Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[CH:13][N:14]2[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)=O>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([NH:7][CH:6]=[O:5])=[CH:9][CH:10]=2)[N:14]([CH2:17][C:18]2[CH:23]=[N:22][CH:21]=[N:20][CH:19]=2)[CH:13]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cncnc3)c2c1
Solvent: O=CO
Product: O=CNc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cncnc3)c2c1
Reaction time: 4 h

Procedure:
[3-(2-Nitro-phenylsulfanyl)-1-pyrimidin-5-ylmethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (3.8 g, 8.0 mmol) was dissolved in 150 mL of formic acid and stirred for 4 hours. The solution was concentrated in vacuo. NaHCO3-sat was added and the mixture was extracted with CH2Cl2 (2×) The combined organic layers were washed with brine and dried over Na2SO4. The solution was allowed to stand overnight. The formed solid was filtered affording a mixture of compound 118 and structure 23 of Scheme VII, where R1=3,5-pyrimidyl, R2=2-nitrophenyl, R3=R4=H (2.4 g).
Reaction SMILES: [CH2:1]([C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:36]>O>[CH2:1]([C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[Na+:36]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A suspension of the product of Example 33C (0.054 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.108 mL, 0.107 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.052 g, 93%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.57 (m, 1 H) 0.68 (m, 3 H) 0.87 (m, 1 H) 1.06 (m, 2 H) 1.38 (m, 3H) 1.71 (m, 1 H) 2.13 (m, 1 H) 2.95 (m, 3 H) 7.31 (m, 3 H) 7.46 (m, 3 H) 8.05 (m, 1 H) 9.86 (m, 1 H) 15.48 (m, 1 H). MS (ESI−) m/z 502 (M−H)−.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[P:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]=[N:31][NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCSP(=O)(OCC)Oc1ccc(C=O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCCSP(=O)(OCC)Oc1ccc(C=NNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl O-(4-formylphenyl) thiophosphate (5.44 grams; 0.019 mole), ethanol (150 ml) and benzoylhydrazine (2.57 grams; 0.019 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then stripped of ethanol under reduced pressure having a viscous oil as the residue. The residue was then dissolved in diethyl ether resulting in the formation of a precipitate. The ether solution was decanted from the precipitate and was stripped of solvent under vacuum leaving an orange-brown oil. This oil was chromatographed on a silica gel column using methylene chloride and methylene chloride-acetone mixtures as the eluant. Fourteen fractions were recovered and fractions 3 plus 4, 7, 8 and 9 were analyzed by infra red spectroscopy revealing that fraction 8 was the desired product. This fraction was stripped of solvent to yield the desired product O-ethyl S-propyl O-[4-(benzoylhydrazonomethyl)phenyl] thiophosphate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:18])=[O:25])=[CH:15][CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1NC(=O)c1ccc(S(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Ten grams of N-(2,6-dimethylphenyl)-4-(methylthio)benzamide were dissolved in a small volume of chloroform and chilled to 0° C. A solution of 7.9 g of m-chloroperoxybenzoic acid in chloroform was added in dropwise fashion. The reaction was stirred at room temperature for 1 hour, washed with a sodium bicarbonate solution, water, and a saturated chloride solution, dried over sodium sulfate and evaporated in vacuo. The resulting foam was chromatographed over silica gel eluting with an ethyl acetate in hexane gradient. The appropriate fractions were combined and the solvent removed in vacuo and the resulting residue was crystallized from ethyl acetate/hexane providing the desired title product in 59% yield, m.p. 144°-146° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]1(C)[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1.[OH2:24]>C1(C)C=CC=CC=1.Cl.CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:13]2[CH2:18][CH2:17][C:16](=[O:24])[CH2:15][CH2:14]2)[CH2:11][CH2:12]1
Reactant: O
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene-ketal (50.0 g), 1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in 500 ml of toluene is refuxed with a Dean-Stark trap until the theoretical amount of water is collected (about four hours). The solvent is evaporated in vacuo and the residue is dissolved in 750 ml of methanol. This solution is cooled in an ice bath and sodium cyanoborohydride (30.1 g) is added in small portions over a two-minute period. The resulting suspension is stirred mechanically and over the next 30 minutes enough concentrated hydrochloric acid solution is added dropwise to the reaction mixture to maintain a pH of about 4. The solvent is removed in vacuo to leave a semisolid residue which is dissolved in 300 ml of a 10% solution of hydrochloric acid in a well ventilated fume hood. This solution is diluted with an equal volume of acetone and refluxed for two hours. The volatile components of the mixture are removed in vacuo and the residue is cooled in an ice bath and made basic with concentrated ammonium hydroxide. The white solid which forms is recrystallized from ethyl acetate-heptane to give 52.4 g of the title compound; mp 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1ccc(Br)c(O)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(Br)c(O)c1

