Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:56][CH2:57][CH2:58][C:59]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[NH:61][CH:60]=1>CCOC(C)=O>[NH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:59]([CH2:58][CH2:57][NH:56][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])=[CH:60]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.19 g (1.41 mmol) of 1-hydroxybenzotriazole hydrate in 20 mL of anhydrous EtOAc (under a N2 atmosphere) was treated in one portion with 0.34 g (1.65 mmol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 2 hours, treated with 0.26 g (1.62 mmol) of tryptamine, and stirred for an additional 18 hours. The precipitated solid was filtered, washed with a small amount of fresh EtOAc, and discarded. The filtrate was diluted to 150 mL with EtOAc and washed with 5% aqueous citric acid (3×150 mL), brine (1×150 mL), 5% aqueous NaHCO3 (3×150 mL), and brine again. The organic layer was dried (Na2SO4) and evaporated (vacuum) to a tan solid. The residue was chromatographed (E. Merck prepacked Lobar column, 37×440 mm, eluted with 2% MeOH in CH2Cl2) to yield the purified product as a white foam, 0.32 g (47%); 1H NMR (CDCl3) δ 1.46-1.92 (17H, m), 2.83 (2H, t, J 7 Hz), 3.23 (1H, d, J 15 Hz), 3.40 (1H, d, J 15 Hz), 3.52 (2H, m), 4.78 (1H, m), 6.82 (1H, m), 7.06-7.58 (8H, m), 7.96 (2H, br s).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].[C:38](Cl)(=[O:46])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[C:40]1([O:39][C:38]([N:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:8](=[O:9])[C:7]5[C:6]([F:24])=[CH:5][CH:4]=[C:3]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:2]=5[F:1])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)[CH:23]=[N:22]2)=[O:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cn[nH]c4)cc23)c1F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C(=O)Oc5ccccc5)c4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
In a reaction vial, propane-1-sulfonic acid {2,4-difluoro-3-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (23, 7 mg, 0.02 mmol) is dissolved in 0.05 mL of acetonitrile and potassium carbonate (4 mg, 0.03 mmol) and carbonochloridic acid, phenyl ester (24, 0.0025 mL, 0.02 mmol) are added and the reaction is stirred at room temperature overnight. The reaction is concentrated under vacuum and the resulting material is purified by reverse phase HPLC to provide the desired compound (P-1016, 0.7 mg).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:15])(=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[SH:9].[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>O>[OH:24][C:18]1[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]2[S:9][C:8]3[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:15])[C:20]=2[CH:19]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Cc1cccc(O)c1C
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)cc2c(=O)c3ccccc3sc2c1C
Reaction time: 0.08 h

Procedure:
Concentrated sulphuric acid (300 ml) was slowly added to thiosalicylic acid (30.9 g) and the mixture was stirred for 5 minutes to ensure thorough mixing. To the stirred mixture was added slowly over a period of 30 minutes 2,3-dimethyl-phenol (138 g). After the addition, the mixture was stirred at room temperature for 1 hour, and then at 80° C. for 2 hours, after which it was left to stand at room temperature overnight. The resulting mixture was poured carefully with stirring into 10 times its volume of boiling water after which it was boiled for a further five minutes, cooled, and filtered. The residue was recrystallised from acetone to give 2-hydroxy-3,4-dimethyl-thioxanthone as a yellow product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH2:71])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH:71][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:20])=[N:64][CH:63]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: Cc1ccc(NC(=O)c2ccc(NCCN)nc2)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(NCCNC(=O)c3c(C)[nH]c(/C=C4\C(=O)Nc5ccc(F)cc54)c3C)nc2)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-methylphenyl)-6-(2-aminoethylamino)nicotinamide (299 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (420 mg, 74%) as a yellow solid. LC-MS (m/z) 568 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[C:7]1([CH3:17])[CH:12]=[CH:11]C(S(O)(=O)=O)=C[CH:8]=1>C1C=CC=CC=1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH:4]([O:5][CH2:11][CH:12]=[C:7]([CH3:8])[CH3:17])[CH2:3][C:2]([CH3:6])=[CH2:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CC=O
Solvent: c1ccccc1
Product: C=C(C)CC(OCC=C(C)C)OCC=C(C)C

