Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12]>>[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:12])=[O:5]
Reactant: O=C1C=CC(=O)O1
Agent: O=C(O)/C=C/C(=O)O
Product: O=C(O)/C=C\C(=O)O

Procedure:
cooling said dehydrator bottom stream comprising molten maleic anhydride and fumaric acid to a temperature of about 250° F. to about 330° F. to precipitate the fumaric acid and form a slurry of fumaric acid in molten maleic acid;
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=N[CH:12]=1)(=[O:4])=[O:3].[F:13][C:14]([F:24])([F:23])[C:15]1C=C(CO)C=NC=1>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:15]([C:14]([F:24])([F:23])[F:13])[CH:12]=1)(=[O:4])=[O:3]
Reactant: OCc1cncc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCc1cncnc1
Product: CS(=O)(=O)OCc1cncc(C(F)(F)F)c1

Procedure:
(5-(Trifluoromethyl)pyridin-3-yl)methyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using (5-(trifluoromethyl)pyridin-3-yl)methanol instead of pyrimidin-5-ylmethanol. LCMS-ESI+ (m/z): [M+H]+ calc'd for C8H8F3NO3S: 256.02; found: 256.06.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([O:20]CC(Cl)(Cl)Cl)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CN(C)C=O.C(O)(=O)C.O.[Zn]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CSC[C@H]12
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)O)=CSC[C@H]12
Reaction time: 3 h

Procedure:
To a solution of 43 mg (0.1 mmole) of trichloroethyl cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 6 ml of dimethylformamide and 6 ml of acetic acid is added over a 1.5 hr period 250 mg (3.8 mmole) zinc dust. The mixture is stirred vigorously for 3 hrs and then diluted with 50 ml of water. The mixture is acidified with dilute HCl, filtered and extracted with ethyl acetate. The organic phase is extracted with 5% NaHCO3 which is acidified and reextracted into ethyl acetate. The final extracts are washed with brine, dried, and evaporated to give cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:40]([Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[O:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:41])[CH3:42]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of Intermediate A (223 mg, 1.37 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 168 mg, 4.20 mmol) and the mixture stirred at RT for 15 min. A solution of Intermediate 54b (555 mg, 1.37 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a brown gum (344 mg, 46%). LCMS (Method 3): Rt 3.29 min, m/z 550 [MH+].
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18]>C(#N)C>[CH2:16]=[C:17]1[CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:18]1
Reactant: Oc1ccccc1O
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C1COc2ccccc2OC1
Temperature: 25 °C

Procedure:
Catechol (5.09 g, 46.2 mmol) and potassium carbonate were combined in acetonitrile and heated to reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued at reflux for 24 hours. The solution was cooled to room temperature and filtered. The filtrate was evaporated and the residue was diluted with water and extracted with diethyl ether (3×). The combined organic solution was dried over MgSO4 and concentrated. Chromatography (2% ethyl ether in hexane) yielded 3-methylene-3,4-dihydro-2H-benzo[b][1,4]dioxepine as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>[Pd].C(OCC)(=O)C.CO>[CH2:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(4-butyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-2-nitro-phenylamine (1.0 g, 2.5 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[5-(4-butyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine as an orange solid that was used in the next step without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].NC1C(O)=C(Br)C=C(Br)C=1>C(O)C.O.O>[NH2:8][C:4]1[C:3]([OH:11])=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: Nc1cc(Br)cc(Br)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(Br)c1O
Reaction time: 2 h

Procedure:
2-Bromo-6-nitrophenol (1.506 g, 0.0057 mol, containing 2,4-di-bromo-6-nitrophenol, 18% w/w) and sodium hydrosulfite (3.05 g, 85%, 0.015 mol) were heated at reflux in ethanol/water (50 ml of a 5:1 v/v mixture). After 2 hours, the reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (3×50 ml), and ethyl acetate (100 ml). The organic extracts were combined, dried over calcium sulfate, evaporated in vacuo, and purified by flash chromatography (SiO2, petrol/ether 1:1 v/v) to furnish a mixture of the title compound and 6-amino-2,4-di-bromophenol (0.600 g, of a 76:24 w/w mixture as judged by 1 H-NMR). Yield 6-amino-2-bromophenol, 43%.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH:8]=[CH2:9])=[CH:2][CH3:3].[SiH:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12]>C1(C)C=CC=CC=1>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][Si:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12])=[CH:2][CH3:3]
Reactant: CO[SiH](OC)OC
Reactant: C=COCCOC=CC
Solvent: Cc1ccccc1
Product: CC=COCCOCC[Si](OC)(OC)OC
Temperature: 85 °C
Yield: 36 %

