Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29]([O:31][CH2:32][P:33](=[O:38])([O:36][CH3:37])[O:34][CH3:35])=[O:30])=[CH:25][CH:24]=1)=[O:22])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([O:31][CH2:32][P:33](=[O:38])([O:36][CH3:37])[O:34][CH3:35])=[O:30])=[CH:39][CH:40]=1)=[O:22]
Reactant: COP(=O)(COC(=O)NCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COP(=O)(COC(=O)NCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OC
Reaction time: 0.25 h

Procedure:
Dimethyl {[({[4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]amino}carbonyl)oxy]methyl}phosphonate 0.496 g, 0.841 mmol) was dissolved in DCM (4 ml). TFA (1 ml, 12.98 mmol) was added. The reaction was allowed to stir for ˜1 h 15 min. The reaction was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. 1H NMR (DMSO-d6, 600 MHz) δ 9.67 (s, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.44 (bs, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.32 (dd, J=5.1 Hz, 1.0 Hz, 1H), 7.26 (dd, J=8.4 Hz, 2.2 Hz, 1H), 7.21 (d, J=3.1 Hz, 1H), 7.01 (dd, J=5.1 Hz, 3.7 Hz, 1 H), 6.77 (d, J=8.2 Hz, 1H), 5.11 (s, 2H), 4.39 (d, J=7.9 Hz, 2H), 4.25 (d, J=6.2 Hz, 2H), 3.66 (d, J=10.6 Hz, 6H). MS: calc'd 490 (MH+), exp 490 (MH+).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([CH2:19][O:20]C(=O)C)[CH:15]=2)[O:7][C@H:6]1[N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][C:27]([Cl:42])=[N:28][C:29]=2[NH:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[F:41])(=O)C.C(N)(C)(C)C>CO>[Cl:42][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)[O:7]2)=[C:29]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[F:41])[N:28]=1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Solvent: CO
Solvent: CC(C)(C)N
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To (2R,3R,4R,5S)-4-(acetyloxy)-5-{3-[(acetyloxy)methyl]isoxazol-5-yl}-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (4.02 mg) in methanol (2 ml) at 0° C. was added tert-butylamine (0.012 ml), and the mixture was allowed to stand at 0 ° C. for 3 h. The solvent was evaporated in vacuo to furnish the title compound as a yellow gum (2.48 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][S:31]([CH3:30])(=[O:33])=[O:32])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg), triethylamine (490 mg), 4-dimethylaminopyridine (39 mg) and tetrahydrofuran (35 ml) was added methanesulfonyl chloride (440 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]methane sulfonamide (686 mg, 58%). The crystals were recrystallized from ethyl acetate-hexane.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.BrC1SC(C(C)C)=NC=1.O1C2(CCC(=O)CC2)OCC1.[NH:37]1[CH2:40][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:58])([F:57])[F:56])[CH:53]=3)[N:48]=[CH:47][N:46]=2)[CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:37]2[CH2:38][CH:39]([NH:41][C:42](=[O:59])[CH2:43][NH:44][C:45]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([C:55]([F:56])([F:58])[F:57])[CH:53]=4)[N:48]=[CH:47][N:46]=3)[CH2:40]2)[CH2:4][CH2:3]1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)c1ncc(Br)s1
Agent: O=C1CCC2(CC1)OCCO2
Product: CC(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
Reaction of 4-hydroxy-4-(2-isopropylthiazol-5-yl)cyclohexanone (prepared by the reaction of 5-bromo-2-isopropylthiazole with 1,4-dioxaspiro[4.5]decan-8-one using the sequence described in Example 24 Step A-B) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1>CC(C#C)CO>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:4]=[C:5]([CH:6]([CH3:1])[CH2:7][OH:8])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Agent: C#CC(C)CO
Product: CC(CO)c1cc(C(=O)c2ccc(Cl)cc2)no1
Yield: 254.7 %

