Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[CH:39][C:38](I)=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[CH:39][C:38]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: COC(=O)CC[C@H](NC(=O)c1cc(I)ccc1F)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)ccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of 0.016 g (0.093 mmol) of palladium chloride and 0.0486 g (0.185 mmol) of triphenylphosphine in 5 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 10 mL of acetonitrile and 0.80 g (1.89 mmol) of dimethyl N-(2-fluoro-5-iodobenzoyl)L-glutamate, 0.50 g (1.85 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0088 g (0.046 mmol) of copper iodide, and 0.54 mL (3.89 mmol) of triethylamine. The mixture is then heated to reflux for 3 hours. After cooled to room temperature, the solvent is removed in vacuo and the residue is flash chromatographed on silica gel using 1:19 methanol:chloroform as the eluent to yield 0.92 g (88%) of dimethyl N-(2-fluoro-5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)-ethynyl]-benzoyl)-L-glutamate as a dark yellow solid m.p. 189°-191° C. (dec); Rf =0.48 (1:19 methanol:chloroform), Mass (FD)=565; IR (KBr, cm-1)=1146, 1228, 1263, 1440, 1488, 1549, 1596, 1607, 1622, 1673, 1742; UV (EtOH) λmax =319 (epsilon=30600), 259 (epsilon=11200), 212 (epsilon=42100); 1NMR (300 MHz, CDCl3) delta 1.38 (s, 9H), 2.19 (m, 1H), 2.3-2.6 (m, 3H), 3.72 (s, 3H), 3.85 (s, 3H), 4.95 (m, 1H), 7.21 (dd, 1H, J=8.5, 11.2 Hz), 7.45 (m, 1H), 7.68 (m, 1H), 8.26 (dd, 1H, J=2.0, 7.2 Hz), 8.37 (s, 1H), 8.63 (d, 1H, J=2.2 Hz), 9.0 (d, 1H, J=2.0 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:35])[CH2:31][O:30][CH:29]([C:32]([OH:34])=O)[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.O[N:46]=[C:47]([C:49]1[CH:50]=[CH:51][C:52]([CH3:67])=[C:53]([NH:55][C:56]([C:58]2[N:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]3=[N:60][CH:59]=2)=[O:57])[CH:54]=1)[NH2:48]>CN(C=O)C>[F:35][C:26]1([F:25])[CH2:31][O:30][CH:29]([C:32]2[O:34][N:46]=[C:47]([C:49]3[CH:50]=[CH:51][C:52]([CH3:67])=[C:53]([NH:55][C:56]([C:58]4[N:62]5[CH:63]=[CH:64][CH:65]=[CH:66][C:61]5=[N:60][CH:59]=4)=[O:57])[CH:54]=3)[N:48]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C(O)C1CCC(F)(F)CO1
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: Cc1ccc(-c2noc(C3CCC(F)(F)CO3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
HATU (0.134 g, 0.355 mmol) was added in one portion to a stirred solution of 5,5-difluorotetrahydro-2H-pyran-2-carboxylic acid (17) (53 mg, 0.31 mmol) and DIEA (60 L, 0.355 mmol) in dry DMF (3 mL). After 10 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (0.1 g, 0.323 mmol) was added in one portion and continued to stir for another 30 minutes, then heated at 110° C. for 30 minutes. The reaction was filtered and purified by preparative reverse phase HPLC to afford N-(5-(5-(5,5-difluorotetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F10) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 9.73 (d, J=7.2 Hz, 1H), 8.74 (s, 1H), 8.17 (m, 1H), 7.98-7.95 (m, 3H), 7.52-7.50 (m, 2H), 5.06 (dd, J=8.4, 2.8 Hz, 1H), 4.07-4.00 (m, 1H), 3.91-3.81 (m, 1H), 2.44 (s, 3H), 2.40-2.21 (m, 4H). MS m/z 440.1 (M+1)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:27]5[CH2:28][O:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (28.4 mg, 45.4%), MS (ISP) m/z=459.5 [(M+H)+], was prepared in accordance with the general method of example 1 Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid obtained from saponification of the racemic [1,4]Dioxan-2-yl-acetic acid ethyl ester prepared as reported in Tetrahedron Vol. 45, 1989, pp. 69-76.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:32]1([C:39]2[C:48]3[O:47][CH2:46][CH2:45][O:44][C:43]=3[C:42]([O:49][CH3:50])=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)#[N:31].O>C1COCC1>[CH3:50][O:49][C:42]1[C:43]2[O:44][CH2:45][CH2:46][O:47][C:48]=2[C:39]([C:32]2([C:30]#[N:31])[CH2:37][CH2:36][C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33]2)=[CH:40][CH:41]=1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (34 g, 99 mmol) in THF (320 mL) was added potassium tert-butoxide (11 g, 99 mmol). The mixture was stirred at room temperature for 15 minutes, and a solution of Compound 1 (15 g, 52 mmol) obtained in Example 1 in THF (150 mL) was added dropwise, followed by stirring at room temperature for 45 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 6 (14 g, 82%) as a white solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Cl[C:15]([O:17][CH3:18])=[O:16].O>CCOC(C)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: Fc1cccc(Cl)c1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An oven-dried round bottom flask successively purged and evacuated with N2 was charged with anhydrous THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol) neat. The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added followed by EtOAc. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].CN(C)[CH:29]=[O:30]>O1CCCC1>[Si:20]([O:19][CH2:18][CH2:17][CH2:16][N:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:7]([CH:29]=[O:30])[C:8]=2[CH:9]=[CH:10]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(C=O)cccc21
Temperature: 0 °C

