Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])=[CH:19][C:18]=2[F:24])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CC(C)CCC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCC(C)C)cc2F)CC1
Reaction time: 16 h
Yield: 74.7 %

Procedure:
A solution of [4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (35 mg, 0.10 mmol) in DCM (2 mL) was treated with 4-methylvaleroyl chloride (15 mg, 0.11 mmol) followed by TEA (16 μL, 0.11 mmol). After 16 h, the mixture was purified directly by PTLC to give a beige solid (33 mg, 73%). MS (ESI): mass calcd. for C25H32FN3O3, 441.55; m/z found, 442.5 [M+H]+. 1H NMR (CDCl3): 7.46-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 3H), 7.05-7.03 (m, 1H), 6.98 (br s, 1H), 6.88-6.84 (m, 1H), 4.06 (s, 1H), 3.70 (s, 3H), 3.10-3.06 (m, 4H), 2.34-2.31 (m, 4H), 2.35-2.31 (m, 2H), 1.62-1.60 (m, 3H), 0.92 (d, J=6.1, 6H).
Reaction SMILES: C(O[C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=O)C.Cl.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=[NH:19])[NH2:18].[OH-].[Na+]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:6]2[N:19]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:18]=[C:4]([OH:15])[CH:5]=2)[CH:13]=1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccn1
Reactant: N=C(N)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Reaction time: 7 h

Procedure:
13.15 g (58 mmol) of 3-(4-chloropyrid-2-yl)-3-oxopropionic acid ethyl ester are dissolved in 400 ml of ethanol, and 9.10 g (58 mmol) of 2-amidinopyridine hydrochloride are added. After the addition of 14.44 ml of 4N sodium hydroxide solution, refluxing is carried out for 7 hours. The mixture is cooled and concentrated to a fifth of its original volume. The crude product is filtered off and recrystallised from methanol, yielding 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol in the form of beige needles.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])C(O)=O)(=O)C.[C:16](Cl)(=[O:20])[O:17][CH2:18]C.C([N:24](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:18][O:17][C:16]([NH:24][C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([OH:4])[CH:6]=1)=[O:20]
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Nc1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
3-Acetoxy-4-methoxybenzoic acid (5.0 g) was dissolved in the mixture of acetone (95 ml) and water (5 ml). To this solution were added ethyl chlorocarbonate (3.4 g) and triethylamine (2.9 g) under ice-cooling, and the mixture stirred for 0.5 hour. To this mixture was further added a solution of sodium azide (2.3 g) in water (10 ml), and the resulting mixture was further stirred at 0° for 1 hour, poured into ice-water, and extracted with ether. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude acyl azide. The product, without purification, was dissolved in toluene (50 ml), and the solution was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure. The crude isocyanate was dissolved in methanol (100 ml), and the mixture was heated under reflux for 1 hour. After the mixture was left to cool to room temperature, potassium carbonate (5.0 g) was added. The mixture was stirred at room temperature for 1 hour, and then water was added to the mixture. It was acidified with 10% hydrochloric acid and extraction with chloroform was conducted. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 100 g). Elution with chloroform gave N-methoxycarbonyl-3-hydroxy-4-methoxyaniline (4.1 g).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([C:16](=[O:17])[CH2:15][Cl:14])[CH:11]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1cc(Br)ccc1O
Temperature: 0 °C
Yield: 58.5 %

Procedure:
35.3 g (264.6 mmol) of aluminium trichloride are added in portions to a solution of 10 ml (80.2 mmol) of 4-bromoanisole and 18.5 ml (232.6 mmol) of chloroacetyl chloride in 90 ml of methylene chloride at a temperature less than 30° C., and the resultant reaction mixture is heated under reflux for six hours. 100 ml of ice-water are subsequently carefully added to the reaction mixture with ice-cooling, the organic phase is separated, the aqueous phase is washed twice with 50 ml of methylene chloride each time, the combined organic phases are then washed with 50 ml of water and dried over sodium sulfate. Filtering-off of the desiccant and stripping-off of the solvent gives 11.7 g of 1-(5-bromo-2-hydroxyphenyl)-2-chloroethanone as beige solid; m.p. 79° C. (lit. m.p. 80-82° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:27])[CH3:26])[CH2:6][C:5]2=1.C([Li])(C)(C)C.CN(OC)[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>O1CCCC1>[C:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:18])[CH3:17])[CH:22]([CH3:24])[CH3:23])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:26])[CH3:27])[CH2:6][C:5]2=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:26])[CH3:27])[CH2:6][C:5]2=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(Br)ccc31)CC(N(C)C)CC2
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(C(=O)c4ccccc4)ccc31)CC(N(C)C)CC2
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)c4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109 %

