Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][O:51][CH:52]=2)O1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:48]3[CH:49]=[N:50][O:51][CH:52]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4cnoc4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 14.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (57.5 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino propionic acid.
Reaction SMILES: [ClH:1].CC(C)(C)C(O[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1)=O>O1CCOCC1>[ClH:1].[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)C(=O)ON[C@H]1CSc2cccc(F)c2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2cccc(F)c2NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 mL of a solution of hydrogen chloride in dioxane (4 M) are added to a 25 mL round-bottomed flask containing 68.4 mg of 50 (0.219 mmol). The mixture is stirred for 4 hours at room temperature under argon. After concentrating the reaction medium to dryness, 51 mg of amine 51 (yellow solid) are thus obtained in the form of the hydrochloride.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[C@@H:14]2[CH2:25][CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:28])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO.OO.S(=O)(=O)(O)O>O>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[C@@H:14]2[CH2:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[OH:28])=[CH:11][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
5.00 g (9.6 mmol) (3R,4S)-4-[4-(tert-butyl-dimethyl-silanyl-oxy)-phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxo-propyl]-azetidin-2-on was solved in 9.6 ml water-free dichloromethane, and then 1.92 ml (0.96 mmol) (R)-o-tolyl-CBS-oxazaborolidine 0.5 M-toluenic solution was added. The mixture was cooled to a temperature between 0 and −5° C., and at this temperature a dichloromethanic solution of 1.9 ml 1.0 M borane-dimethyl was added for 6 h. The reaction mixture had been stirred at this temperature until the spot of the starting keton disappeared according to the thin-layer chromatographic investigation. Then 10 ml methanol, 0.5 ml 5% hydrogen-peroxide solution, and 10 ml 2M sulphuric acid were added. Having been stirred the mixture for 0.5 h, the phases were separated. The organic phase was washed with 50 ml 2N sulphuric acid and then 50 ml 5% sulphite-solution. The solution was dried on anhydrous sodium-sulphate, filtered and evaporated.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:52])[O:28][C@H:29]([CH3:51])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3C4C=CC(C(=O)C)=CC=4N=[C:38]3[CH2:49][CH3:50])=[CH:33][CH:32]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:52])[O:28][C@H:29]([CH3:51])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]=4[N:9]=[C:38]3[CH2:49][CH3:50])=[CH:35][CH:36]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][NH:22][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.00 g), 1-amino-2-methylpropan-2-ol (0.55 g), 1H-1,2,3-benzotriazol-1-ol (0.50 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.71 g) at 0° C., and the mixture was stirred at 60° C. overnight. Water was added to the reaction mixture and the mixture was acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.77 g, yield 65%) as colorless crystals. melting point>234° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C(N1C2C=C(C3C=C4C=CNC4=NC=3)C=C(C(OC)=O)C=2C=N1)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH2:74][CH2:75][C:76]1[C:77](=[O:84])[NH:78][C:79]([CH3:83])=[CH:80][C:81]=1[CH3:82]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:74][CH2:75][C:76]2[C:77](=[O:84])[NH:78][C:79]([CH3:83])=[CH:80][C:81]=2[CH3:82])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylic acid, 1 (6.5 g, 21.88 mmol) in DCM (250 mL) was added EDC.HCl (5.01 g, 26.23 mmol), HOBt (3.545 g, 26.20 mmol) followed by diisopropyl ethyl amine (14.11 g, 109.37 mmol) and stirred at room temperature for 15 min. To the resulting mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (3.32 g, 21.84 mmol) followed by DMAP (catalytic amount) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (300 mL) and washed with 1N HCl solution (250 mL), saturated NaHCO3 solution (250 mL) and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (100 mL), filtered, and dried to afford 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide as an off white solid (5.5 g, 58%). H NMR (DMSO-d6, 400 MHz): δ 1.412 (d, J=6.4 Hz, 6H), 2.112 (s, 3H), 2.215 (s, 3H), 2.383 (s, 3H), 4.319 (d, J=5.2 Hz, 2H), 4.907-4.972 (m, 1H), 5.864 (s, 1H), 7.129 (d, J=1.2 Hz, 1H), 8.011 (d, J=1.2 Hz, 1H), 8.473 (t, J=5 Hz, 1H), 11.479 (brs, 1H). LCMS (ES+): 431.02 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:11]=[C:10]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[CH:8][N:7]=1)([CH3:5])[CH3:4].Br[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[F-].[Cs+]>CN(C=O)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH3:1][O:2][C:3]([C:6]1[CH:11]=[C:10]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=3)[N:28]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C(C)(C)OC)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(C)(C)c1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 120 °C