Procedure:
Add tert-butyl lithium (27.07 ml, 46.03 mmol, 1.7 M in pentane) to a solution of 4-Bromo-1-[3-(tert-butyldimethyl-silyloxy)prop-1-yl]-1H-indole (6.76 g, 18.41 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. Stir the reaction at −78° C. for 30 min, quench with N,N-dimethylformamide (4.7 ml, 64.45 mmol), warm to 0° C., quench with pH=7 buffer, and extract into ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane gradient (100% hexane to 50% ethyl acetate:hexane over 45 minutes) gives the title compound as a clear oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:54](O)=[O:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)=[O:42])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:54](=[O:55])[C@H:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[NH:43][C:41](=[O:42])[CH2:40][NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 93.6 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-[N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (550 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (300 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosine (415 mg) according to a similar manner to that of Example 5, mp. 78°-84° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:23]1[CH:24]=[C:25]([CH2:32][OH:33])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(#N)C>[OH:33][CH2:32][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([NH:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:7][CH2:8]2)[CH:24]=1
Reactant: CC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(trans-4-aminocyclohexyl)acetamide hydrochloride (200 mg, 1.038 mmol) and DIPEA (0.494 mL, 2.83 mmol) in ACN (2 mL) was added (3-fluoro-4-nitrophenyl)methanol (161 mg, 0.944 mmol). The resulting mixture was stirred overnight at 80° C. After 16 hours, the reaction was concentrated and the residue purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide N-(trans-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)acetamide as a yellow powder (50 mg, 17.24% yield). MS, m/z (C15H21N3O4): calcd, 307.2. found, 308.1 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH3:20])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2n1CC
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of 4,5-dichloro-1H-indole-2-carboxylic acid ethyl ester (207 mg, 0.80 mmol) in DMF (2 mL) was added drop wise a suspension of NaH (41.2 mg, 60% dispersion in mineral oil, 1.03 mmol) in DMF (5 mL). The reaction mixture was stirred for 30 min, then ethyl iodide (156 mg, 1.0 mmol) diluted in 1 mL of DMF was added drop wise at room temperature and the mixture was stirred for an additional 1 hr. The reaction mixture was diluted with 100 mL of EtOAc and washed with saturated ammonium chloride (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 70% yield). The 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.56 mmol) was diluted in 10 mL of methanol and 4 mL of 1N NaOH and placed in a sealed tube. The reaction mixture was heated under microwave condition at 120° C. for 25 min. The reaction mixture was diluted with 150 mL of EtOAc and washed with 100 mL of 1N HCl, brine (50 L) and dried. The solvent was removed to afford the product 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (120 mg, 84% yield) as a white solid. LCMS for C11H9Cl2NO2 calcd. (m/e) 257, observed 256 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]OS(C)(=O)=O)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:33]=[N+:34]=[N-:35])[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Reaction time: 5 h
Yield: 64.4 %

Procedure:
(5R)-3-(4-((3R)-3-(t-butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-methane-sulfonyloxymethyloxazolidin-2-one (1.25 g, 2.64 mM) was dissolved in N,N-dimethyl-formamide (20 ml), treated with sodium azide (275 mg, 4.23 mM), and heated with stirring at 50° for 5 hours. After cooling the mixture was diluted with water (100 ml), and extracted into ethyl acetate (3×75 ml). The combined organics were dried (magnesium sulfate), and evaporated to give a yellow solid, which 5:19 PM was recrystallised from isopropanol to give the required product (715 mg).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5]CC)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C:3](=[O:5])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1

Procedure:
Prepared according to Procedure A using diethyl 2-methylmalonate (24.485 g, 141 mmol), aniline (9.00 mL, 99 mmol) and pyridine (16 mL) to afford product as a colorless oil after purification by chromatography on silica gel, eluting with EtOAc gradient in hexane. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66 (1H, br. s.), 7.55 (2H, d, J=7.8 Hz), 7.33 (2H, t, J=8.0 Hz), 7.13 (1H, t, J=7.4 Hz), 4.20-4.33 (2H, m), 3.46 (1H, q, J=7.2 Hz), 1.56 (3H, d, J=7.4 Hz), 1.26-1.39 (3H, m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1)=O.Cl.[OH-].[NH4+:17]>[Ni].CO>[F:12][C:11]([F:14])([F:13])[O:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:17])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: [NH4+]
Agent: [Ni]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(N)c1cccc(OC(F)(F)F)c1
Yield: 63 %