Procedure:
3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis et. al., J. Med. Chem., (1985), 28, 1263-1269] (5 g, 0.02 mol) was heated in quinoline (200 mL) at 160° C. for 1 h. On cooling, the product was partitioned between Et2O and 3M HCl. The organic extract was washed with water and brine then dried (MgSO4), filtered and evaporated to give the title compound which was recrystallized from 5% ethyl acetate/hexane (4 g, 97%); m.p. 40°-42° C. Anal. Calc. for C7H7 BrO2 : C, 41.41; H, 3.48. Found C, 41.39; H, 3.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:11][CH2:10]1.[H][H]>O1CCOCC1.C(O)C.[Ni]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: N#CCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
8.0 g (20.6 mmol) 4-{1-[bis(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyronitrile are dissolved in 240 ml dioxane/ethanol (1/5) and added to 1.5 g Raney-nickel. The mixture is stirred at RT under hydrogen atmosphere until uptake of the theoretical amount of hydrogen. The reaction solution is filtered from the catalyst and the solvent is removed under vacuum. The residue is dispersed between 100 ml 10% sodium hydroxide solution and 300 ml acetic acid ethyl ester. The organic phase is dried with sodium sulfate and the solvent is removed under vacuum. The resin is processed further without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8]([O:23][C:20]2[CH:21]=[CH:22][C:15]([Br:14])=[C:16]([CH:17]=[O:18])[CH:19]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCOC(=O)c1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1Br
Temperature: 80 °C
Yield: 30.8 %

Procedure:
To a solution of 3-bromo-6-chloro-pyridine-2-carboxylic acid ethyl ester (22, 8.0 g, 30.24 mmol) and 2-bromo-5-hydroxy-benzaldehyde (7.29 g, 36.29 mmol) in DMF (100 mL) was added cesium carbonate (22.6 g, 69.55 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, and the residue was diluted with EtOAc (200 mL), washed with water (2×50 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 23 (4.0 g, 31%) as transparent oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.51 (dd, J=8.7, 2.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H); MS (ES) m/z: 430 (M+1)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:35][C:36]([CH3:44])([CH2:40]C(O)=O)[C:37]([OH:39])=[O:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(C(C)C)CC)(C)C.ClCCl>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:5])[CH2:35][C:36]([CH3:44])([CH3:40])[C:37]([OH:39])=[O:38])[CH2:13][CH2:12]3)=[CH:19][CH:18]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Reactant: CC(C)(CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)CC(C)(C)C(=O)O)CC4)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
4-{4-[(7-Methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (139 mg, 0.3 mmol) (see example 1) was stirred in 5 mL of 1:3 TFA/CH2Cl2 at r.t. overnight, then concentrated. The residue was dissolved in 5 mL of 30:70 diisopropylethylamine/anhydrous dichloromethane, 2,2-dimethyl-succinic acid (72 mg, 0.49 mmol), N-hydroxybenzotriazole (61 mg, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) were added. The reaction mixture was stirred at room temperature overnight. After the reaction, solvent was evaporated. The resulted mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were collected, combined, washed with brine before dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by reverse phase HPLC (10%-80% acetonitrile in water) to gave 7 mg of 4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid. LCMS calcd for C27H32N4O5 (m/e) 492, obsd 493 (M+H).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]#[N:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]#[N:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 89 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.82 g.), methanol (13.3 ml.) and tetrahydrofuran (25 ml.) were treated in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.75 g.).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]1([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(NC[C@H]2CCCN2)cc1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCC[C@@H]2CNc2ccccc2)c2ccccc12
Yield: 18.3 %

Procedure:
The title compound (7 mg, 18% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and (R)-(−)-2-phenylaminomethylpyrrolidine (82 mg, 0.468 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].O1CCCC1>>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH:14][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CN
Reactant: Cc1ccc(Cl)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(NCC(C)C)c(C)c1
Temperature: 70 °C
Yield: 96.3 %

Procedure:
A mixture of 1-chloro-2,4-dimethylbenzene (1687 mg, 12 mmol), isobutylamine (1755 mg, 24.00 mmol), and Caddick catalyst (140 mg, 0.238 mmol) was treated with lithium hexamethyl disilizide in tetrahydrofuran (1M LHMDS in THF, 15 mL, 15.00 mmol) under nitrogen. The reaction mixture was heated to 70° C. for 45 min in a septum-sealed vessel. The cooled mixture was concentrated in vacuo and the residue was partitioned between aqueous citric acid (50 mL) and tert butyl methyl ether (TBME) (2×50 mL). The organic phase was treated with dried MgSO4, the solid removed by filtration and the organic phase was concentrated in vacuo to give (2,4-dimethylphenyl)(2-methylpropyl)amine (2.05 g, 11.56 mmol, 96% yield) as an orange oil.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O.C(=O)([O-])O.[Na+]>C(OC(C)(C)C)(=O)C>[C:7]([O:1][CH:2]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4])([CH3:8])([CH3:12])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reaction time: 0.08 h
Yield: 38 %