Procedure:
To a solution of 0.50 gm (1.11 mMol) 6-bromo-3-(dimethyl)amino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole in 50 mL tetrahydrofuran at -78° C. were added 1.96 mL (3.33 mMol) t-butyllithium (1.7M in pentane) and the resulting dark solution was allowed to stir for 30 minutes. To this mixture were then added 0.20 gm (1.22 mMol) N-methyl-N-methoxybenzamide and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then treated with 0.1N sodium hydroxide and then extracted well with chloroform. The organic phases were combined, dried over potassium carbonate and concentrated under reduced pressure to give 0.48 gm (91%) of the desired compound as a red-orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([SH:13])[N:8]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:12]=[CH:11][N:10]=1
Reactant: Sc1ncnc(-c2ccccn2)n1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1ncnc(-c2ccccn2)n1
Reaction time: 8 h

Procedure:
To a stirred suspension of the product of step 1 (0.707 g, 3.72 mmol) in acetone (36 mL) was added sodium carbonate (0.79 g, 7.5 mmol) followed by iodomethane (0.35 mL, 5.6 mmol). After overnight stirring, the reaction was filtered free of undissolved solid and concentrated to afford product as light brown solid: 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.84-8.76 (m, 1H), 8.55-8.43 (m, 1H), 8.11-8.00 (m, 1H), 7.69-7.60 (m, 1H), 2.63 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:18]=O)=[CH:5][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Cl.Cl.[NH:22]1[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=[CH:23]1.C([BH3-])#[N:31].[Na+]>CO>[NH2:29][C:27]([C:26]1[NH:22][CH:23]=[N:24][C:25]=1[NH:31][CH2:18][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:5]=1)=[O:28]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2c(F)cccc21
Reactant: NC(=O)c1cnc[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2c(F)cccc21
Yield: 15.2 %

Procedure:
A mixture of tert-butyl 4-fluoro-3-formyl-1H-indole-1-carboxylate (1.10 g, 3.0 mmol, obtained from Example 11(a)), 1H-imidazole-5-carboxamide dihydrochloride (0.49 g, 3.0 mmol) and sodium cyanoborohydride (0.38 g, 6.0 mmol) in MeOH (10 mL) was stirred o.n. The reaction mixture was partitioned between H2O (25 mL) and CHCl3 (3×25 mL), the combined organic phase was dried over MgSO4 and evaporated. Purification by flash chromatography using a gradient of MeOH (5-10%) in CHCl3 gave the title compound (0.17 g, 15%). MS (ESI) m/z 374 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH:23]([N:26](C(C)C)CC)(C)C.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1.CN(C=O)C>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:26][CH2:23][CH:34]3[CH2:33][CH2:32][CH2:36][O:35]3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCC3CCCO3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 156: step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), c-(tetrahydro-furan-2-yl)-methylamine (0.015 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (10%–35% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C17H19BrN2O5S4: 508.45 (N+H); found 507.1, 509.0
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccc(F)c2)cc1
Yield: 55.4 %