Procedure:
A mixture of 3-trifluoromethoxyacetophenone, oxime, Preparation 14 (3.08 g, 12.36 mmol), Raney nickel (1 mL) in methanol (50 mL) and ammonium hydroxide (5 mL) was hydrogenated (H2, 50 psi) for 16 hours. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The suspension obtained was acidified with hydrochloric acid (6N) (100 mL). The aqueous layer was washed with diethyl ether (2×50 mL). The aqueous layer was then made basic with sodium hydroxide (10 N) (with cooling). The basic aqueous layer was then extracted with CH2Cl2 (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo to provide the title compound (1.82 g, 63%) as an oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C(Br)C=C.[Cl:10][C:11]1[S:15][C:14]([CH2:16]Cl)=[CH:13][CH:12]=1>CCOCC>[Cl:10][C:11]1[S:15][C:14]([CH2:16][CH2:3][CH:2]=[CH2:1])=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: C=CC[Mg]Br
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCCc1ccc(Cl)s1
Temperature: 0 °C
Yield: 195.9 %

Procedure:
A solution of allyl magnesium bromide (from 14.6 g of magnesium and 24.2 g (0.2 M) of allyl bromide) in 100 ml ether is added dropwise with stirring to 29.9 g of 5-chloro-2-chloromethylthiophene in 10 ml ether over half an hour and the resulting mixture heated under reflux overnight. The mixture is then poured into 300 ml ice cold dilute sulfuric acid, the ether layer separated and the aqueous phase extracted with 200 ml of ether. The combined ethereal solutions are washed with aqueous potassium carbonate, dried over MgSO4 and evaporated to give crude 4-(5-chloro-2-thienyl)-1-butene as a yellow oil (34 g).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH2:36][S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1>C1COCC1.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][S:37]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:39])=[O:38])=[CH:41][CH:42]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccc(Cl)cc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 4-chlorobenzylsulfonyl chloride (198 mg, 0.879 mmol). The reaction mixture was then stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 4-chlorobenzylsulfonyl chloride (79.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 473 [M+1]+, Rt 1.42 min (basic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][S:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])=[O:13].C(OO)(=[O:23])C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][S:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])(=[O:23])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CS(=O)c2cccc[n+]2[O-])c(Cl)c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)c2cccc[n+]2[O-])c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 16.1 g (0.055 mole) of 2-[[(2-chloro-4-nitrophenyl)-methyl]sulfinyl]-pyridin-1-oxide and 60 ml of acetic acid was added, dropwise at room temperature over 0.5 hours, 13.5 g (1.3 mole) of peracetic acid in acetic acid (40%). The mixture was heated at 70° C. for six hours. The reaction was worked up in the usual fashion, but the product proved to be a mixture of the starting material and desired sulfone. The isolated material (10 g), estimated to contain about 16% sulfoxide, was subsequently redissolved in 40 ml of acetic acid and 1.33 g of 40% peracetic acid in acetic acid was added. The mixture was heated for seven hours at 70° C. and then stirred at room temperature overnight. The excess peracetic acid was destroyed with sodium bisulfite, the mixture was then poured into ice water and then neutralized with potassium carbonate. The solid was filtered off and dried, having a melting point of 199-201 ° C. An NMR spectrum supported the proposed structure.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7](=[O:44])[C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:11]([O:28]CC2C=CC=CC=2)=[CH:10][C:9]=1[O:36]CC1C=CC=CC=1.C(OCC)(=O)C>CO.[Pd]>[CH3:5][O:6][C:7](=[O:44])[C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:11]([OH:28])=[CH:10][C:9]=1[OH:36]
Reactant: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 60 °C
Yield: 15.2 %

Procedure:
Ammonium formate (172 mg, 20 eq) was added to a solution of 2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (72 mg, 0.13 mmol) in methanol (2 ml)/ethyl acetate (1 ml) under a nitrogen atmosphere. 10% Palladium on carbon (cat.) was added and the suspension heated at 60° C. overnight. The solution was allowed to cool. Ethyl acetate (5 ml) added, solution washed with water (2×5 ml) and saturated aqueous sodium chloride solution (5 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate in hexane (gradient 25% to 45% ethyl acetate) to give 2,4-dihydroxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (7.0 mg).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][O:21]C1C=C(C=CC=1)C(Cl)=O>>[CH3:20][O:21][C:8]1[CH:7]=[C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(-c2nc3ccc(OC)cc3s2)c1
Yield: 91 %

Procedure:
The same method as described for 2-(p-methoxyphenyl)-6-methoxybenzothiazole can be used to obtain the corresponding meta isomer by replacing p-methoxybenzoyl chloride with m-methoxybenzoyl chloride. Yield: 91%; melting point: 155°-157° C.