Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Yield: 81.7 %

Procedure:
To a solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 2.02 g, 10 mmol) in DMF (30 mL) was added imidazole (6.5 g, 100 mmol) and tert-butylchlorodiphenylsilane (8.22 g, 30 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 3.6 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propoxy-tert-butyl-diphenyl-silane (compound 3a).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Br)cc(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Tribromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-tribromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH3:51])[C@@H:45]([CH2:49][CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:49][CH3:50])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (118 mg, 90%) as a white solid. MS m/z 712 (MNa)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]2)=[C:12]([F:27])[CH:11]=1.CN([CH:31]=[O:32])C>C1COCC1>[Br:9][C:10]1[C:11]([CH:31]=[O:32])=[C:12]([F:27])[C:13]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCCC1CCC(CCc2ccc(Br)cc2F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CCC(CCc2ccc(Br)c(C=O)c2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, LDA (299.0 mL, 328.9 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (400 mL) solution of compound (76) (89.7 g, 274.1 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (30.1 g, 411.1 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 400 mL of 1N hydrochloric acid aqueous solution, and extracted with 200 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 6-bromo-2-fluoro-3-(2-(4-propylcyclohexyl)ethyl)benzaldehyde (77) (61.4 g, yield 63.1%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2].[OH-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20](=[O:23])[CH3:21])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[CH3:2]
Reactant: [OH-]
Reactant: C#CCn1c(-c2ccccc2)nc(C(F)(F)F)c(CC)c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c(C(F)(F)F)nc(-c2ccccc2)n(CC(C)=O)c1=O

Procedure:
To a stirred solution of 4.83 g (15.8 mmol) of 5-ethyl-3-propargyl-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 46) in 50 mL of THF was added 50 mL of 10% aq NaOH. The mixture was heated at reflux for 2 h, cooled and diluted with 150 mL of ethyl acetate. The organic layer was separated, washed with 50 mL of water and 50 mL of brine and dried over MgSO4. Removal of the solvent afforded 4.74 g of 5-ethyl-3-(2-oxopropyl)-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone (compound 179) as a white solid. 1H-NMR (CDCl3) 1.2(3H), 2.2(3H,s), 2.7(2H,q), 4.7(2H,s), 7.45(5H,m).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: c1ccncc1
Product: O=C(NCCCOC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl chloroformate (47 ml.) was added dropwise to a stirred solution of 3-aminopropanol (11.4 ml) in pyridine (150 ml) at 0°. The mixture was then stirred at room temperature overnight. This was poured into ice-water (300 ml.) and extracted with ethyl acetate (3×200 ml). The organic extract was washed with hydrochloric acid (5m, 3×400 ml), dried with anhydrous sodium carbonate-magnesium sulphate and evaporated to give the desired compound as an oil contaminated with a little dimethylcarbonate (30.23 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:57][C@H:56]([CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=1)[CH2:58][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23.1 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]acetamide (0.500 g, 1.08 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.4 g, 0.973 mmol) according to Procedure G to give the title compound (0.185 g, 0.225 mmol).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl.C(Cl)(=O)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:28]([O:29][CH3:30])=[O:31])=[CH:17][CH:18]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.9 %

Procedure:
Methyl 2-(4-fluorobenzyl)piperidine-4-carboxylate (4.981 g, 19.82 mmol) was dissolved in DCM (150 mL) and DIPEA (4.14 mL, 23.79 mmol), then methyl carbonochloridate (1.873 mL, 23.79 mmol) was added. The solution was stirred at room temperature for 50 min. More methyl carbonochloridate (a few drops) were added and the reaction continued at room temperature for 1 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (5.82 g, 95%) as a yellow oil. MS m/z 310 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:25])[CH2:23][CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.CS(C)=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)O
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: CCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Yield: 69.2 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (500 mg, 1.14 mmol), propionic acid (253 mg, 3.42 mmol), HBTU (1.23 g, 3.42 mmol) and N,N-diisopropylamine (737 mg, 5.7 mmol) in 6.5 ml of dimethylformamide is stirred overnight at room temperature. The reaction medium is evaporated to dryness. The dry residue is extracted twice with 50 ml of ethyl acetate and washed with water. The organic phase is then washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then evaporated. The oil obtained is dissolved in 35 ml of dimethyl sulfoxide and then purified 7 times by preparative HPLC on a Nucléodur C18, 100′10 μm reverse-phase column with a gradient over 52 minutes of 5% to 95% acetonitrile supplemented with 0.07% trifluoroacetic acid in water, supplemented with 0.07% trifluoroacetic acid. The flow rate is 70 ml/min. The fractions containing the clean product are concentrated to give 300 mg of 4-fluorobenzenesulfonic acid 2-propionylaminobenzothiazol-6-yl ester in a yield of 69%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])O[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]>C(O)(=O)C>[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:38](=[O:39])[C:33]7=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:41][CH:40]=[C:34]7[C:35]6=[O:36])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc([N+](=O)[O-])cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1
Yield: 73 %

