Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1COCC1>[O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:25](=[O:34])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=C1C=C(Oc2ccccc2)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C. After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After 15 min, the reaction mixture was poured into 0.5 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), filtered, and concentrated under reduced pressure. Chromatography of the residue with 4:1 hexanes/ethyl acetate as eluant provided 220 mg (43%) of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone as a yellow solid (220 mg, 43%): 1H NMR (CDCl3) (enol form) δ 2.66 (t, 2H, J=7.2 Hz), 2.84 (t, 2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J=15.6 Hz), 7.02 (d, 2H, J=8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H). HRMS M+H+ calc: 319.1334, found 319.1340.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:53][C:52]3[C:47](=[C:48]([O:60]C)[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51]=3[O:54]C)[CH2:46]2)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:46][C:47]3[C:48](=[O:60])[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51](=[O:54])[C:52]=3[CH2:53]2)=[CH:43][CH:44]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A water (1.0 ml) solution of CAN (976 mg, 1.78 mmols) was dropwise added to an acetonitrile (7.0 ml) solution of ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (350 mg, 0.711 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) followed by recrystallization from hexane-ethyl acetate to obtain the entitled compound (178 mg) as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:16])[NH:5][S:6]2(=[O:8])=[O:7].[H][H]>O.[Pd]>[CH3:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:16])[NH:5][S:6]2(=[O:8])=[O:7]
Reactant: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Cc1c(N)ccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C

Procedure:
33.6 g (0.13 mol) of 4-methyl-5-nitrosaccharin are dissolved in 1.2 l of water with warming and 5 g of Pd/C (10 percent on active carbon) are added. Hydrogen gas is then passed in with vigorous stirring (pressurelesshydrogenation). 9 l of H2 are absorbed in the course of 4.5 hours. After cooling to 25° C., the catalyst is filtered off, and the filtrate is concentrated to a volume of 200 ml and then acidified to pH 1.The deposited precipitate is filtered off with suction, washed with water and dried under reduced pressure at 50° C. 23.4 g (0.11 mol=85% of theory) of a white solid of m.p.: 272°-273° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Reactant: Ic1ccccc1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccccc2)cc1

Procedure:
The title compound was prepared in accordance with Example 10 using 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.70 g (258 mol) 2-aminoindane hydrochloride and 53.43 g (528 mmol) triethylamine were added to 250 ml of tetrahydrofuran, 42.89 g (270 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at RT.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18]CC1C=CC=CC=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7].[C:33]1(=O)[O:38][C:36](=[O:37])[CH:35]=[CH:34]1>C(O)(=O)C>[O:37]=[C:36]1[CH:35]=[CH:34][C:33](=[O:38])[N:1]1[C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[OH:18])[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N)c(OCc1ccccc1)c2=O
Solvent: CC(=O)O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1C(=O)C=CC1=O)c(O)c2=O
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of N-(2-aminobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0 050 g, 0.114 mmol) in acetic acid (1.5 mL) was added maleic anhydride (0.013 g, 0.131 mmol) and the reaction mixture stirred in a sealed tube at 115 C for 18 h. Acetic acid was evaporated in vacuo and the residue was purified by preparative HPLC (YMC-Pack C-18) to afford the title compound (0.013 g, 27% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 8.03 (1H, broad t), 7.59 (1H, m), 7.48 (2H, m), 7.19 (1H, m), 6.92 (2H, s), 4.48 (2H, d, J=6.1 Hz), 4.04 (4H, s), 1.62 (6H, s); HRMS calcd for C21H21N4O6: 425.1461. Found 425.1451.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[OH-].[Na+].CO>C1COCC1>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (140 mg, 0.44 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred for 5 h at r.t. The resulting mixture was concentrated to approximately one-third of its original volume and then placed in an ice bath. Hydrochloric acid (1 M) was added until pH ˜2, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 132 mg of the title compound as a white solid. MS: (−) m/z 305.26 (M−1).
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[C:12]1([CH2:18][C:19]([O:21][CH3:1])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccccc1
Temperature: 90 °C

Procedure:
DBU (3.35 g, 22.0 mmol) was added to a mixture of phenylacetic acid (3.0 g, 22.0 mmol) in DMC (30 mL) and the resulting mixture was heated to reflux (90° C.) for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl phenylacetate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Cl:13]Cl.O>C(O)(=O)C>[Cl:13][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: ClCl
Reactant: O=C1CCc2c(O)cccc2N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c(ccc(Cl)c2O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
16.4 grams of 5-hydroxy-3,4-dihydrocarbostyril are dissolved in 300 ml of acetic acid. This solution is stirred at room temperature, and 50 ml of acetic acid solution containing 7 g of chlorine are added dropwise and the reaction is continued for 3 hours with stirring. The reaction mixture is poured into 500 ml of water and allowed to stand for 1 hour and the precipitate thus formed is separated by filtration, washed with water and then dried. Recrystallization from ethanol-water obtains 13.5 g of 6-chloro-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 209°-210° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[C:20](=[O:22])[NH:21][C:17](=[O:23])[C@@H:18]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 27 h
Yield: 90.6 %

