Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][S:29][C:28]([CH3:33])([CH3:32])[C@@H:27]2[C:34]([O:36]C)=[O:35])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][S:29][C:28]([CH3:33])([CH3:32])[C@@H:27]2[C:34]([OH:36])=[O:35])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCNC(=O)OC(C)(C)C)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)NCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1

Procedure:
The methyl ester of methyl (3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate was converted into the analogous carboxylic acid using lithium iodide according to the procedure of Example 250 to provide (3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 541.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:7])=[O:6].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[C:8]([S:5]([O:4][CH2:3][C:2]([CH3:29])([CH3:1])[CH3:28])(=[O:7])=[O:6])[CH:13]=1
Reactant: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)COS(=O)(=O)c1cc(N)ccc1C=Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
5-Nitro-2-[2-(4-nitro-phenyl)-vinyl]-benzenesulfonic acid 2,2-dimethylpropyl ester (Example 56, 1.10 g, 2.62 mmol) was dissolved in 52 mL of ethyl acetate. Tin chloride dihydrate (2.95 g, 13.1 mmol) was added and a reflux condenser attached. The solution was heated to reflux and stirred overnight. After cooling to room temperature the solution was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate. The whole mixture was filtered thru Celite and the aqueous layer discarded. The organic layer was then washed with brine and dried over MgSO4. After concentration on a rotovap the crude material was purified by a gradient flash column using 3 to 10% ethyl acetate in dichloromethane as the eluant to afford 0.33 g of the title compound as a oily red solid (35%): 1HNMR (CDCl3): δ7.63 (d, J=9 Hz, 1H), 7.58 (d, J=16 Hz, 1H), 7.33 (d, J=9 Hz, 2H), 7.31 (d, J=3 Hz, 1H), 6.89 (dd, J=9 Hz, 3 Hz, 1H), 6.86 (d, J=16 Hz, 1H), 6.68 (d, J=9 Hz, 2H), 3.89 (br s, 4H), 3.61 (s, 2H), 0.86 (s, 9H); MS (ES-POS): [M+H]+ 361; Analytical HPLC determined that this compound was 90% pure by C-18 reverse phase.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:9]=2)[CH2:4][CH2:3]1.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>[Fe].CO>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:9]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2N)CC1
Yield: 86.4 %

Procedure:
A flask was charged with 4-methyl-6′-(4-methyl-piperazin-1-yl)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (101 mg, 0.320 mmol), methanol (10 mL), ammonium chloride (171 mg, 3.20 mmol), and iron powder (88 mg, 1.6 mmol) and refluxed for 10 h. Additional amounts of ammonium chloride (171 mg, 3.20 mmol) and iron powder (88 mg, 1.6 mmol) were added after 2.5 h and 6 h during the reflux operation. The cooled mixture was poured into satd aq sodium bicarbonate (100 mL), extracted with dichloromethane (4×20 mL), and the organic layers were dried over Na2SO4. The solvents were removed in vacuo to yield 80 mg (87%) of the title compound as a green glass. 1H-NMR (400 MHz, CDCl3): δ 6.89 (d, 1H, J=8.3), 6.21 (d, 1H, J=8.3 Hz), 3.45-3.36 (m, 8H), 2.71 (m, 2H), 2.54 (m, 4H), 2.34 (s, 3H), 1.74-1.71 (m, 2H), 1.52 (m, 1H), 1.31 (m, 2H), 0.98 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C16H28N5, 290.2 (M+H); found: 290.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[K+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=2)[C:6]([OH:8])=[O:7])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27 mmol), potassium hydroxide (5.4 g, 30 mmol) and 4-fluorobenzylbromide (5.7 g, 30 mmol) in water (13 mL) was heated under reflux for 5 h. After cooling to room temperature, the mixture was washed with ether. The aqueous phase was then acidified to pH 2 at 0° C. with concentrated HCl and then extracted with ethyl acetate. The organic extracts were then washed with water and dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, CHCl3:Acetone:AcOH: 90:9:1) to afford the title compound (2.3 g, 29%) as a colorless oil. MS: m/e=289.0 (M−H+).
