Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH+]1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]=1[CH3:30])=[O:10].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:16]1[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]([CH2:30][C:32]2[NH:31][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:9]([O:8][CH3:7])=[O:10]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: c1c[nH]cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(Cc2ncc[nH]2)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
Pyridinium perbromide hydrobromide (5.6 g, 17.5 mmol) was added to a stirred ice-cooled solution of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid dimethylester (5.55 g, 15 mmol) and pyridine (2 g) in methylene dichloride (80ml). The solution was stirred at ice temperature for 40 minutes then washed with ice cold water (1×100 ml). The organic phase was separated and imidazole (6.8 g, 0.1 mol) added followed by anhydrous Na2SO4. After drying for 20 minutes the solution was filtered to remove NaSO4, evaporated and the residue heated on a steam bath for 40 minutes. The residue was then dissolved in EtOAc, washed with water (2×50 ml), dried, evaporated and crystallised from methyl acetate (15 ml) to give the crystalline title compound (3.34 g). This was suspended in isopropyl alcohol/methyl acetate (2:3 v/v)and acidified with ethanolic HCl to give the hydrochloride salt on cooling, m.p. 167°-170° C.
Reaction SMILES: [CH2:1](Br)[CH3:2].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]4[CH:28]=[CH:29][C:30]5[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=5[CH:37]=4)=[O:26])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]4[CH:28]=[CH:29][C:30]5[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=5[CH:37]=4)=[O:26])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCBr
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
Ethyl bromide (12.8 μL, 0.17 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (75 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by potassium carbonate (28.1 mg, 0.20 mmol, 1.3 eq). After 3 hours stirring at 60° C., solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-ethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white powder (15 mg, 18% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:12](=[O:14])[CH2:11][C@H:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@H]1CCc2ccccc2C1
Yield: 72 %

Procedure:
Colorless crystals of 1-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester were prepared in the same manner as in Reference Example 1, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively yield: 72%).
Reaction SMILES: N1([O:10][C:11](=O)[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:20][C:18]1[CH:19]=[C:14]([CH:13]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)[C:11]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:10])[CH:15]=[C:16]([CH3:21])[CH:17]=1
Reactant: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Reactant: C1COCCN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: Cc1cc(C)cc(C=C(C(=O)N2CCOCC2)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Yield: 95.8 %

Procedure:
To a suspension of 48 (116 mg, 0.2 mmol) in dichloromethane (5 mL) at room temperature was added morpholine (87 μL, 1 mmol). Solution became clear. After 10 min the mixture was treated with 10% citric acid (4 mL). The dichloromethane layer was dried (MgSO4) and directly loaded onto a column which was eluted with hexanes:ethyl acetate (2:3) to yield 50 (104 mg, 86%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.85 (s, 1H), 6.72 (s, 2H), 6.61 (s, 1H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.59 (bs, 8H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.13 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH2:32])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>C(O)C>[OH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[S:33])[NH:32][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(C)CCN
Reactant: CC(CN1CCC[C@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@H]1CO)c1ccccc1S2
Reaction time: 16 h

