz, 2H), 1.47-1.50 (m, 9H). LC/MS (m/z)=524 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 42.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.415 g, 0.985 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with diethylamine (2.04 mL, 19.7 mmol), acetic acid (1.10 mL, 19.7 mmol) and sodium triacetoxyborohydride (0.626 g, 2.96 mmol) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(diethylaminomethyl)indol-2-yl]isoindolinone (0.202 g, 43%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.C1COCC1.[NH4+:27].[OH-]>C(OCC)(=O)C>[NH2:27][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: N#Cc1cc(Cl)nc(SCc2ccc3ccccc3c2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)nc(SCc2ccc3ccccc3c2)n1

Procedure:
6-chloro-2-(2-naphthylmethyl)thio-4-pyrimidine carbonitrile (Cpd 276; 60 mg, 3.07 mmol) was stirred in THF/NH4OH (1:1, 15 ml) at 22° C. for 6 hrs. The reaction was diluted with ethyl acetate, washed with brine, dried with MgSO4, then concentrated in vacuo: 871 mg (2.97 mmol, 97%), mp 154-155° C.
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[CH2:9][CH2:8][S:7]1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH3:11][N:10]1[CH2:9][CH2:8][S:7][C:6]1=[N:5][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:20]
Reactant: CN1CCSC1=N
Reactant: S=C=Nc1ccccc1
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: CN1CCSC1=NC(=S)Nc1ccccc1

Procedure:
Sodium methoxide (2.16 g) was added to a mixture of 2-imino-3-methylthiazolidine hydroiodide (10.0 g) in ethanol (50 ml) and brought to reflux, with stirring. Phenylisothiocyanate (5.4 g) in ethanol (20 ml) was added to the mixture over 5 minutes and the resultant mixture heated under reflux, with stirring, for one hour then cooled in ice. Filteration gave analytically pure product, mpt 169°-170°, which may be recrystallised from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH2:10]([O:9][C:7]([C:6]1[O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[N:1]=[CH:18][N:19]([CH3:21])[CH3:20])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1oc2ccccc2c1N
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4.2 g (20.0 mmol) of ethyl 3-amino-2-benzo[b]furancarboxylate (EP 187487 A1) in 10 mL of N,N-dimethylformamide dimethyl acetal is heated at reflux temperature for 1.5 hours, then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over sodium sulfate, passed through a pad of diatomaceous earth and concentrated in vacuo. The solid is collected by filtration to provide 3.90 g (75%) of a white solid, mp 89–90° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2ccc(N)cc2)c1
Reactant: C=C(CC(=O)O)C(=O)O
Product: COc1cccc(CCc2ccc(N3CC(C(=O)O)CC3=O)cc2)c1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 4-[2-(3-methoxy-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a white solid; MS: m/e=338 (M−H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[N:32]([C@H:33]2[C@H:38]([OH:39])[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[C:31](=[O:47])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:30]3/[C:31](=[O:47])[N:32]([C@H:33]4[C@H:38]([OH:39])[CH2:37][CH2:36][NH:35][CH2:34]4)[C:28](=[O:27])[S:29]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:30]([CH:29]([C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[O:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:45][CH:44]=1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(Oc1ccc(CBr)cc1)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1)c1ccc2c(c1)OCO2
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of 0.020 g (0.10 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 250 gL DMF was added 0.035 g (0.11 mmol) of cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere for 10 minutes. A solution of the product of step B in 300 aL DMF was then added and the reaction mixture was stirred for an additional 1 hour. The mixture was suspended in 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered, evaporated, and the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.029 g (58%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH3:23])[CH:18]=[N:17][C:16]=3[N:15]([CH3:24])[C:14](=[O:25])[CH:13]=2)(=O)=O)=CC=1.[F:26][C:27]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:12]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:14](=[O:25])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3ncn(C)c(=O)c23)cc1
Reactant: Nc1ccc(I)cc1F
Product: Cn1cnc2c(c(Nc3ccc(I)cc3F)cc(=O)n2C)c1=O