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:36]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([Cl:30])[CH:26]=3)[N:20]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(Cl)cc3c(=O)[nH]2)c1
Yield: 94.6 %

Procedure:
According to the preparation of 42, 2-amino-5-chlorobenzamide (31) (1.0 g, 5.9 mmol)and 3-methoxybenzaldehyde (34) (0.8 g, 5.9 mmol) were used to afford 50 (1.6 g, 94.3%) as pale yellow needles.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:39][C:40]1[C:41]2[C:51]([O:52][CH2:53][C:54]([NH2:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=[CH:48][C:42]=2[NH:43][S:44](=[O:47])(=[O:46])[N:45]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:39][C:40]1[C:41]2[C:51]([O:52][CH2:53][C:54]([NH:57][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][N:14]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:7]=3)([CH3:55])[CH3:56])=[CH:50][CH:49]=[CH:48][C:42]=2[NH:43][S:44](=[O:47])(=[O:46])[N:45]=1
Reactant: CC(C)(N)COc1cccc2c1C(N)=NS(=O)(=O)N2
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(-n2ccnc2)c1
Temperature: 50 °C
Yield: 7.1 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)isonicotinic acid (1.00 g, 5.29 mmol), in DMF (41 mL) at room temperature, was added HOBt.H2O (891 mg, 5.82 mmol), EDCI.HCl (1.11 g, 5.82 mmol), 4-amino-5-(2-amino-2-methylpropoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (1.70 g, 5.29 mmol) and triethylamine (1.54 mL, 11.1 mmol). The reaction was heated to 50° C. for one hour, and upon completion was cooled to room temperature, filtered and the filtrate was purified by HPLC (10-90% acetonitrile in water), then the purified product was washed in boiling ethanol for thirty minutes, then cooled to room temperature. The solid was collected by vacuum filtration, sodium carbonate (178 mg) in water (50 mL) was added and the mixture was heated to 60° C. until in solution, then was cooled to 0° C. and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. (295 mg). Sodium carbonate (87.3 mg) in water (7 mL) was added to the white solid and the mixture was heated to 60° C. until in solution. The warm solution was filtered, cooled to room temperature, and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. to yield N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-(1H-imidazol-1-yl)isonicotinamide as a white solid (171 mg, 7% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.50 (s, 6 H), 4.41 (s, 2H), 6.62 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1 H), 7.14 (s, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.63 (dd, J=6.0 Hz, 1H), 7.81 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.47 (s, 1H), 8.58 (m, 3H), 11.00 (s, 1H). MS 456 (MH+).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([O:16]C)=O)[Se:11][C:12]=1[CH3:13])[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([NH2:2])=[O:16])[Se:11][C:12]=1[CH3:13])[CH3:5]
Reactant: COC(=O)c1cc(N=NN(C)C)c(C)[se]1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[se]c(C(N)=O)cc1N=NN(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 42 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (40 mL) was added a solution of methyl 4-[(dimethylamino)diazenyl]-5-methylselenophene-2-carboxylate (550 mg) in THF (10 mL) for 5 min and stirred at rt for 40 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (96:4) as eluents to give the product as off-white solid (220 mg, 42%), mp 170-172° C. IR (neat) νmax 3385, 3188, 2914, 1644, 1604, 1326, 1120, 1066 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.87 (1H, s, H-3), 5.67 (2H, br s, —CONH2), 3.28 (6H, br s, N(CH3)2), 2.63 (3H, s, Ar—CH3); LC-MS (positive ion mode): m/z 261, 259 (M+H)+.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=O.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16](=[O:18])[C:15]1[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:14]=1[O:13][CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COc1ccc(C=O)cc1C(=O)O
Reactant: CCCCCNCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Di-n-pentylamine (873 mg, 5.55 mmol, 2 eq) was added to a solution of 2-methoxy-5-formylbenzoic acid (500 mg, 2.78 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (755 mg, 5.55 mmol, 2 eq), and N-methylmorpholine (0.83 mL, 7.58 mmol, 2.73 eq) in N,N-dimethylformamide (10 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.06 g, 5.55 mmol, 2 eq) and the reaction mixture stirred overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give the product as a pale brown oil (886 mg, 99%). 1H NMR (CDCl3) δ9.83 (s, 1H, O═C—H), 3.85 (s, 3H, OCH3), 3.52 (m, 1H, NCH2), 3.38 (m, 1H, NCH2), 2.98 (m, 2H, NCH2).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])=[CH:8][CH:7]=1)([O-:5])=[O:4].[NH4+].[Cl-]>CCO>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([CH2:19][OH:20])[CH2:14][OH:15])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CC(CO)CO)cc1