Procedure:
A suspension of methyl hydroxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 9, 10.0 g, 23.97 mmol) in tert-butyl acetate (250 mL) was stirred vigorously for 5 minutes prior to the dropwise addition of perchloric acid (70%, 6.15 mL, 71.90 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The mixture was neutralised by addition of a saturated aqueous sodium hydrogen carbonate solution (60 mL) and extracted with ethyl acetate (250 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4 and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography eluting with ethyl acetate/heptane (10-40%) to give the title compound, 4.26 g, in a 38% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9 H), 1.81-1.92 (m, 4 H), 2.66 (s, 3 H), 2.79-2.89 (m, 2 H), 3.21-3.27 (m, 2 H), 3.68 (s, 3 H), 5.95 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:36])=[C:6]([C:8]2[NH:17][CH:16]([NH:18][C@@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]3[C:31](OCC)=[O:32])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:36])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[C@H:20]([CH2:31][OH:32])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:23]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC1NC(c2cc(F)ccc2O)=Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
trans-1-tert-Butyl 3-ethyl 4-(2-(5-fluoro-2-hydroxyphenyl)-3,4-dihydroquinazolin-4-ylamino)pyrrolidine-1,3-dicarboxylate (0.093 g, 0.19 mmol, synthesised using methods outlined in Synthesis 84) was dissolved in THF (1.8 mL) and cooled to 0° C. A 1 M solution of LiAlH4 in THF (0.375 mL, 0.38 mmol) was added dropwise and the mixture was stirred at this temperature for 15 min. The reaction was quenched with sodium potassium tartrate (2 drops) and diluted with water (10 mL). The mixture was extracted with dichloromethane (3×50 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 25% ethyl acetate in hexane to give the title compound as a yellow solid (0.026 g, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=1)([O-])=O>CO.[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnn(Cc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(Cc2ccncc2)c1
Yield: 93.9 %

Procedure:
A solution of 4-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine (247 mg, 1.21 mmol) in methanol (10 mL) is hydrogenated over 10% palladium on carbon (30 mg) under balloon pressure for 3 h. The mixture is filtered through Celite® and the filtrate is concentrated under reduced pressure. The residue is purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol to afford the title compound as a brown oil (198 mg, 94%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:22])[CH3:21])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (10 parts) in water (100 parts) containing sodium hydroxide (15 parts) was slowly added acetic anhydride (10 parts) with cooling to keep the temperature below 10° C. An oil separated which solidified on scratching. This was filtered off, washed with water, dried and recrystallised from 90% aqueous ethanol to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 84°-85° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1.CCCCCC>[OH:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[O:16][N:15]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1cc(O)no1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cc(O)no1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
26(b) 69.1 ml of a 15.13% w/w hexane solution of butyllithium was added dropwise to a solution of 15.42 ml of diisopropylamine in 500 ml of tetrahydrofuran at -10° to -15° C., and the mixture was stirred at the same temperature for 15 minutes. To it was added dropwise a solution of 4.95 g of 3-hydroxy-5-methylisoxazole dissolved in 50 ml of tetrahydrofuran at -10° C., and the mixture was stirred at the same temperature for 30 minutes. It was then cooled to -55° C. after which 41.6 g of tetradecyl bromide were added all at once. After removal from the cooling bath, the mixture was stirred for 3 hours, and then 100 ml of diethyl ether were added. The mixture was washed with 150 ml of 5% w/v aqueous hydrochloric acid, and the organic layer was washed with water, dried and concentrated by evaporation under reduced pressure. 100 ml of hexane were added to the residue, and the precipitated solid was collected by filtration and washed with hexane. It was then dried to give crude crystals (13.65 g) of the title compound. Concentration of the filtered hexane solution gave a residue, which was subjected to column chromatography through 100 g of silica gel. Crude crystals (1.40 g) were obtained from the fractions eluted with a 2:1 by volume mixture of methylene chloride and diethyl ether. The combined crude crystals were recrystallized from methylene chloride to give the pure title compound (9.65 g) melting at 82°-83° C. Further crystals (3.91 g) were obtained by concentration of the mother liquor. The spectra of these compounds were identical with those ofthe compound obtained as described in (a) above.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[CH:8][C:7]=1[OH:21])([O:3][CH2:4][CH3:5])=[O:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[C:1]([C:6]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:14])[CH:9]=[CH:8][C:7]=1[O:21][CH2:22][CH:24]1[O:26][CH2:25]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc(NC(=O)c2ccc(C)s2)ccc1O
Reactant: ClCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2ccc(C)s2)ccc1OCC1CO1
Temperature: 110 °C

Procedure:
In a flask, the mixture of 35 g of 2-carbethoxy 4-(5-methyl-2-thiophene carboxamido)phenol and 175 ml of epichlorohydrin, is heated to 110° C., then 2.9 g of benzyltrimethylammonium chloride are introduced. The reaction mixture is then heated to reflux for 30 mins., then cooled. Once the temperature of the medium has dropped again to 50° C., 200 ml of water are added and the mixture is stirred strongly. After decantation, the aqueous phase is extracted twice with ether and the organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue hardens in ether. After three washings in 50 ml of isopropylic ether, 30 g of 1-[2-carbethoxy 4-(5-methyl 2-thiophene carboxamido)phenoxy]2,3-epoxy propane are obtained in the form of white crystals melting at 109° C.