Procedure:
Into a 100 mL round bottom flask were added 9.17 grams (0.07 mol) of 1-(1-propenoxy)-2-vinyloxyethane, 3 mg of (PPh3)3RuCl2, 11.3 grams of (MeO)3SiH (0.09 mol), and 15 ml of dried toluene. The resulting purple solution was refluxed at 85° C. for 12 hours. Fractional vacuum distillation yielded 1-(1-propenoxy)-2(2-trimethoxysilylethoxy)ethane (V) in 36% yield as a colorless liquid, b.p. 70° C./0.15 mm Hg.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][NH2:35])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:38][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>C(N(CC)CC)C>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][NH:35][S:41]([CH:39]([CH3:40])[CH3:38])(=[O:43])=[O:42])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
Using 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (248 mg), triethylamine (135 μl) and 2-propanesulfonyl chloride (65.5 μl), the same reaction as Example 31 was carried out to yield the titled compound (55 mg) as colorless needle crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:30][C:31]1[CH:32]=[C:33]([C:37](O)=[O:38])[CH:34]=[N:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]([NH:29][CH:17]2[CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:20][N:15]([C:13]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:14])[CH2:16]2)=[O:38])[CH:34]=[N:35][CH:36]=1
Reactant: O=C(O)c1cncc(Cl)c1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cncc(Cl)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
65 mg (0.15 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 21 mg (0.13 mmol, 0.9 eq.) of 5-chloropyridine-3-carboxylic acid were reacted according to General Method 1. Yield: 39 mg (62% of theory)
Reaction SMILES: [N:1]([C:4]1[C:24](=[O:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:27])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[C@H:13]([CH3:16])[CH2:14][OH:15])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][C:4]1[C:24](=[O:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:27])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[C@H:13]([CH3:16])[CH2:14][OH:15]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of (20S)-4-azido-21-hydroxy-20-methylpregn-4-en-3-one (3.15 mmole) in tetrahydrofuran (20 mL)-water (7 mL) was added triphenylphosphine (1.41 g, 5.38 mmole). The reaction was heated at reflux temperature for 16 hours. Most of the tetrahydrofuran was removed under vacuum. Dichloromethane was added to the mixture and the organic solution was placed atop a column of silica gel and flash chromatographed (hexane-30% ethyl acetate). The fractions containing the product were combined and concentrated to a white solid which was crystallized from diethyl ether to give (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one. IR 3510, 3470, 3384, 1648, 1614, 1576 cm-1 ; MS (CI) 346 (100%, M+ +1) (EI) 345 (65%, M+), 302 (100%); 1H NMR δ (CDCl3) 0.73 (3H, s, C18 -Me), 1.04 (d, C21 -Me), 1.15 (s, C19 -Me), 2.42-2.56 (3H m) 3.73 (v br NH2) 3.36 (1H dd 1/2 C21 -CH2), 3.63 (1H, dd, 1/2 C21 -CH2); 13C NMR δ (CDCl3) 132.85, 139.15, 194.38. This compound has the following structure: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:3]([CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COCCOCCl
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)c(C=O)c2ccccc21
Reaction time: 8 h
Yield: 100.6 %

Procedure:
1 g of (1) was dissolved in 25 ml of THF, 268 mg of NaH was added, and then 1.87 g of (2-methyloxyethyl)oxymethylchlorid. The reaction was left with stirring overnight, then added to a 2 N K2CO3 solution. The mixture was extracted with toluene, the organic phase then washed with water and brine, dried, and evaporated to give 1.5 g of oil. The oil was then extracted twice with boiling heptane, and the heptane solutions left for 2 hours to separate out a yellow oily phase. The heptane was finally decanted off, filtered, and evaporated giving 1.21 g of (78). M.p. 52.5-54° C.
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH2:13][S:12][N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3=[N:30][N:31]([CH2:33][C:34]4[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=4)[N:32]=[C:7]([C:8]=23)[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[CH3:42][O:41][C:38]1[C:37]([CH3:43])=[CH:36][N:35]=[C:34]([CH2:33][N:31]2[N:32]=[C:7]3[CH2:6][C:5](=[O:4])[C:14]4[CH2:13][S:12][N:11]=[C:10]([N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]([C:8]=43)=[N:30]2)[C:39]=1[CH3:40]
Reactant: COc1c(C)cnc(Cn2nc3cc(OC(C)=O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Yield: 91.1 %

Procedure:
A mixture of 4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl acetate of Example 39 (507 mg), methanol (12 mL) and potassium carbonate (57 mg) was stirred under cooling in an ice bath for 30 minutes. After confirming that the raw material disappeared, a saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (430 mg, 91%) as an oil.
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)(CO)CCCC
Reactant: CI
Product: CCCCC(CO)(CCCC)COC