Procedure:
A solution of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (76.68 g, 0.29 mol, prepared as in Organic Syntheses (1989), 67, 133-140) in dichloromethane (130 mL) was added to an ice-cooled mixture of maleimide (25.53 g, 0.26 mol) and trifluoroacetic acid (2.2 mL, 0.028 mol) in dichloromethane (350 ml) over 40 min so that the reaction temperature remained between 0-5° C. The resulting bright yellow solution was allowed to warm gradually and stirred at room temperature for 27 h. The mixture was washed with saturated NaHCO3(aq) (80 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum. The residual oil was stirred with 10% EtOAc-heptane (300 mL) for 15 h, and the resulting precipitate was isolated by filtration, washed with 10% EtOAc-heptane (150 mL) and dried under vacuum at 50° C. to provide the crude, title compound as a white solid (54.25 g). This was stirred with methanol (500 mL) and 50% aqueous H2NOH (4.2 mL) at room temperature for 20 h. The mixture was concentrated under vacuum and the residue was taken up in EtOAc (500 mL) and filtered to remove some insoluble material. The filtrate was concentrated under vacuum to leave the pure, title compound as an off-white solid (49.9 g, 83% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32-2.43 (m, 2H), 3.18 (d, J=9.8 Hz, 2H), 3.20-3.26 (m, 2H), 3.59 (s, 2H), 7.13-7.35 (m, 5H); MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][NH:32][CH3:33]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([N:32]([CH3:33])[CH3:31])=[O:22])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Reactant: CNC
Product: CN(C)C(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
This material is prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid and dimethylamine.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:6]([O:12][CH3:13])=[N:7][CH:8]=[CH:9][C:10]=1[I:11])=[O:4]>CO>[OH:4][CH2:3][C:5]1[C:6]([O:12][CH3:13])=[N:7][CH:8]=[CH:9][C:10]=1[I:11]
Reactant: COc1nccc(I)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(I)c1CO

Procedure:
Solid NaBH4 (28 mg, 0.74 mmol) was added in one portion to a solution of 3-formyl-4-iodo-2-methoxypyridine (prepared according to the method of Fang et al., J. Org. Chem., 1994, 59, 6142) (98 mg, 0.37 mmol) in methanol (4 mL) at −5 C. Vigorous bubbling was observed and the yellow reaction solution turned colorless. The reaction was immediately quenched by the addition of water (2 mL) and the methanol was removed under reduced pressure. The resulting residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 mL). The organic fractions were combined, dried (MgSO4), filtered and concentrated to give 3-(hydroxymethyl)-4-iodo-2-methoxypyridine as a colorless, crystalline solid. This material was used in the next reaction without further purification. R/0.4 (30% ethyl acetate/petrol elution). MS (APCI, m/z 266 (M++1, 100%). 1H NMR (200 MHz, CDCl3): δ 3.98 (s, 3H), 4.80 (s, 2H), 7.34 (d, J=4.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.CO>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[NH:3][CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCC(C)NC1
Reaction time: 15 h

Procedure:
Methyl 6-methylnicotinate (4.9 g, 32.4 mmol) was combined with 10% Pd/C (wet, 2.5 g), methanol (40 mL) and acetic acid (50 mL) and hydrogenated at 40° C., (50 psi) for 15 hours. The mixture was filtered through a pad of Celite, washed with methanol, and concentrated under reduced pressure. The residue was co-evaporated with 80 mL of toluene and then with 50 mL of methanol. The residue was partitioned between 40 mL of dichloromethane and 20 mL of saturated K2CO3. The aqueous layer was extracted with dichloromethane and the combined organics dried with anhydrous K2CO3. The solution was concentrated and dried under vacuum to 5.0 g of pale yellow oil. The cis/trans product mixture was not well separated by TLC (Rf=0.55 and 0.57, CH2Cl2:MeOH:NH4OH, 90:9:1). The crude product mixture was taken directly to the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: Cc1ccc(-c2noc(CC(=O)O)n2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2cc(-c3nc(-c4ccc(C)cc4)no3)c(=O)oc2c1

Procedure:
4.5 parts of 2-hydroxy-4-methoxy benzaldehyde and 7.38 parts of the ethyl ester of 3-p-tolyl-1,2,4-oxadiazol-5-acetic acid (melting point: 56° C) are dissolved in 80 parts of ethanol. 0.3 part of piperidine is added and the mixture is heated for 1 hour under reflux. After cooling, the crystalline precipitate obtained is filtered and washed in ethanol. Thus 8.5 parts of 7-methoxy-3-(3-p-tolyl-1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 227° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:19]=[C:18]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2cc(SC)ccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C)c(-c2cc(C(=O)O)ccc2C(=O)O)c1
Yield: 76.7 %