Procedure:
A solution of 8.7 g of 4-chlorophenylglyoxylohydroxamyl chloride in 16.7 g of 2-methyl-3-butyn-1-ol was refluxed under N2 for 3 hours. The resulting mixture was concentrated under reduced pressure to give 13.5 g of an oil. This material was purified by high pressure liquid chromatography with 5% ethyl acetate/CH2Cl2 used as an eluent to give 6.3 g (59%) of an oil which solidified on standing, m.p. 49°-51°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:16])(=[O:15])[CH2:12][C:11](=[O:17])[N:10]2[CH2:18][C:19]([O:21]CC2C=CC=CC=2)=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:15])(=[O:16])[CH2:12][C:11](=[O:17])[N:10]2[CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(CN1C(=O)CS(=O)(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Solvent: CO
Product: O=C(O)CN1C(=O)CS(=O)(=O)C[C@H]1c1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
A solution of benzyl [(3R)-3-(3,5-difluorophenyl)-1,1-dioxido-5-oxothiomorpholin-4-yl]acetate (71.7 mg, 0.145 mmol, 83%, from Step A) in MeOH (3 mL) was purged with nitrogen. The septum sealing the reaction vessel was briefly removed to allow introduction of Pd/C (˜14 mg, 10% Pd/C). The vessel was then purged with hydrogen from a balloon, before a fresh balloon of hydrogen was attached. After 30 minutes the hydrogen atmosphere was replaced with nitrogen. The mixture was then filtered through a pad of celite, washing with MeOH as needed. The filtrate was concentrated in vacuo to provide the title compound. MS: m/z=320 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH2:40][C@H:41]([N:46]([C:48](=[O:72])[C@H:49]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH3:47])[C:42]([O:44][CH3:45])=[O:43])[CH:34]=2)=[CH:29][C:28]=1[CH2:73][C@H:74]([NH:84][C:85]([O:87][CH2:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)=[O:86])[C:75]([O:77]CC[Si](C)(C)C)=[O:76])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH2:40][C@H:41]([N:46]([C:48](=[O:72])[C@H:49]([NH:64][C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:55])[CH3:47])[C:42]([O:44][CH3:45])=[O:43])[CH:34]=2)=[CH:29][C:28]=1[CH2:73][C@H:74]([NH:84][C:85]([O:87][CH2:88][C:89]1[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=1)=[O:86])[C:75]([OH:77])=[O:76])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.9 ml of 1N tetrabutylammonium fluoride in THF are added dropwise to a solution of 980 mg (0.922 mmol) of 2-(trimethylsilyl)ethyl (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl }-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}propanoate (Example 19O) in 20 ml of absolute DMF. After 60 min at RT, the mixture is cooled to 0° C., and ice-water is added. The mixture is immediately extracted with dichloromethane. The organic phase is dried over magnesium sulfate, concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(C(N[C@H](C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar procedure to that described in Example (1b), 820 mg of isomer B of N-[(R)-1-(3,5-difluorophenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 1.13 g of nickel chloride hexahydrate and 328 mg of sodium borohydride were reacted, to obtain 480 mg of isomer B of the title compound as a yellow oil.
Reaction SMILES: C([O-])(O)=O.[Na+:5].[O-]S([O-])=O.[Na+].[Na+].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[Na+:5].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc(Cl)nc1
Temperature: 80 °C

Procedure:
To a solution of 0.81 g of NaHCO3 (9.61 mmol) and 1.21 g of Na2SO3 (9.61 mmol) in water (10 mL) was added 1 g (4.7 mmol) of 6-chloro-pyridine-3-sulfonyl chloride. The reaction was heated at 80° C. for 3 h. The solvent was removed under reduced pressure. The filtrate was concentrated under reduced pressure to give 6-chloro-pyridine-3-sulfinic acid sodium salt.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:17])=[O:16])=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[C:7]=1[CH2:28][CH2:29][CH3:30])(=[O:5])[CH:2]([CH3:4])[CH3:3].[ClH:31]>CO.[Pd].C(Cl)(Cl)Cl>[ClH:31].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[C:7]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1N
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 3-isobutyryl-1-(2-nitrobenzyl)-2-propylindole-6-carboxamide (316 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon at 20° C. for 6 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol and chloroform 1:30) to give an oil which was dissolved in a mixture of chloroform (10 ml) and methanol (20 ml). To this solution was added 10% hydrogen chloride in methanol (0.9 ml), and the mixture was stirred at 20° C. for 1 hour and evaporated in vacuo. The residue was recrystallized from a mixture of methanol and diisopropyl ether to give 1-(2-aminobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide hydrochloride (415 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:30]1COCC1.C[Mg]Br.CCOCC>C(#N)C.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:30])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: C[Mg]Br
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
A 4 mL vial was charged with 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)benzenesulfonamide (synthesized according to general procedures F and G, 100 mg, 0.23 mmol) and 1.5 mL THF. The resultant slurry was cooled to −78° C. in a dry ice-acetone bath, 2.0 M methylmagnesium bromide in Et2O (350 μL, 0.70 mmol) was added dropwise, and the mixture was stirred for five hours. The reaction mixture was subsequently diluted with ˜2 mL of acetonitrile/H2O and purified by reversed phase HPLC to afford N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide: MS (ES) M+Na expected 466.0, found 466.0.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:33]=[CH:32][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([NH:28]C(=O)C)[CH:19]=[C:20]([C:22]5[O:23][C:24]([CH3:27])=[CH:25][CH:26]=5)[CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1>C(O)C.O.C(OCC)(=O)C>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:33]=[CH:32][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([CH:19]=[C:20]([C:22]5[O:23][C:24]([CH3:27])=[CH:25][CH:26]=5)[CH:21]=4)[NH2:28])[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1
Reactant: CC(=O)Nc1cc(-c2ccc(C)o2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(-c2cc(N)cc(-n3cnc4cc(-c5cnn(C)c5)ccc43)c2)o1
Yield: 92 %