Procedure:
2,2-Di-n-butyl-3-methoxy-propanol was prepared from 2,2-di-n-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+].C1COCC1.Cl>C(O)C.O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:27])=[N:15][CH:16]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(COc1ccc(-c2ccccc2Cl)cn1)Nc1cscc1C(=O)O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester (79 mg) in ethanol (10 mL) was added a solution of sodium hydroxide (1M, 0.392 mL) and THF (8 mL) and the reaction mixture was stirred at room temperature over night. After such time the reaction mixture was acidified by addition of a solution of hydrochloric acid (1N, 0.395 mL) and then water was added. The precipitate was isolated by filtration, washed with water and dried in vacuo to yield 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid (51 mg, 67%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(O)(=O)/C=C\C(O)=O.ClC1[N:32]=[N:31]C2CCNCC=2C=1.C(OC(Cl)=O)C=C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13]([NH:31][NH2:32])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: C=CCOC(=O)N1CCc2nnc(Cl)cc2C1
Agent: C=CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Product: C=CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid allyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and chloroformic acid allyl ester. The oily crude product is used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:20]([NH2:22])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:29].[Na+].O.P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.O>[NH2:22][C:20]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:29])=[O:19])=[CH:15][CH:16]=2)[N:11]=1)=[O:21]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C=O)cc2n1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-fluorophenyl)-7-formylquinoline-2-carboxamide (5-2, 200.0 mg, 0.680 mmol, 1.0 equiv.) and 2-methyl-2-butene (3.96 mL, 37.4 mmol, 55 equiv.) in t-BuOH (14.0 mL, 0.05 M) was added a solution of sodium chlorite (553.0 mg, 6.12 mmol, 9 equiv.) and sodium dihydrogen phosphate monohydrate (559.0 mg, 4.08 mmol, 6 equiv.) in water (6.5 mL). The resulting mixture was stirred at room temperature for 1 hour. A white solid precipitated. Water (100.0 ml) was added and the mixture stirred for 30 minutes. The solid was collected via suction filtration, washed with water, dried in vacuo to give 2-(aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3, 150.0 mg, 71.1%) as a white solid. LRMS m/z (M+H)+ 311.1 found, 311.1 required.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17](S(C)(=O)=O)[N:16]=1.O>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[N:16]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
25 g (230 mmol) Methyl thioglycolate was dissolved in 250 ml dimethylformamide and treated with 16.3 g (115 mmol) potassium carbonate. After 20 minutes stirring at room temperature, 50 g (2.3 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added and the mixture heated for 3 hours at 90° C. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulphate. The solvent was distilled and the resulting crude product was recrystallised from diisopropyl ether.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][NH:22][C:1]2=[S:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCNc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: S=C1NCCN1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
1,1′-Thiocarbonyldiimidazole (4.51 g, 25.3 mmol) was added to a solution of N-phenylethylenediamine (3 mL, 23.02 mmol) in THF (230 mL) and the mixture was stirred for 2 h at room temperature. DCM was added and the solution was washed with 1N HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure affording title compound 301 (1.45 g, 8.13 mmol, 35.3% yield). m/z: 179.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.BrN1C(=[O:24])CCC1=O>CC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Solvent: O
Solvent: CC(C)=O
Product: COCCC(=O)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A solution of 10.6 g (38.1 mmol) of tert-butyl 2-(2-methoxyethyl)-1,3-dithiane-2-carboxylate in 365 ml of acetone and 18 ml of water was added dropwise to a solution, cooled to −18° C., of 54.2 g (305 mmol) of N-bromosuccinimide in 365 ml of acetone and 18 ml of water such that the internal temperature did not exceed −5° C. After the addition had ended, the mixture was stirred for another 10 min and the reaction was then terminated using 630 ml of sodium sulphite solution (1N). 420 ml of n-heptane were added to the reaction mixture and, after phase separation, the aqueous phase was extracted three times with 315 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed at 25° C. and 75 mbar. The resulting suspension was stirred with 100 ml of n-hexane and the precipitate was filtered off. The solvent was removed under reduced pressure, giving the target compound. Yield: 5.28 g (59% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyridin-2-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:12]1[CH2:16][C@H:15](OS(C(F)(F)F)(=O)=O)[CH:14]([O:25][CH3:26])[O:13]1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[C:1]([O:9][CH:10]([C@@H:12]1[CH2:16][C@@H:15]([N:27]=[N+:28]=[N-:29])[CH:14]([O:25][CH3:26])[O:13]1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 206 %

Procedure:
To a solution of 1-[(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]ethyl benzoate (compound 25j, 400 mg, 1 mmol) in DMF (2 mL) was added sodium azide (65 mg, 1.05 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O, the organic layer was separated and the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 600 mg crude product of 1-[(2S,4R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]ethyl benzoate (compound 25k), which was used in next step without further purification.