Procedure:
A DMF (83 mL) solution of K2CO3 (12.60 g, 91.3 mmol), 4-bromobenzonitrile (15.00 g, 83.0 mmol) and 3-fluorophenol (8.2 mL, 91.3 mmol) was stirred at reflux (24 h). DMF was removed by distillation and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 5/95) as the eluent to obtain 4-((3′-fluoro)phenoxy)benzonitrile as a white solid (9.81 g, 56%): Rf=0.54 (EtOAc/hexanes 5/95); mp 67-69° C.; IR (nujol) 3073, 2961, 2912, 2862, 2219, 1593, 1461, 1376, 1265, 1225, 1163, 1119, 954, 869, 830, 788, 677, 543 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.79 (dt, J=2.1, 9.9 Hz, 1 ArH), 6.84-6.98 (m, 2 ArH), 7.05 (d, J=9.0 Hz, 2H3), 7.32-7.41 (m, 1 ArH), 7.64 (d, J=9.0 Hz, 2H2); 13C NMR (75 MHz, CDCl3) δ 106.7 (C1), 107.9 (d, J=23.9 Hz, C2′ or C4′), 111.9 (d, J=21.1 Hz, C4′ or C2′), 115.6 (d, J=3.4 Hz, C6′), 118.5, 118.6 (CN, C3), 131.0 (d, J=9.7 Hz, C5′), 134.2 (C2), 156.2 (d, J=10.3 Hz, C1′), 160.7 (C4), 163.6 (d, J=247.1 Hz, C3′); HRMS (M+H+)(ESI+) not observed [M+H+] (calcd for C13H8FNOH+ 214.0668); Anal. Calcd. for C13H6FNO: C, 73.23; H, 3.78; F, 8.91; N, 6.57. Found: C, 73.18; H, 3.69; F, 8.68; N, 6.53.
Reaction SMILES: [C:1]1([S@@:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[N:9][Si](C)(C)C)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+]>CO.O>[C:1]1([S@@:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[NH:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[S@@](=O)(=N[Si](C)(C)C)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C[S@](=N)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A solution of Ethyl [S-phenyl-N-(trimethylsilyl)sulfonimidoyl]acetate (18.7 mmol, obtained as crude oil from step 2) in MeOH—H2O (10:1, 7.5 mL) was treated with cesium fluoride (0.25 g, 1.65 mmol) in one portion. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was concentrated, the residue absorbed to silica gel and purified by chromatography (silica gel, EtOAc-Hexane, Et3N 0.1%). The product containing fractions were concentrated to give the title compound as a pale yellow oil (1.65 g, 39% for steps 1-3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:19].[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11][C:12]([OH:19])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A 2 L, one-necked flask (equipped with a magnetic stir bar and a nitrogen inlet) was charged with (S)-2-isopropyl-5-oxo-pyrrolidine-1-carboxylic acid, tert-butyl ester prepared in Step C above (77.4 g, 0.341 mol) and acetone (260 mL). To this solution was added 1M aqueous sodium hydroxide (408 mL, 0.408 mol), and the reaction mixture was stirred 30 minutes. The acetone was removed in vacuo and the resulting aqueous slurry was acidified, with vigorous stirring, by addition of solid sodium bisulfate (55 g, 0.45 mol) and diluted to 1 L with deionized water. The slurry was stirred for 2 h and the resulting white solid was collected by filtration, washed with deionized water, and dried in a vacuum oven to yield the product as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: COc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12j and 3-bromoanisole
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[O:7][C:8]2[C:9](=[C:11]([C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=1)(=[O:5])=[O:4].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:8]3[O:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[CH3:20])=[CH:10][C:9]=23)=[O:19])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: COc1ccc(C(=O)O)c2cc(S(=O)(=O)N(C)C)oc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(S(=O)(=O)N(C)C)oc12
Yield: 86.9 %

Procedure:
Prepared from 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid (0.5 g), 4-nitrophenol (270 mg), 4-dimethylaminopyridine (11 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (370 mg) in dichloromethane (30 ml). Trituration from ethyl acetate and hexane afforded the desired product as a cream solid (0.61 g).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCOCCO
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 2-[(2-aminoethyl)oxy]ethanol (0.176 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. Transferred the mixture to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 1 H), 2.79 (t, J=6.81 Hz, 2 H), 3.45-3.61 (m, 8 H), 4.12-4.17 (m, 2 H), 4.22 (t, J=6.74 Hz, 2 H), 4.62 (s, 1 H), 7.10-7.18 (m, 2 H), 7.33-7.42 (m, 2 H), 8.07-8.16 (m, 1 H), 8.46-8.54 (m, 1 H), 10.44 (t, J=5.19 Hz, 1 H); ES+ MS: 445 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>[Ru]>[N:17]1[CH:18]=[CH:19][C:14]([C@H:11]([OH:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccncc1
Agent: [Ru]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: C[C@@H](O)c1ccncc1
Temperature: 28 °C
Yield: 55.7 %

