Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Cc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 512 mg) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (1.52 g) at room temperature, 2-bromo-4-methylpyridine (2.0 g) was added, and the mixture was stirred at 60° C. for 72 hr. The reaction mixture was diluted with water and extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane→hexane-ethyl acetate=24:1) to give the title compound as a brown oil (yield 1.40 g, 56%).
Reaction SMILES: [CH:1]([NH:14][C:15]1[C:20]([Cl:21])=[C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[C:37](=[O:38])[C:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[CH:35][NH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[F:46])[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62]Cl)=[O:60])[CH2:55][CH2:54]1>CN(C=O)C.C(Cl)Cl>[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:54][CH2:55][CH:56]([C:59]([O:61][CH2:62][N:34]2[CH:35]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37](=[O:38])[C:32]([C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:19]4[CH:18]=[CH:17][N:16]=[C:15]([NH:14][CH:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:20]=4[Cl:21])=[C:24]([F:46])[CH:25]=3)=[CH:33]2)=[O:60])[CH2:57][CH2:58]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of N-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (120 mg, 0.189 mmol), K2CO3 (104 mg, 0.756 mmol) and 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate (157 mg, 0.567 mmol) in DMF (2 mL) was stirred at rt for 3 h. The reaction mixture was then diluted with DCM and the solid that formed was filtered off. The residue was washed with sat. aq. KH2PO4 solution. The organic layer was dried over MgSO4 and the desired product was purified by flash column chromatography (SiO2, eluting with a DCM/EtOAc gradient) to give the desired compound (145 mg) as a white solid. MS (ESI+) m/z 876 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1COCC1.C(OCC)C>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1c(N)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzoic acid (7.888 g, 40 mmol) in MeOH (40 mL) and THF (40 mL) at room temperature was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether. The mixture was stirred at room temperature overnight. After the solvent was evaporated under reduced pressure, water and EtOAc was added to the residue. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with 20-40% EtOAc/hexane as eluants to afford methyl 2-amino-4,6-dimethoxybenzoate as a solid (6.462 g, 76%). 1H NMR (300 MHz, CDCl3) δ 5.83 (d, 1H), 5.78 (d, 1H), 5.53 (br, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H); LC-MS (ESI) m/z 212 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][Mg]Br>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH3:11])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde 101 (100 g, 0.492 mol.) in ether (500 mL), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (i.e., diethyl ether) (173 mL, 0.516 mol.) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-bromo-2-fluoro-phenyl)-ethanol 102 (106 g, 0.484 mol.) which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and allyl bromide, white solid N-[2-(3-allyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30]C(=O)C)[CH:26]=4)[CH:21]=3)=[N:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>C(O)C>[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=4)[CH:21]=3)=[N:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(OC(C)=O)ccc4c3)s2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
0.62 g (9.39 mM) of potassium hydroxide was dissolved in 30 ml of ethanol at 60°-65° C. To the solution, 1.50 g (3.48 mM) of 2-(4-hexylphenyl)-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole was added, followed by stirring for 10 minutes at 60°-65° C. The reaction mixture was poured into 100 ml of iced water and 0.83 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from acetone to obtain 1.19 g of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 87.9%). ##STR35##
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][OH:10])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[CH3:1][N:2]([CH2:8][CH2:9][O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1nccs1
Product: CN(CCOc1ccc(C=O)cc1)c1nccs1

Procedure:
The title compound was prepared from 2-[N-methyl-N-(2-thiazolyl)amino]ethanol (10.7 g) and 4-fluoro-benzaldehyde (15.9 g) by an analogous procedure to that described in Preparation 5.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18]/[C:19](=[CH:21]/[CH2:22]O)/[CH3:20])[CH3:15]>ClCCl.N1(C2C=CN=CC=2)CCCC1>[CH3:20][C:19]([CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[CH:21][CH2:22][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)CCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCC(=O)CCC(=O)OCC=C(C)CCC=C(C)C
Yield: 59.7 %

Procedure:
A solution of 20 g 4-oxo-nonanoic acid, 19.3 g geraniol, 26.8 g N,N-dicyclohexyl-carbodiimide and 1.0 g 4-pyrrolidinopyridine in 300 ml of dichloromethane was stirred for 24 hours at room temperature. The precipitate was filtered off, the filtrate was diluted with ether, washed with aqueous hydrochloric acid, saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The resulting oil-crystal mixture was purified by chromatography to yield 21.4 g of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]([F:18])([F:17])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][CH:12]([F:18])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Reaction time: 3 h
Yield: 29.4 %