Procedure:
3-Methylbutylamine (1.74 cc) is added to a solution of 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (1.20 g) in absolute ethanol (20 cc). The mixture is brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is diluted with ethyl acetate (100 cc), washed with distilled water (2×50 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) before being purified by chromatography on a column (height: 14.5 cm; diameter: 2.8 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa) eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 65:35 (1.2 liters) and 35:65 (1.2 liters), collecting 60-cc fractions. Fractions 5 to 13 are combined and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (0.64 g) in the form of a yellow resin.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH3:22])([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12](=[O:14])[N:13]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[C:23]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][C:11]2([CH3:22])[S:10][C:9]([NH:8][C@H:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][CH2:5]4)=[N:13][C:12]2=[O:14])[CH2:17][CH2:18]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(CC2CCNCC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-5-(piperidin-4-ylmethyl)thiazol-4(5H)-one (130 mg, 0.41 mmol), acetic anhydride (Aldrich, 83 mg, 0.81 mmol) and diisopropylethylamine (157 mg, 1.22 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for ca. 18 h. Brine was then added, and the mixture was extracted with CH2Cl2 (4×60 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-3.5% MeOH in CH2Cl2) afforded the title compound as a colorless thin film (116 mg). MS (ESI, pos. ion) m/z: 364 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.C([O:17][C@@H:18]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[CH2:29][S:28][C@H:19]1[O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](Br)[CH:26]=1)(=O)C>>[O:20]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:26]=1)[C@@H:19]1[S:28][CH2:29][C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:18]1[OH:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)c(OC)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2,4-dimethoxyphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2,4-dimethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=71%).
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:41][O:42][CH:43]([F:45])[F:44])[C:38]([OH:40])=O)[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)=O.Cl.[F:51][CH2:52][C@H:53]1[NH:56][C:55](=[O:57])[C@H:54]1[NH2:58]>C(N(CC)CC)C.C(Cl)Cl>[F:51][CH2:52][C@H:53]1[NH:56][C:55](=[O:57])[C@H:54]1[NH:58][C:38](=[O:40])[C:37]([C:35]1[N:36]=[C:32]([NH:31][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:33][CH:34]=1)=[N:41][O:42][CH:43]([F:45])[F:44]
Reactant: N[C@@H]1C(=O)N[C@@H]1CF
Reactant: O=C(O)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CF)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
0.339 g of tosyl chloride were added to a mixture of 0.914 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-difluoromethoxyimino-acetic acid, 7 ml of acetone and 0.25 ml of trietylamine and the mixture was stirred for 50 minutes after which a solution of 0.23 g of cis 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride, 7 ml of methylene chloride and 0.45 ml of triethylamine was added thereto. The mixture was stirred for 90 minutes and was evaporated to dryness. The residue was added to methylene chloride and water and then 3 ml of 10% sodium bicarbonate solution. The mixture was stirred and the decanted aqueous phase was extracted with methylene chloride. The combined organic phases were dried and evaporated to dryness. The residue was taken up in ethanol and the solution was cooled and vacuum filtered. The crystals were rinsed with ethanol, then with ether and dried to obtain 0.537 g of racemate of the syn isomer of cis 4-fluoromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-difluoromethoxyimino-acetamido]-2-oxo-azetidine. STEP B: Racemate of the syn isomer of cis 4-fluoromethyl-3-[2-(2-amino-4-thiazolyl)-2-difluoromethoxyimino-acetamido]-2-oxo-azetidine-1-sulfonic acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:10])=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
10.0 g (69.9 mmol) of crude 4-chloro-2-methoxypyridine obtained in Step (d) was dissolved in 100 ml of dimethylformamide, and 37.2 g (279 mmol) of N-chlorosuccinimide was added, followed by stirring at room temperature for 12 hours. 400 ml of water was added to terminate the reaction, followed by extraction with ethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 9.10 g (crude yield: 73%) of crude 4,5-dichloro-2-methoxypyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH2:17][CH:18]([O:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])[CH:14]=[CH:15][CH:16]=2)[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.O.[OH-].[Li+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH2:17][CH:18]([O:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: CCOC(Cc1cccc(NCCCN2CCOc3ccccc32)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1cccc(NCCCN2CCOc3ccccc32)c1)C(=O)O
Yield: 60.7 %