Procedure:
A mixture of KOH (0.614 g, 10.94 mmol) and the compound of Example 73 (3.0 g, 7.29 mmol) in ethanol (5 ml) and water (2 ml) was heated at 60° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and was washed with water (50 ml) and brine (25 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum and the residue was purified by column chromatography to afford the product in 92% yield (2.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].O>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
trans-Cyclohexane-1,4-dicarboxylic acid dimethyl ester (34.2 g, 0.171 mol) was dissolved in 400 mL of anhydrous methanol and the solution brought to reflux. Slowly (dropwise), a solution of KOH (11.2 g, 0.171 mol, 85% purity) in dry methanol was added to the refluxing solution. The solution continued to reflux for 5 hours, and was then cooled and concentrated under reduced pressure to give a white solid. Water was added to dissolve most of the solid, and the aqueous mixture was washed with ether (3×) in a separatory funnel. The aqueous layer was brought to pH ˜6, the resulting white precipitate was collected via filtration and washed (1×) with a small amount of water. Air drying afforded trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1)OCC
Yield: 44 %

Procedure:
Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.4 g, 5.4 mmol) and methyl thiosalicylate (1.8 g, 10.9 mmol) were dissolved in toluene (8 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 6 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (10:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.96 g, 43%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[CH:4][C:3]=1[F:31].[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[CH:4][C:3]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)c(F)c3)nc2C#N)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1nn(-c2ccc(Br)c(F)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(1-(4-bromo-3-fluorophenyl)-3-cyano-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (493 mg, 1.0 mmol) in DCM (5 mL) at room temperature under argon was added 4 M HCl in dioxane (1.25 mL, 5.0 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 411 mg (100%) of 1-(4-bromo-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 393 (M+H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]2[O:24][CH2:23][CH2:22][N:21]3C([O:27][C:28]([C:30]([CH:31]=1)=[C:20]23)=O)=O)([O-:16])=[O:15].Cl>CN(C)C(=O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]2[CH2:22][CH2:23][O:24][C:19]3[C:20]2=[C:30]([CH:31]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=3)[C:28]=1[OH:27])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n2c3c(cc([N+](=O)[O-])cc13)OCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc([N+](=O)[O-])cc3c2n(c1=O)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of diethyl malonate (0.54 g) in N,N-dimethylacetamide (10 ml) was added sodium hydride (60%; 135 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 3,4-dihydro-7-nitro-2H-1,4-benzoxazine-4,5-dicarboxylic anhydride (0.73 g), and the mixture was stirred at 120° C. for 2 hours. The mixture was poured into diluted HCl, and the precipitates were collected and washed with water to afford yellow crystals of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-9-nitro-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.85 g).
Reaction SMILES: [C:1]([NH2:11])(=[S:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:10][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCc1csc(/C=C/c2ccccc2)n1
Yield: 55.6 %

Procedure:
A mixture of thiocinnamamide (11.7 g), 1,3-dichloroacetone (9.10 g) and ethanol (145 ml) was heated for one hour under reflux. The reaction mixture was poured onto ice-water, neutralized with potassium carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:5, v/v), 4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole (9.40 g, 66%) was obtained. Recrystallization from diethyl ether-hexane gave colorless plates, mp 88-89° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of Compound 68 (0.8 g, 2.43 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (628 mg g, 7.29 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was then removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 0.9 g (98%) of yellow solids. M.P. 156° C. 1H NMR (DMSO-d6): δ 2.94 (m, 4H), 3.55 (m, 4H), 5.47 (s, 2H), 7.19 (m, 2H), 7.24 (m, 1H), 7.31 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.64 (dd, J=2.6, 8.9 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H). EIMS m/z 379 (M+1).
Reaction SMILES: [CH2:1]1[N:9]2[C:4](=[N:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20]>>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:18][CH3:17])=[O:20])[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][C:4]2=[N:5]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(O)cc21
Product: COC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
The procedure is as in Step B of Example 1, using the compound obtained in Step A of Example 1 and [3-(methoxycarbonyl)phenyl]boronic acid as starting materials.