Procedure:
3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere. After stirring at 60°-65° C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether. The aqueous layer was extracted three times with ether. The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38%). mp 83°-85° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]([C:25]3[C:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)=[N:19]2)[CH2:13]1>ClCCl.C(N(CC)CC)C.C(OCC)(=O)C>[O:11]=[C:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]([C:25]3[C:26]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)=[N:19]2)[CH2:13]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of oxalyl chloride (160 μl) in dichloromethane (10 ml) was added dropwise in turn with dimethyl sulfoxide (210 μl), a solution of 3-[2-(3-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (366 mg) in dichloromethane (10 ml) and triethylamine (663 μl) at −70° C. under nitrogen atmosphere. A reaction mixture was allowed to warm to ambient temperature and diluted with ethyl acetate (100 ml), which was washed in turn with 1N-aqueous hydrochloric acid (50 ml×2), brine (50 ml), saturated sodium hydrogen carbonate in water (50 ml) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting in turn with 30% and 50% ethyl acetate in dichloromethane. Fractions containing desired product were combined and concentrated in vacuo to give solid, which was recrystallized from ethanol to give 3-[2-(3-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (310 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[CH2:14]([S:17](Cl)(=[O:19])=[O:18])[CH2:15][CH3:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:17]([CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18])=[C:7]([CH3:12])[CH:6]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
According to the general procedure described in Example 1-C, 3-methyl-4-aminophenyl N-methylcarbamate (4.0g., 0.022 mole) was reacted with n-propanesulfonyl chloride (31.5g., 0.022 mole) and triethylamine (2.47g., 0.024 mole) in benzene. The product (4.0g.) showed the characteristic carbonyl absorption at 5.8μ in the infrared (KBr).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:34])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([CH3:34])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCOCC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (70.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 98.5 mg (79%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.28 (br s, 1H, NH), 11.68 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.56 (m, 4H, 2×CH2), 3.45 (m, 4H, 2×CH2), 2.31 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[O:3][C:4]([C:12]([F:14])([F:13])[F:15])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(C(F)(F)F)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(C(F)(F)F)cc1CO
Reaction time: 3 h

Procedure:
To a mixture of ethyl 2-methyl-5-(trifluoromethyl)furan-3-carboxylate (720 mg) and THF (dry) (10 mL) was added lithium aluminum hydride (123 mg) at 0° C., and the mixture was stirred for 3 h. The mixture was quenched with EtOAc at 0° C. and 1N HCl was added to the mixture at same temperature. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo to give title compound.
Reaction SMILES: C([N:8]1[C@H:11]([CH2:12][Cl:13])[C@H:10]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:9]1=[O:25])C1C=CC=CC=1.[O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].O.P(O)([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[C:15]1(=[O:24])[N:14]([C@H:10]2[C@@H:11]([CH2:12][Cl:13])[NH:8][C:9]2=[O:25])[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](CCl)N1Cc1ccccc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1N[C@H](CCl)[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 120 °C
Yield: 40.8 %