Procedure:
Methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (350 mg, 1 eq, 0.87 mmol) obtained in example 13, was hydrolyzed using lithium hydroxide monohydrate (110 mg, 3 eq, 2.64 mmol), in methanol-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using methanol and chloroform to afford the title compound (203 mg, yield 61%) as viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[N:12]=[C:11]([CH2:20][N:21]2[C:25](=[O:26])C3=CC=CC=C3C2=O)[C:10]=1C(OCC)=O.O.NN>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[N:12]=[C:11]2[CH2:20][NH:21][C:25](=[O:26])[C:10]=12
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(C)c(C(=O)OC)c1-c1cccc(Cl)c1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(C)nc2c(c1-c1cccc(Cl)c1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.9 g (3.6 mmol) of the compound from Example III are suspended in 100 ml of ethanol and treated with 0.5 ml (10 mmol) of hydrazine hydrate. After stirring at RT for 30 min a clear solution is formed. After reflux for 30 min a white precipitate is deposited. The mixture is allowed to cool and the precipitate is filtered off with suction. The solid is purified by chromatography (methylene chloride/ethyl acetate 20+1) and finally recrystallized from ethanol. 0.56 g (44%) is obtained.
Reaction SMILES: [C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:29])([F:28])[F:27])[OH:25])([O:3]CC)=[O:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:28])([F:29])[F:27])[OH:25])([OH:3])=[O:2]
Reactant: CCOC(=O)C1C(c2cccc(C#N)c2)C2=C(CCCC2=O)NC1(O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
A suspension of 3-carboethoxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5 (1H)-quinolone (3.39 g) in ethanol (20 ml) and water (20 ml) was treated with lithium hydroxide monohydrate (0.75 g). The mixture was heated at 90° C. for 1.5 hours, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed (water and brine), dried, filtered, and evaporated to yield a foam which was purified by chromatography (ethyl acetate and ethyl acetate/methanol, 3:1) to afford 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5 (1H)-quinolone (2.67 g) as a pale yellow foam; MS: m/z =381(m).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH2:16][CH:17]=[CH2:18])([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:6][CH:7]=[CH2:8])C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH2:6]([C:5]([C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)([CH2:16][CH:17]=[CH2:18])[CH2:4][OH:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)(C(=O)OCC)c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=CCC(CO)(CC=C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of crude 2-allyl-2-(4-bromo-phenyl)-pent-4-enoic acid ethyl ester (2.64 g) in CH2Cl2 (40 mL) at 0° C. is treated with diisobutylaluminum hydride (1.0 M toluene, 17.5 mL) dropwise for 8 min, warmed to room temperature, and stirred for 45 min. The reaction mixture is cooled to 0° C., quenched with 1M tartaric acid (25 mL), and stirred overnight. The organic layer is separated and the aqueous layer is extracted with CH2Cl2 (3×25 mL). The combined organic extracts are dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 50% EtOAc to provide 1.319 g (56%-2 steps) of the title compound as a light yellow oil. 1H NMR (CDCl3): δ 7.47-7.43 (m, 2H), 7.23-7.19 (m, 2H), 5.59 (ddt, J=17.1, 10.2, 6.7 Hz, 2H), 5.09-5.01 (m, 4H), 3.76 (d, J=6.8 Hz, 2H), 2.48 (dd, J=14.1, 6.8 Hz), 2.42 (dd, J=13.6, 7.2 Hz, 2H), 1.29 (t, J=6.1 Hz).
Reaction SMILES: [CH2:1]([C:3]([CH2:22]C)([CH3:21])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:8]=2[N:9]=1)C>C(O)C.[Pd]>[CH3:1][C:3]([CH3:21])([CH3:22])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)C=Cc1ccc2oc(CC(C)(CC)CC)nc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2oc(CC(C)(C)C)nc2c1
Reaction time: 6 h
Yield: 92.4 %

Procedure:
A solution of ethyl 3-[2-(2,2-diethylpropyl)benzoxazol-5-yl]propenoate (0.500 g, 0.00174 mol) in ethanol (30 ml) was hydrogenated at 4.0 bar (4×105 Nm−2) over 5% Pd on C for 4 hours at room temperature and then at 5.5 bar (5.5×105 Nm−2) for 6 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 3:97, to give ethyl 3-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propanoate (0.465 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][N:15]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:16][CH2:17][CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O.C(Cl)Cl>[OH:21][CH2:20][C:19]([N:15]1[CH2:16][CH2:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)COC(C)=O)C3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)CO)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyridin-3-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 70, Step 3, 105 mg) and anhydrous potassium carbonate (67 mg) in methanol (4.8 mL) is stirred under N2 at ambient temperature for 2 hrs and is then neutralized with hydrochloric acid (1 M), diluted with water (10 mL) and methylene chloride (40 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which is then chromatographed on silica gel (70-230 mesh, 15 g), eluting with methanol/methylene chloride (5/95). Pooling and concentration of those fractions with an Rf =0.30 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 188-190° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[N:18][C:17]([N:20]([CH2:28][C:29]4([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:32][CH2:31][CH2:30]4)C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:7][C:4]1[N:3]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[N:18][C:17]([NH:20][CH2:28][C:29]4([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:30][CH2:31][CH2:32]4)=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C)n1-c1ccc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)nc1
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
To a 20 dram vial was added tert-butyl 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (245 mg, 0.5 mmol) and a 5 mL of a 50% mixture of TFA and CH2Cl2. The reaction was stirred for 15 min, concentrated, and then diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (60% EtOAc/hexanes) to give 91 mg (46%) of 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine. This product was transferred to a 100 mL round bottom flask to which was added hydroxylamine hydrochloride (270 mg), triethylamine (5 mL), and ethanol (20 mL). The reaction mixture was heated to reflux overnight and then concentrated, diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 28 mg of 6-(5-aminopyridin-2-yl)-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine, m/z=351.2 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12]>CO.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:13])=[C:4]([CH3:12])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1N(C)C
Yield: 72.9 %

Procedure:
A solution of dimethyl-(2-methyl-4-nitro-phenyl)-amine (0.49 g, 2.74 mmol) in methanol (10 ml) was hydrogenated over 10% Pd/C at 30 psi until no further gas uptake was observed. The reaction mixture was then filtered over celite and the filtrate evaporated to yield 4-amino-2-methyl-N,N-dimethyl aniline (0.3 g, 73%).