Procedure:
2.67 parts of 3-methylbutenal, 5.5 parts of pulenol, 0.001 part of p-toluenesulfonic acid, and 20 vol. parts of benzene were charged to the same rectification column employed in Example 53, and reacted at 90° C. for 2 hours, while the volume of the system was maintained constant by feeding 10 vol. parts of fresh benzene per hour and distilling 10 vol. parts per hour of the water-containing benzene off from the system. Thus 100% of 3-methyl-3-butenal-1 was converted and 3-methyl-3-butenal-1-dipulenylacetal was obtained with the selectivity of 80.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH:19]([CH2:26]CCO)[C@@:18]([CH2:40][F:41])([C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=2F)[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1C[O:47][CH2:46]C1.CN(C=O)C>>[F:41][CH2:40][C@@:18]12[C:30]3[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=3[O:47][CH2:46][CH2:26][C@@H:19]1[S:20](=[O:24])(=[O:25])[C:21]([CH3:23])([CH3:22])[C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:15])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:17]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(CCCO)S(=O)(=O)C1(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc([N+](=O)[O-])ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-2-(3-hydroxypropyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (1.95 g, 3.30 mmol) in THF:DMF (10:1, 44 mL) at 0° C. was added NaH (264 mg, 6.60 mmol, 60% suspension in mineral oil) portion wise. The reaction mixture was stirred at RT for 1 h and an additional amount of NaH was added (264 mg, 6.60 mmol, 60% suspension in mineral oil). The reaction mixture was stirred at RT for 1 h, quenched with satd. aqueous NH4Cl, and diluted with EtOAc. Water was added to dissolve solids, and the organic layer was separated. The organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using a 0-25% EtOAc/hexanes gradient to afford the less polar cis-isomer, tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (647 mg, 34%) as a white solid, LC/MS (ESI+) m/z=594 (M+Na), and the more polar trans-isomer, tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (594 mg, 31%) as a white solid. LC/MS (ESI+) m/z=594 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=3)[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4([C:34]5[CH:35]=[CH:36][C:37]([N:40]6[C:11](=[O:13])[C:4]7=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=[C:5]7[C:6]6=[O:8])=[CH:38][CH:39]=5)[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[C:28]5[C:33]4=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:19][CH:20]=3)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc(O)cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 4-hydroxyphthalic acid (4.0 g, 22 mmol), 9,9-bis(4-aminophenyl)fluorene (3.5 g, 10 mmol), and 40 ml of acetic acid was stirred and heated under reflux for 48 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with acetic acid (2×25 ml) to provide the title compound as a colorless powder having a melting point greater than 300° C. (3.4 g, 53.1% yield). The nuclear magnetic resonance and infrared spectrum were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([F:19])[CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C.FC1C(F)=CC=CC=1B(O)O>C1COCC1>[F:19][C:4]1[CH:3]=[C:2]([B:25]([OH:28])[OH:26])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCOc1ccc(Br)cc1F
Agent: OB(O)c1cccc(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
Quantities: compound 12 (9.84 g, 0.03 mol) in anhydrous THF (120 ml), n-butyllithium (12.5 ml, 2.5M in hexane, 0.031 mol), trimethyl borate (6.24 g, 0.06 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 2.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: Cc1cc(Br)ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(Br)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Bromo-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-bromo -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-bromo-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6](/[CH:13]=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[C:4]([C:20]([F:21])([F:22])[F:23])=[CH:5][C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:8]=1[C:9]([F:10])([F:12])[F:11]
Reactant: CCOC(=O)/C=C\c1cc(C(F)(F)F)c(OC)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cc(C(F)(F)F)c(OC)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl (2Z)-3-[4-methoxy-3,5-bis(trifluoromethyl)phenyl]prop-2-enoate (280 mg, 0.82 mmol, 1.00 equiv), Palladium carbon (0.28 g), methanol (10 mL). The mixture was subjected to 2 atm of H2 and stirred overnight at 25° C. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.28 g (99%) of ethyl 3-[4-methoxy-3,5-bis(trifluoromethyl)phenyl]propanoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C14H14F6O3, 345.1 (M+H). found 345.1.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ClC(OCC)=O.C(N(CC)CC)C.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]=[CH:9][C:10]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:12])=[CH:13][CH:14]=1
Reactant: CC(C)N
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
The precursor 4-(4-chlorophenyl)-N-(1-methylethyl)-4-oxo-2-butenamide (7A) was prepared by the procedure shown in the previous examples by treating 1A with ethyl chloroformate and triethylamine in toluene at 0°, then adding at 0° a solution of isopropylamine in toluene. 7A was obtained as a solid, m.p.: 162°-163°. It was converted to 7 by treatment with hydrogen peroxide, by the procedure described in Example 1, 7 being obtained as a solid, m.p.: 128°-129°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[S:30]([CH3:29])(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1