Yield: 85 %

Procedure:
To a suspension of NaBH4 (14.35 g, 379.3 mmol) in EtOH (200 mL) was added dropwise a solution of 23 (11.2 g, 37.93 mmol) in EtOH (100 mL) and the mixture was refluxed for 16 hours. After addition of an aqueous NH4Cl solution (5%, 150 mL) in small portions, the solution was distilled under vacuum to remove EtOH. CH2Cl2 (200 mL) was added and the mixture was filtered. The two layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phases were washed with aqueous NaHCO3 (5%, 100 mL), dried over MgSO4 and concentrated under vacuum. The resulting yellow oil was recrystallized from EtOAC/hexane to give off-white powder 24 (6.81 g, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=[CH:11][CH:10]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:30]1)#[N:23]
Reactant: O=C(O)c1cccn1-c1ccc(F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1cc(NC(=O)c2cccn2-c2ccc(F)cc2)ccc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
1-(4-Fluorophenyl)pyrrole-2-carboxylic acid (2 g), 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.4 g), 1-hydroxybenzotriazole (1.8 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.2 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1) to give an oily substance. The obtained oily substance was recrystallized from a mixed solvent of toluene-n-hexane to give the title compound (1.5 g), melting point: 170–171° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:18])=[CH2:17]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([I:9])[C:7]=1[O:8][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)COc1c(I)cc(CO)nc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
C2 (6.3 g, 22 mmol) is dissolved in 30 mL DMF in a dry flask under N2. The flask is placed in an ice bath, and 60% sodium hydride in mineral oil (880 mg, 22 mmol) is added. The reaction is stirred 30 min while the flask is kept in an ice bath. The ice bath is removed for 30 min and then the flask is placed back into the ice bath to cool the reaction. 3-Bromo-2-methylpropene (23.1 mmol) is added, and the reaction is stirred overnight at rt. The reaction is diluted with 150 mL EtOAc and is washed with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to a pale oil which is crystallized from hexanes to afford (6-chloro-4-iodo-5-[(2-methyl-2-propenyl)oxy]-2-pyridinyl)methanol (C19) (86% yield). HRMS (FAB) calculated for C10H11ClINO2+H: 339.9603, found 339.9604 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=3)[CH2:17]2)[CH:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([OH:26])[CH:22]=3)[CH2:17]2)[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc2nc(N3CCc4cc(OCc5ccccc5)c(OC)cc4C3)cc(N)c2cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1O)CCN(c1cc(N)c3cc(OC)c(OC)cc3n1)C2
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
A suspension of the product of part (A) (3.0 g) in methanol (400 ml) was warmed at about 50° until the majority of the product dissolved. The reaction mixture was then transferred to a hydrogenator and hydrogenated under a hydrogen pressure of 2.068×105Pa (30 psi) in the presence of 5% Pd/C (400 mg) at room temperature with stirring for 1.5 hours. The reaction mixture was filtered through "Arbacel" (a microcrystalline cellulose filtration aid), and evaporated to yield impure 4-amino-6,7-dimethoxy-2-(6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline (600 mg). The catalyst was then stirred in methylene chloride/methanol (4:1, 200 ml) for 30 minutes, and the mixture was filtered and the filtrate evaporated to yield a further 1.05 g of the impure product. The total of the impure product (1.65 g) was dissolved in methylene chloride/methanol (4:1, 300 ml) and shaken with 10% sodium carbonate solution (50 ml). The organic phase was washed (H2O), dried and evaporated. Medium pressure chromatography of the residue on silica (Merck "Art.9385") eluting with methylene chloride containing gradually increasing amounts of ethanol (1-25%) followed by collection and evaporation of appropriate fractions gave the title compound. The compound was slurried in boiling methylene chloride (20 ml), cooled, precipitated with hexane, filtered, and the solid washed with hexane and dried to give the pure title compound as a quarter-hydrate (900 mg), m.p. 250°- 251°.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][CH2:19]Cl)=[C:12]([CH:16]=1)[C:13]([O-:15])=[O:14]>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH:18]=[CH2:19])=[C:12]([CH:16]=1)[C:13]([O:15][CH3:1])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: O=C([O-])c1cc(Cl)ccc1OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1ccc(Cl)cc1C(=O)OC