Procedure:
Triethylamine (315 mL, 2.26 mol) was added dropwise to formic acid (150 mL, 3.91 mol) with overhead stirring while maintaining the internal temperature below 60° C. with ice-bath cooling. Neat 4-acetylpyridine (100 mL, 0.904 mol) was then added rapidly while maintaining the temperature below 50° C. Following this addition, the reaction was allowed to cool to 28° C. and the chiral ruthenium catalyst [N-[(1R,2R)-2-(amino-N)-1,2-diphenylethyl]-2,4,6-trimethylbenzenesulfonamidato-N]chloro[(1,2,3,4,5,6-n)-1-methyl-4-(1-methylethyl)benzene]ruthenium (CAS #177552-91-9; for catalyst preparation, see: Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.; J. Am. Chem. Soc. 1996, 118, 4916-4917) (3 g, 4.46 mmol) was added. The mixture was stirred under house vacuum for 4 h and then overnight under an atmosphere of nitrogen. The reaction mixture was added dropwise to a stirred solution of 10% Na2CO3 (4 L) and then extracted with EtOAc (3×1 L). The combined EtOAc layers were washed once with brine (1 L), treated with MgSO4 and Darco G-60 decolorizing charcoal and filtered through a 100 g plug of silica gel washing with 10% MeOH/EtOAc (1 L). The filtrate was concentrated to provide a dark oil that crystallized upon standing. The solid was dissolved in warm t-butyl methyl ether (250 mL) and the warm solution was filtered to remove a small amount of insoluble material. The filtrate was allowed to stir with cooling to room temperature and then to −15° C. The solids were collected by filtration, washing with cold t-butyl methyl ether and heptane, and then dried under high vacuum to yield (1R)-1-(4-pyridinyl)ethanol as a dark beige solid (62 g, 52.9% yield). This solid material was 96% ee based on chiral HPLC (HPLC conditions: AS-H column, 5% MeOH/CO2, 40° C., 140 bar, 2 mL/min). The filtrate was combined with the insoluble solid from the crystallization and concentrated in vacuo to yield additional (1R)-1-(4-pyridinyl)ethanol as a dark oil (37.5 g, 32% yield). This oily material was 78% ee based on chiral HPLC (see HPLC conditions above). 1H NMR (400 MHz, DMSO-d6): δ 8.47-8.43 (m, 2H), 7.32-7.28 (m, 2H), 5.37 (d, 1H, J=4.4 Hz), 4.72-4.64 (m, 1H), 1.44 (d, 3H, J=6.6 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.O[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1>O>[Cl:3][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: OCC1COc2ccccc2O1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: ClCC1COc2ccccc2O1

Procedure:
In a three neck flask fitted with a stirring device, 218 g thionyl chloride are mixed with 1000 g pyridine while cooling. They are added further, portionwise 500 g 2(hydroxy methyl) (2,3-dihydro [4H] 1,4-benzodioxin) while keeping the inner temperature below 20°. When the reaction is completed, the mixture is heated at 100° for 3 hours then poured into water and extracted with chloroform. The solvent is distilled off and the raw residue is purified by fractional distillation under reduced pressure. 340 g of the chloromethylated derivative are obtained. It boils at 85°-90°/0.2 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1.Cl[C:18]1[C:19]2[S:26][CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1.[OH-].[NH4+].O>CC(O)C>[O:14]1[CH2:15][CH2:16][CH:12]([O:11][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[NH:1][C:18]2[C:19]3[S:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C:6]([NH2:8])=[O:7])[CH2:13]1
Reactant: Clc1ncnc2ccsc12
Reactant: NC(=O)c1ccc(N)c(OC2CCOC2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1ccc(Nc2ncnc3ccsc23)c(OC2CCOC2)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 324.8 %

Procedure:
The reaction was carried out in 4 batches using ACE pressure tubes. The 4-amino-3-(tetrahydrofuran-3-yloxy)-benzamide (0.52 g, 1.0 eq, 2.34 mmol) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (0.40 g, 1.0 eq, 2.34 mmol) in IPA (4 ml). The reaction mixtures were then stirred at 120° C. for 18 hours before being allowed to cool. 28% w/w Ammonium hydroxide solution (4 ml) followed by water (8 ml) were added and the reactions combined. The precipitate was isolated by filtration, washed with water (4×50 ml), dried on the sinter, washed with cyclohexane (8×50 ml), and then dried in vacuo to give the title compound as an off-white solid (2.71 g, 7.6 mmol, 81%). LCMS: [M+H]+=357; Rt=1.27 min, 100% purity.
Reaction SMILES: Br[C@:2]1([CH3:12])[O:6][C@@H:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]1=[O:11].C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:7]([C@@H:5]1[O:4][C:3](=[O:11])[C:2](=[CH2:12])[O:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](C)(Br)O1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C1O[C@H](C(C)(C)C)OC1=O
Yield: 88.7 %

Procedure:
In 500 ml of carbon tetrachloride, 50.5 g of the (2S,5S)-5-bromo-2-tert-butyl-5-methyl-1,3-dioxolan-4-one obtained in Step 2 was dissolved. To the resulting solution, 50.0 g of triethylamine was added, and the solution was refluxed for 4 hours. After the reaction solution was left to have cooled, insolubles were separated by filtration, the carbon tetrachloride was evaporated under reduced pressure, and the resulting residue was recrystallized from hexane to obtain 29.5 g of (2S)-2-tert-butyl-5-methylene-1,3-dioxolan-4-one.