Procedure:
Intermediate 29 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 481. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H) 8.39 (d, 1H) 8.2 (d, 1H) 7.6 (d, 1H) 7.5 (s, 1H), 7.3 (m, 3H), 7.0 (d, 1H), 6.9 (d 1H), 6.8 (d, 2H), 6.5 (d, 2H), 4.6 (s, 2H), 3.6 (m, 4H), 2.8 (t, 2H), 1.2 (d, 3H).
Reaction SMILES: [Cl-].[Li+].[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](I)[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>CN(C=O)C>[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:20]=[CH2:21])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1N
Temperature: 90 °C

Procedure:
A 50 ml two-neck round bottom flask was filled with argon gas and the solution of tetrakis(triphenyl phosphine)palladium(0) (123.7 mg, 0.107 mmol, 0.06 eq.) and lithium chloride (211.9 mg, 4.998 mmol, 2.8 eq.) in DMF was put into the flask. To the solution was added (4-amino-3-iodobenzyl) carbamic acid t-butyl ester (621.4 mg, 1.875 mmol, 1 eq.) and tributylvinyltin (782.5 mg, 2.678 mmol, 1.5 eq.). The mixture solution was heated to 90° C. to reflux for one night. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and evaporated. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=3/1) to yield brown liquid.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]1.[CH:9]1([CH2:14][C@H:15]([CH2:19][N:20]([CH:29]=[O:30])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16](F)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[CH:9]1([CH2:14][C@H:15]([CH2:19][N:20]([CH:29]=[O:30])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([N:1]2[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)C1CC=NN1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
4,5-Dihydro-1H-pyrazole-5-carboxylic acid (939 mg, 8.23 mmol) in 20 ml of DCM was added into a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (3035 mg, 9.88 mmol) in 21.8 ml of DCM, and followed by Hunig's base (4.3 ml, 24.69 mmol). The resulting solution was stirred at ambient temperature for 1 hr. HOAc (8 ml) was added to neutralize the solution, and then it was purified by RP-HPLC to give (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (660 mg, 1.644 mmol, 40% yield). MS (ES+) m/z 401.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: ClC/C=C/c1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (E)-(3-chloro-1-propenyl)benzene (0.763 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from diethyl etherhexane to provide 0.8 g of (E)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid methyl ester 0.1 molar hydrate, mp 80°-82° C.
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]#[N:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(Cl)Cl.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](=[N:1][OH:2])[NH2:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: NO
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C(N)=NO
Temperature: 0 °C
Reaction time: 65 h
Yield: 15.4 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.69 mL, 11.0 mmol) was added to 5-chloro-2-(2,4-dimethylthiophen-3-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (42 mg, 0.11 mmol) in DCM (5 mL) at 0° C. and the reaction was stirred at 0° C. for 65 h. Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified by preparative HPLC to give 5-chloro-2-(2,4-dimethylthiophen-3-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (7.0 mg, 35%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 414.5; 412.4 (M+H), 412.3; 409.9 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.65 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=8.8, 2.1 Hz), 7.10 (m, 2H), 6.83-6.80 (m, 3H), 2.18 (s, 3H) and 1.95 (d, 3H, J=1.1 Hz).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[N:6]=[CH:5]2.[OH-].[Na+]>CO.O>[CH:1]1[S:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[N:6]=[CH:5]2
Reactant: COC(=O)c1cc2cscc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cscc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Methyl thieno[3,4-c]pyridine-6-carboxylate (250 mg, 1.3 mmol) is dissolved in MeOH (7 ml) and water (1 ml). 2M NaOH (0.72 ml, 1.43 mmol) is added drop-wise. The reaction is stirred overnight at rt and is monitored by TLC. The volatiles are removed in vacuo and the residue is dissolved in water (2 ml). 10% HCl is used to adjust the pH to 3, and the reaction again stirred overnight at rt. The aqueous solution is extracted repeatedly with EtOAc (20×10 ml). The combined organics are dried over MgSO4, filtered, and concentrated to a yellow solid. The amount of isolated product via extraction is minimal (67 mg), so the aqueous layer is concentrated and found to contain the majority of product. Extraction of the solid aqueous residue with EtOAc provided 225 mg (97%) of thieno[3,4-c]pyridine-6-carboxylic acid as a yellow solid. MS (EI) m/z: 179 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: COCCN
Solvent: O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCOC)cc21
Yield: 94 %

Procedure:
A suspension of Example A3 (1.50 g, 4.26 mmol) in 2-methoxyethylamine (3 mL, 34.51 mm) was heated at 120° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to provide 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridin-2(1H)-one (1.56 g, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.65 (s, 1H), 7.18 (d, J=11 Hz, 1H), 7.03 (m, 1H), 6.72 (d, J=9.5 Hz, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.07 (m, 2H), 3.47 (m, 4H), 3.25 (s, 3H), 1.20 (s, 3H); MS (ESI) m/z: 391.1 [M+H]+.