Procedure:
A mixture of 9,9-bis(4-aminophenyl)fluorene (3.5 g, 10 mmol) and 40 ml of acetic acid was stirred and then 4-nitrophthalic anhydride (4.1 g, 21 mmol) was added to the mixture. The resulting mixture was stirred and heated under reflux for 7 hours. After cooling, the beige-colored precipitate was filtered, washed with acetic acid (2×100 ml) and then with water (500 ml). The washed precipitate was recrystallized from dimethylformamide-methanol to provide the title compound as an off-white powder (5.1 g, 73% yield) having a melting point of 360°-363° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 91 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 231 mg, 91%) which was obtained as a white solid. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:16](=[O:17])[CH2:15][Cl:14])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2ccsc2C1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(C(=O)CCl)sc2C1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 1.7 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes and refluxed under heating for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated to give 2.2 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]2[S:24][C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:17][C:7]=2[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: Nc1ccccc1S
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c2c(c1O)Nc1ccccc1S2
Reaction time: 2 h

Procedure:
To a solution of 3,5-di-t-butyl-1,2-benzoquinone (2.2 q) in methanol (15 ml) cooled in an ice bath was added 2-aminothiophenol (1.38 g) and the mixture was stirred for 2 hours. A solid precipitate was filtered off and crystallized from heptane to yield the title compound m.p. 202°-212° (dec.). From the methanol filtrate there was obtained, after chromatography and crystallization, an additional crop of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:22][CH:21]=[CH2:20])[C:6]=2[CH:13]=1
Reactant: C=CCI
Reactant: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Yield: 56 %

Procedure:
6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (700 mg, 3.544 mmol) was suspended in dry DMF (20 ml) under argon at rt, and the stirred suspension was treated with K2CO3 (1.614 mg, 11.695 mmol) and allyl iodide (0.43 ml, 4.607 mmol). It was then stirred at rt for 2 h before addition of further allyl iodide (0.86 ml, 9.214 mmol) and then the reaction was heated at 60° C. for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid which was purified by column chromatography on silica with a 0-5% MeOH in DCM gradient to give the desired product as a light brown solid (472 mg, 56%).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]=1[F:36])[O:17][C:18]1[N:23]=[C:22]2[S:24][C:25]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[N:26][C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C.[F:44][C:45]([F:54])([F:53])[C:46]1[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:35]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[N:23]=[C:22]3[S:24][C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[N:26][C:21]3=[CH:20][CH:19]=2)=[CH:15][C:14]=1[NH:13][C:1](=[O:12])[NH:52][C:49]1[CH:50]=[N:51][C:46]([C:45]([F:54])([F:44])[F:53])=[CH:47][CH:48]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (30 mg, 0.102 mmol) in tetrahydrofuran (2 mL) was added dropwise a suspension of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) and triethylamine (80 μL, 0.580 mmol) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 6-(Trifluoromethyl)pyridin-3-amine (56 mg, 0.348 mmol) was added to the reaction mixture, and the mixture was stirred at 50° C. for 2 hr and at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with aqueous sodium hydrogen carbonate solution (15 mL), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with acetone (3 mL) to give the title compound (40 mg, 26%) as a white solid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:38])[C@H:8]([N:19]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C@H:9]([O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:10])(C)(C)C.C(O)C.C(Cl)[Cl:43]>>[ClH:43].[ClH:43].[OH:5][NH:6][C:7](=[O:38])[C@H:8]([N:19]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C@H:9]([O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:10]
Reactant: ClCCl
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)OCc2cccnc2)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)[C@@H](C)OCc2cccnc2)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 48 h

Procedure:
N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide (1.3 g, 2.4 mmol) is dissolved in methylene chloride (50 mL) containing ethanol (0.14 mL, 2.4 mmol) in a round bottom flask, and the reaction is cooled to -10° C. Hydrochloric acid gas (from a lecture bottle) is bubbled through for 20 minutes. The reaction is sealed, allowed to slowly warm to room temperature, and stirred for two days. The solvent is reduced to 1/3 the volume by evaporation and the residue is triturated with ether. The mixture is filtered, the fiter cake is removed and dried in vacuo to provide N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3(R)-(3-picolyloxy)-butanamide dihydrochloride as a white solid; [α]D25 =+35.26° (c=5.58, DMSO).
Reaction SMILES: [CH2:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH2:8][OH:9])=[C:6]([F:14])[C:5]=1[F:15])[C:2]#[CH:3].[Cl-:16].[Li+].[ClH:18]>[Cu](Cl)Cl.C(#N)C>[Cl:16]/[C:2](=[CH:3]/[Cl:18])/[CH2:1][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: C#CCc1c(F)c(F)c(CO)c(F)c1F
Reactant: [Cl-]
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: CC#N
Product: OCc1c(F)c(F)c(C/C(Cl)=C\Cl)c(F)c1F

Procedure:
A mixture of 4-(prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.1 g), copper (II) chloride (1.3 g), lithium chloride (0.62 g) and dry acetonitrile (23 cm3) was heated at the reflux temperature for 40 hours. The resulting dark solution was poured into dilute hydrochloric acid, and extracted into ethyl acetate. The organic phase was washed with more dilute hydrochloric acid, dried, and the solvent evaporated under reduced pressure to give E-4-(2,3-dichloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.1 g) as an orange oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:22]Br>[N+](C1C=CC=CC=1)([O-])=O.CO>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8]([Br:22])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)Nc1cccc2c1C(=O)c1c(O)cccc1C2=O
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)Nc1ccc(Br)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
55 g of 1-isopropylamino-8-hydroxy-anthraquinone are dissolved in 110 ml of nitrobenzene at 100°, the solution is cooled to 15°-20° whilst stirring, 40 g of bromine are added over the course of approx. 10 minutes, the mixture is stirred overnight until cold and is diluted with 150 ml of methanol whilst cold, the whole is stirred for some time longer and the product is filtered off, washed with methanol and dried. Yield: 53 g.