Procedure:
Dimethyl 2-thioanisylterepthalate (3.92 g) was suspended in methanol (45.9 ml), 5M NaOH (13.5 ml) was added. The reaction mixture was heated at reflux for 1.5 hours. The methanol was removed under reduced pressure. The residue was treated with ethyl acetate and water and the layers separated. The aqueous layer was washed once with ethyl acetate. The aqueous layer was then acidified with 2N HCl and extracted three times with ethyl acetate. These combined organic extracts were then dried over MgSO4, filtered and evaporated under reduced pressure gave the product (2.75 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 57.8 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (2.2 g, 7.13 mmol) and methyl 2-iodobenzoate (1.06 mL, 7.0 mmol) according to the methods of Example 6 Step 4. Purification by flash column chromatography eluting with a 20-50% ethyl acetate/isohexane gradient gave methyl 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}benzoate (1.7 g, 58%). 1H NMR (500 MHz, CDCl3) δ 8.58 (1H, s), 8.25-8.16 (1H, m), 8.06 (1H, d, J=8.5 Hz), 8.01 (1H, s), 8.00-7.92 (2H, m), 7.81 (1H, dd, J=1.7, 8.5 Hz), 7.71-7.54 (5H, m), 7.23-7.13 (2H, m), 3.96 (3H, s); m/z (ES+) 421 [MH+].
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([N:40]([CH3:44])[C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:45][C:46]([F:51])([CH3:50])[C:47](O)=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([N:40]([CH3:44])[C:28]1[CH:29]=[CH:30][C:31]([NH:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[C:26]([NH:25][C:47](=[O:48])[C:46]([F:51])([F:45])[CH3:50])[CH:27]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(F)F)c1
Reaction time: 8 h

Procedure:
HATU (1.44 g, 3.78 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide (1.00 g, 3.60 mmol) (for preparation, see Example 1, steps B to E) were added to a solution of 2,2-difluoropropanoic acid (0.40 g, 3.60 mmol) and DIPEA (0.75 mL, 4.32 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred overnight. The solvent was concentrated and the crude product was recovered in EtOAc. The organic was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield: 1.00 g (75%); MS (ESI) (M+H)+: 370.2.
Reaction SMILES: CN.[CH3:3][C:4]1[N:5]=[C:6]([NH:15][C:16]([N:18]2C=CN=[CH:19]2)=[O:17])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>O.CN(C=O)C>[CH3:19][NH:18][C:16]([NH:15][C:6]1[S:7][C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([CH3:3])[N:5]=1)=[O:17]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (0.030 ml of a 40% w/w/solution in water, 0.351 mmol) is added to a stirred suspension of imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (18a) (0.1 g, 0.351 mmol) in DMF (3 ml). The reaction mixture is stirred at room temperature for 1 hour and then the solvent is removed in vacuo. The crude product is dissolved in THF/DMF (10:1, 3 ml) and passed through a polymer supported isocyanate resin (0.9 g, 1.1 mmol/g loading) and washed through with THF. The solution is concentrated in vacuo and the residue washed with ethyl acetate and methanol to afford the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].C([O-])([O-])=O.[K+].[K+].O.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[C:9]([C:3]1[S:4][C:5]([CH3:8])=[C:6]([NH:7][C:22](=[O:23])[CH2:21][Cl:20])[C:2]=1[CH3:1])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1sc(C)c(N)c1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc(C)c(NC(=O)CCl)c1C

Procedure:
To 12.25 g (0.066 mol) of methyl 3,5-dimethyl-4-aminothiophene-2-carboxylate, 9.1 g (0.066 mol) of K2CO3, 25 ml of water and 150 ml of methylene chloride are added without cooling 7.5 g (0.066 mol) of chloroacetyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:16]=2[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:18])[CH2:9]1)=O)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][NH:19][C:17](=[O:18])[C:16]1[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:15]=1[NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCNC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[1-(tert-butoxycarbonyl)piperidin-3-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (190 mg) and 4 N hydrogenchloride solution in ethyl acetate (5 mL) was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residual crystals were collected by filtration and washed with ethyl acetate to give N-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide hydrochloride (138 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cl-].[NH4+].[CH2:16](O)C>O.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])c1cccc([N+](=O)[O-])c1Br
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1cccc(N)c1Br
Temperature: 80 °C

Procedure:
To stirred solution of above crude 2-bromo-3-nitrobenzoate (4 g, 15.38 mmol) in ethanol (20 mL), ammonium chloride (4 g, 74.0 mmol) dissolved in water (20 mL) and iron powder (6.87 g, 123 mmol) were added under stirring. The resulting reaction mixture was heated at 80° C. for 7 h. On completion, the reaction mixture was filtered through celite, washing with water and ethyl acetate and the filtrate extracted with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure giving the desired crude product (3 g).