Procedure:
3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate (compound 1D, 80 mg of 60% pure material) and 2-fluoro-4-iodoaniline (300 mg, large excess) were heated at 125° C. for 2 hours to yield 5-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (Example 1). The product was confirmed by LC-MS and isolated by HPLC to give the title compound as a tan solid (17 mg). 1H NMR (400 MHz, MeOD) δ ppm 3.57 (s, 3H) 3.64 (s, 3H) 5.76 (s, 1H) 7.30 (t, J=8.34 Hz, 1H) 7.61 (dt, J=8.34, 1.01 Hz, 1H) 7.66 (dd, J=9.85, 1.77 Hz, 1H) 8.48 (s, 1H); [M+H] calc'd for C15H12FIN4O2, 427. found, 427.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:8][CH:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Cl:21][C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([CH:7]3[CH2:8][CH:6]3[CH2:5][CH2:4][NH2:1])[CH2:10][CH2:11]2)=[N:20][CH:19]=1
Reactant: [N-]=[N+]=NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{4-[2-(2-azidoethyl)cyclopropyl]piperidin-1-yl}-5-chloropyrimidine from step 2 of this example (28 mg, 0,091 mmol) was dissolved in 0.821 mL THF. PPh3 (47.9 mg, 0.182 mmol) was added, followed by addition of 0.091 mL water. The reaction mixture was stirred at room temperature for 1 hour then 40° C. for 3 hours before cooled back to room temperature. The solvent was evaporated in vacuum. The residue was purified by column chromatography eluting with 10% 2M NH3-MeOH/ethyl acetate to give the titled compound. LRMS calc: 280.8; obs: 281.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:15]([C:16]([O:18]CC)=[O:17])C(O)(C)CC(=O)[CH:11]3[C:24]([O:26]CC)=[O:25])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH2:11][C:24]([OH:26])=[O:25])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C1C(=O)CC(C)(O)C(C(=O)OCC)C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(CC(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
Diethyl 2-(1,3-benzodioxol-5-yl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate (19 g) was suspended in ethanol (140 ml) and an aqueous solution of NaOH (50%, 270 ml). The mixture was heated at reflux for one hour. After the mixture was cooled to room temperature, the ethanol was removed under reduced pressure. Then, concentrated HCl was added until pH 1 was achieved while maintaining the temperature below 50° C. The mixture was filtered. The solid was washed with ether. The two layers were separated. The aqueous layer was extracted with ether (3×). The ether layers were combined, dried, and concentrated to give product. 1H NMR (DMSO-d6) δ 12.06 (br s, 2H), 6.88–6.68 (m, 3H), 5.98 (s, 2H), 3.4–3.3 (m, 1H), 2.62–2.42 (m, 4H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>C(O)(C(F)(F)F)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[CH2:35][CH2:36]3)=[CH:29][CH:30]=2)[N:10]=1
Reactant: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: COC(=O)Cc1ccccc1CCc1ccnc(S(C)(=O)=O)n1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
A solution of methyl 2-(2-(2-(2-(methylsulfonyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A3) (150 mg, 449 μmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (K2) (168 mg, 538 μmol) in TFE (5 mL) containing TFA (180 μL) was heated at 100° C. under microwave irradiation for 60 minutes. Additional TFA (200 μL) was added and the resulting solution heated at 120° C. under microwave irradiation for a further 40 minutes. Additional TFA (200 μL) was again added and the mixture was heated at 150° C. under microwave irradiation for a further 20 minutes. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A4 as a brown oil (76 mg, 30%). LCMS-A: rt 6.212 min; m/z 566.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11](Cl)([Cl:13])=[O:12]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][C:11]([Cl:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: O=C(Cl)Oc1cccc([N+](=O)[O-])c1