Procedure:
2-(1-methoxy-1-methyl-ethyl)-4-tributylstannanyl-pyridine 13AO (0.1 g, 0.24 mmol), 3-bromo-5-nitro-1-trityl-1H-indazole 1AJ (0.12 g, 0.24 mmol), CsF (0.08 g, 0.53 mmol), [Pd2(dba)3] (5 mg, 0.005 mmol), Pd[P(t-Bu)3)2, and CuI (4 mg, 0.024 mmol) in DMF (2 ml) was degassed for 5 minutes. Then it was heated at 120° C. for two hours. Cooled to room temperature and diluted with EtOAc (10 ml). It was then filtered on a celite pad. Filtrate was washed with water (3 ml) and the organic extracts were dried over MgSO4. It was filtered again on a celite pad and concentrated. The residue was purified on silica gel eluting with 1/3 EtOAc/Hexane to give the desired product 3-[2-(1-methoxy-1-methyl-ethyl)-pyridin-4-yl]-5-nitro-1-trityl-1H-indazole 14AO (0.05 g, 39%).
Reaction SMILES: C(OC(=O)CSC1S[C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28]C2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[O:14])=NC=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC)=C(F)C=2)CCCC1.C([O:79][C:80](=[O:89])[CH:81]([S:83][C:84]1[S:88][CH:87]=[N:86][CH:85]=1)N)C>>[CH:25]1([N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:10])[C:87]2[S:88][C:84]([S:83][CH2:81][C:80]([OH:79])=[O:89])=[CH:85][N:86]=2)[CH2:26][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C(N)Sc1cncs1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC)c(F)c2)s1
Agent: COc1ccc(NCC2CCCC2)cc1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)cc1F

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-fluoro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanylacetic acid ethyl ester.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]1>>[NH:1]([C:5]1[S:6][C:7]([C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]2)=[O:12])=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COCC1CCCNC1
Reactant: N=C(N)Nc1ncc(C(=O)O)s1
Agent: Cl
Product: CCOC(=O)COCC1CCCN(C(=O)c2cnc(NC(=N)N)s2)C1

Procedure:
In the same manner as described in Example 4, from 2-guanidino-thiazole-5-carboxylic acid and ethyl (RS)-(piperidin-3-ylmethoxy)-acetate hydrochloride there is obtained ethyl (RS)-[1-(2-guanidino-thiazole-5-carbonyl)-piperidin-3-ylmethoxy]-acetate, m.p. 156° C., MS: 370 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH3:10]>CO>[CH2:6]([O:11][C:12]1[N:13]=[N:14][C:15]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:16][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCS
Reactant: CCCCCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCCCC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 75 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 10.03 g(0.05 mol) of 3-(n-pentyloxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow needle crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:18]#N)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(=[O:40])C.[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:40])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Temperature: -15 °C

Procedure:
To a solution of 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbonitrile (1.000 g, 3.537 mmol) in toluene (3.537 mL, 3.537 mmol) at −78° C. was added with stirring, DIBAL-H, 1 M sol. in Toluene (3.891 mL, 3.891 mmol) and the mixture was allowed to warm to −15° C. with stirring over 13 h. The mixture was cooled in ice water bath, quenched by addition of 1 N aq. HCl (14.15 mL, 14.15 mmol), and stirred for 2 h. To the mixture was added potassium acetate (3 g, 30.56 mmol, 8.6 eqv) and the mixture extracted with ethyl acetate (50 mL×2). The combined organic layers were washed saturated NaHCO3 (50 mL×1), brine (50 mL x), filtered, and concentrated at reduced pressure to give a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbaldehyde as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (1H, s), 9.11 (1H, s), 8.44 (1H, dd, J=9.1, 6.4 Hz), 7.92 (1H, dd, J=10.3, 2.6 Hz), 7.72-7.78 (1H, m), 7.50-7.66 (4H, m); LC-MS (ESI) m/z 286.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]2[CH:19]=1)(=[O:3])[CH3:2]>C(OC(OC(C)(C)C)N(C)C)(C)(C)C>[CH3:6][N:7]([CH3:19])/[CH:8]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]2[CH:19]=1)=[O:3]
Reactant: CCOC(=O)CC1CNC(=O)c2cc(C(C)=O)cn21
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Product: CCOC(=O)CC1CNC(=O)c2cc(C(=O)/C=C/N(C)C)cn21
Temperature: 110 °C
Reaction time: 6 h