Reaction time: 1 h
Yield: 34.5 %

Procedure:
Potassium tert-butoxide (40.4 g, 0.36 mol) was added portionwise to a solution of 5-chloro-2-(2-chloroethoxy)benzoate (76 g, 0.3 mol) in 600 mL of THF at 0° C. After stirring at that temperature for 1 hour, TLC showed complete consumption of starting material and the mixture was poured into ice water. The aqueous layer was extracted twice with EtOAc (200 mL), and the combined organics were evaporated to dryness. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=50:1-30:1) to afford 22 g (34%) of methyl 5-chloro-2-(vinyloxy)benzoate. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, 1H), 7.38 (dd, 1H), 7.00 (d, 1H), 6.52 (dd, 1H), 4.67 (dd, 1H), 4.44 (dd, 1H), 3.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)[nH]c2n1

Procedure:
To a solution of 7-chloro-1H-[1,8]naphthyridin-2-one (prepared as described in J. Org. Chem. (1990), 55, 4744; 5.36 g, 29.68 mmol) in MeOH (98 mL) was added NaOMe (25 wt % in MeOH, 161 mL). The resulting solution was stirred at reflux for 15 h. The solvent was removed in vacuo. Water (100 mL) and EA (80 mL) were added. The phases were separated and the aq. layer was extracted with EA (8×80 mL). The combined org. layers were washed with brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The title compound was obtained as a beige solid (5.22 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N+:25]([O-])=[CH:24][CH:23]=[CH:22]3)=[O:18])=[C:11]([CH3:30])[CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5].P(Cl)(Cl)([Cl:35])=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:35][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([C:17]([NH:16][C:12]3[C:13]([CH3:15])=[CH:14][C:9]([C:3]([F:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:32])([F:31])[F:1])=[CH:10][C:11]=3[CH3:30])=[O:18])[CH:20]=2)[N:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc[n+]2[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nccc(Cl)c2c1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
To crude product of N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylpheyl]quinoline-6-carboxamide-1-oxide (97 mg), phosphorus oxychloride (3.0 g) was added and the mixture was stirred under heating at 100° C. for 1 hour. The reaction solution was poured into ice water, neutralized with potassium carbonate and extracted twice with ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 2-chloro-N-[4-(,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]quinoline-6-carboxamide (35 mg, yield 35%) and 4-chloro-N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]quinoline-6-carboxamide (23 mg, yield 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.[Cl-].[NH4+]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 4-hydroxycyclohexanecarboxylic acid ethyl ester as a mixture of cis and trans isomers (8.7 g, 50.51 mmol) in THF (300 mL) at 0° C. was added imidazole (4.8 g, 70.72 mmol), DMAP (20 mol %, 1.23 g, 10.10 mmol,) and tert-butyl dimethylchlorosilane (9.1 g, 60.61 mmol). The reaction mixture was warmed to room temperature, stirred overnight, and diluted with ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. Solvent was removed and the crude oil was filtered through silica gel and solvent removed to give 4-(tert-butyldimethylsilanyloxy)cyclohexanecarboxylic acid ethyl ester (11.1 g, 77%) as a mixture of diastereomers.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[O:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(N)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl)amino}phenylcarbamate (85 mg) in methanol (1 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo. The solid residue was collected and washed with ethyl acetate to give 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamide hydrochloride (70 mg).