Procedure:
The 3-nitrophenyloxycarbonyl compound can be prepared by reaction of 3-nitrophenol with phosgene to yield 3-nitrophenyloxycarbonyl chloride. The latter can then be reacted with a thiol:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](=S)/[N:8]=[C:9]1\[S:10][C:11]2[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=2[N:13]\1[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[N:35]#[C:36][NH2:37]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:7](=[N:37][C:36]#[N:35])/[N:8]=[C:9]2\[S:10][C:11]3[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=3[N:13]\2[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:25]=1
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Reactant: N#CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of Example 89H (0.18 g, 0.42 mmol) in acetonitrile (10 mL) were added mercuric acetate (0.18 g, 0.55 mmol, Aldrich), triethylamine (0.18 mL, 1.27 mmol) and cyanamide (0.04 g, 0.85 mmol, Aldrich). After stirring at 80° C. for 16 hr, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined the organic extracts were washed with water (1×25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) and followed by crystallization from ethyl acetate/hexanes to afford 0.04 g (21%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.8 Hz, 6H), 1.51 (s, 6H), 2.06-2.35 (m, 1H), 2.66-2.87 (m, 2H), 3.81 (s, 3H), 3.94-4.14 (m, 4H), 7.21 (d, J=9.2 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.52 (dd, J=9.2, 2.7 Hz, 1H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C21H25ClN4O2S: C, 58.25; H, 5.82; N, 12.94. Found: C, 58.30; H, 5.79; N, 12.64.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.0 g. (0.0196 moles) of 3-dimethylaminopropylamine in 40 ml chloroform was added dropwise to an ice cold chloroform solution (50 ml) of myristoyl chloride (4.17 g., 0.0169 moles). After addition, the ice bath was removed and the solution was stirred for 2 hours. A 25 ml aqueous sodium bicarbonate solution was added and stirred for 30 minutes. The organic layer was then washed with 30 ml aqueous sodium bicarbonate/sodium chloride solution and dried with magnesium sulfate. The solution was concentrated in vacuo and the amide was recrystallized in ethyl acetate to yield 3.29 g. (0.0105 moles, 62.3%) of the subject compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:15][CH2:16][NH:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(CCN)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.3 %

Procedure:
Benzoyl chloride (0.922 g, 6.61 mmol) was added to a solution of 3-methoxyphenethylamine (1.000 g, 6.61 mmol) and Et3N (2.8 ml, 19.8 mmol) in anhydrous THF (30 ml) at rt under N2. The resulting suspension was stirred at rt under N2 for 20 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1.811 g of white solid. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.689 g (100% yield) of white solid.
Reaction SMILES: [P:1]([O:44]C(C)(C)C)([O:39]C(C)(C)C)([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2].Cl.O1CCOCC1>CO>[P:1]([OH:39])([OH:44])([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)N[C@H](COP(=O)(O)O)c2cc(F)cc(I)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
(S)-2-(4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (4600 mg, 5.72 mmol) was fully dissolved in MeOH (Volume: 70 mL). Then HCl 4M in Dioxane (14.29 mL, 57.2 mmol) was added and stirred at room temperature for 3 hours, followed by LCMS. The solvent was concentrated mostly off. Then MeOH (Volume: 70 mL) was added and the solvent was concentrated off to residue, additional MeOH (Volume: 70 mL) was added and the residue concentrated to constant mass. The product was dissolved in 90 ml of 1:1 ACN/water and lyophilized to give 3.99 grams of the desired product as HCl salt. (94% yield). LCMS (m/z): 692.9 (MH+), 0.63 min. 1H NMR (<cd3od>) d: 7.84-7.93 (m, 1H), 7.75 (s, 1H), 7.60-7.71 (m, 3H), 7.45-7.51 (m, 1H), 7.26 (dt, J=9.7, 1.6 Hz, 1H), 5.40 (t, J=5.9 Hz, 1H), 4.31-4.50 (m, 1H), 4.22-4.30 (m, 2H), 3.64 (tdd, J=11.7, 8.6, 5.1 Hz, 1H), 2.82-2.98 (m, 1H), 2.32 (ddt, J=11.7, 5.8, 2.8 Hz, 1H), 2.01-2.15 (m, 1H), 1.89-1.97 (m, 1H), 1.75-1.89 (m, 1H), 1.58-1.72 (m, 1H), 1.42-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.00 (s, 1P).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:47])=[C:25]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:32][CH:33]=[N:34][N:35]=2)(=[O:29])=[O:28])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:20][C:21]1[C:22]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:23][C:24]([F:47])=[C:25]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:32][CH:33]=[N:34][N:35]=2)(=[O:28])=[O:29])[CH:26]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 93 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 16 hours. The crude material was partitioned between ethyl acetate (20 mL) and water (20 mL), the organic layer separated, concentrated in vacuo and purified by silica gel column chromatography (ISCO™, 12 g silica, 0-100% ethyl acetate in heptane gradient elution). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a gum (100 mg, 72%).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: CCC(C=O)C(C)=O
Reactant: N#CCC(N)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
According to the method described in J.Heterocyclic Chem., 24, 351 (1987), a mixture of 2-ethyl-3-oxobutanal, sodium salt (37.5 g, 0.275 mmol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature, the product was collected by filtration, washed with cold water and air dried to yield 22.3 g (50%), m.p. 237°-240° C.