Procedure:
The intermediate ethyl (7-acetyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate 1 g (3.78 mmol) was dissolved in 5 ml of N,N-dimethylformamide ditert butyl acetal and stirred at 110° C. for 6 hours. The reaction mixture was concentrated and then partitioned between H2O and DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:29])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:30])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)([CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To a solution of 3-methyl-3-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (20 g, 49.8 mmol) in CH2Cl2 (240 mL) and MeOH (120 mL) was added tetra-n-butylammonium tribromide (24.02 g, 49.8 mmol) in portions and the reaction mixture was stirred for 4 h. Saturated aqueous Na2S2O3 solution (100 mL) and saturated aqueous NaHCO3 solution (50 mL) was added to quench the reaction. The aqueous solution was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 20-50% EtOAc in petroleum ether) to give 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (20 g, 84%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.68 (brs, 1H), 7.14 (s, 1H), 4.63-4.57 (m, 1H), 4.56-4.45 (m, 2H), 4.34 (s, 1H), 4.08-4.01 (m, 2H), 3.96-3.90 (m, 2H), 1.62 (s, 3H), 1.51-1.45 (m, 12H). LCMS (Table 1, Method 25) Rt=0.867 min; MS m/z: 482 [M+H+2]+& 480 [M+H]+. SFC (Table 1, Method 31) Rt=5.402 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Yield: 91.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-phenylphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt. %, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.7 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)[CH3:26]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and iodoethane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as white needles (61%), m.p. (EtOAc/hexanes) 138-142° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.29 (s, 1H), 8.52 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.45 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H). Anal. Calcd for C16H16FIN2O3: C, 44.7; H, 3.8; N, 6.5. Found: C, 45.0; H, 3.6; N, 6.4.
Reaction SMILES: [N:1]#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3C=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[N:1]=[C:18]([NH2:20])[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2csc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Reactant: N#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(c2csc(Cn3ncc(N)n3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4-nitro-1H-pyrazole (115 mg, 0.39 mmol), iron powder (65 mg, 1.16 mmol) and NH4Cl (106 mg, 1.97 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. The filtrated was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil: TLC: rf (EA)=0.63. LC-MS-conditions 02: tR=0.76 min; [M+H]+=267.09.
Reaction SMILES: [F:1][C:2]([CH3:17])([CH3:16])[CH:3]([NH:8]C(=O)OC(C)(C)C)[C:4]([NH:6][CH3:7])=[O:5].[ClH:18].C(OCC)C>ClCCl>[ClH:18].[NH2:8][CH:3]([C:2]([F:1])([CH3:17])[CH3:16])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNC(=O)C(N)C(C)(C)F
Reaction time: 2 h

Procedure:
Intermediate 66B (306 mg, 1.23 mmol) was dissolved in dichloromethane (5 mL) and was treated with 2M hydrochloric acid solution in diethyl ether (6.18 mL, 12.4 mmol). The resulting mixture was stirred for 2 hour then was concentrated under reduced pressure. The oily residue was dried overnight in a 40° C. vacuum oven to provide intermediate 66C as an off-white solid in quantitative yield. 1H-NMR (400 MHz, (CD3)2SO) δ:1.38 (d, 3H), 1.43 (d, 3H), 2.67 (d, 3H), 3.97 (d, 1H), 8.51 (broad s, 3H), 8.76 (q, 1H).