Procedure:
A mixture of 17.75 g of the product of Step B, 31 g of potassium peroxodisulfate, 110 ml of water and 160 ml of acetic acid was heated for 25 minutes with strong agitation in an oil bath at 120° C. and was then cooled to room temperature. 50 g of dipotassium phosphate were added to the mixture to adjust the pH to neutrality and was evaporated to dryness under reduced pressure. 250 ml of water and 150 ml of ethyl acetate were added to the residue and after stirring, sodium bicarbonate was added in small quantities until evolution of gas ceased. The mixture was filtered and the filtrate was rinsed with ethyl acetate. The decanted aqueous phase was re-extracted with 50 ml of ethyl acetate and the combined organic phases were dried, filtered, rinsed and evaporated to dryness under reduced pressure. The residue was chromatographed over 200 g of silica gel and eluted with methylene chloride with 25% of ethyl acetate. The rich fractions were recovered and evaporated to dryness. The residue was dissolved in ether, and the solution was rinsed and dried to obtain 5.4 g of cis 3-phthalimido-4-chloromethyl-2-azetidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:28]O>C(O)(=O)C>[O:28]=[S:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([O:9][CH2:8][C:7]3[CH:26]=[CH:27][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: OO
Reactant: O=C(Nc1ccc2sc3ccccc3c2c1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
2-(4-Nitrobenzoxycarbonylamino)dibenzothiophene (Example 1; 364 mg, 1.0 mmol) was suspended in a mixture of glacial acetic acid (5.0 ml) and 30% hydrogen peroxide (565 mg, 5 mmol) and the mixture was warmed at 60° C. for 2 hours. The suspension of the title compound was filtered and air dried. TLC: (2:1; EtOAc:isohexane) Rf=0.30.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][N:10]([CH2:12][CH2:13][CH3:14])[C:9]2[N:8]3[CH2:15][N:16]([OH:18])[CH:17]=[C:7]3[CH:6]=[N:5][C:4]=2[C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[OH-].[Na+].Cl[C:27]([F:32])([F:31])C(O)=O>CN(C)C=O>[F:31][CH:27]([F:32])[O:18][N:16]1[CH:17]=[C:7]2[CH:6]=[N:5][C:4]3[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:2]([CH3:1])[CH2:11][N:10]([CH2:12][CH2:13][CH3:14])[C:9]=3[N:8]2[CH2:15]1
Reactant: CCCN1CC(C)=C(NS(C)(=O)=O)C2=C1N1CN(O)C=C1C=N2
Reactant: O=C(O)C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN1CC(C)=C(NS(C)(=O)=O)C2=C1N1CN(OC(F)F)C=C1C=N2
Temperature: 150 °C

Procedure:
4.98 g 3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol (Example 86) and 1.6 g sodium hydroxide were dissolved in 20 ml dimethylformamide. After 10 min stirring 1.85 ml chlorodifluoroacetic acid was added dropwise. The mixture was heated 5 h at 150° C. bath temperature with stirring. After cooling the product was extracted with ethyl acetate (200 ml, 300 ml), the combined organic phases were washed with water (2×100 ml), the organic phase was dried over sodium sulfate, filtered off, and evaporated to dryness.
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1)=[O:25])[CH:9]([OH:22])[CH2:10][CH:11]([C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]#[C:37]Br.C(=O)([O-])O.[K+]>O1CCOCC1.O>[NH2:36][C:37]1[O:19][C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:22])[CH:8]([NH:23][C:24]([C:26]2[CH:35]=[N:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][N:21]=1
Reactant: N#CBr
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1nnc(N)o1
Yield: 55.4 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide (110 mg, 0.228 mmol) in dioxane (0.5 mL) and water (0.5 mL) was added cyanogen bromide (31 mg, 0.296 mmol) and potassium hydrogencarbonate (31 mg, 0.310 mmol). The reaction was heated to reflux for 1 hour then cooled to ambient termperature. The dioxane/water was removed by adding benzene (5 mL) and concentrating (2×). The remaining solid was dissolved in ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. Recrystallization of the crude product using a mixture of ethyl acetate, hexanes and methanol gave the title compound (64 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[CH:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.Cl>O1CCOCC1>[CH3:10][CH:6]1[C:5]2[CH:11]=[C:12]([CH3:13])[C:2]([N:1]3[CH:16]=[CH:20][CH:19]=[CH:18]3)=[CH:3][C:4]=2[O:8][C:7]1=[O:9]
Reactant: Cc1cc2c(cc1N)OC(=O)C2C
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-n1cccc1)OC(=O)C2C
Temperature: 25 °C

Procedure:
1.8 g of 6-amino-3,5-dimethylbenzofuran-2-(3H)-one are dissolved in 20 ml of dioxane and, while stirring at room temperature, 2 ml of 2,5-dimethoxytetrahydrofuran and 1.4 ml of 37% strength hydrochloric acid are added. After 30 minutes the aqueous phase is removed and the organic phase is concentrated to dryness by evaporation in vacuo. The residue is chromatographed over silica gel with methylene chloride. The resulting pale-yellow oil crystallises from butyl oxide. In this manner 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran-2(3H)-one having a melting point of 61°-63° C. is obtained.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]2[O:48][CH2:47]2)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:49]([NH2:53])([CH3:52])([CH3:51])[CH3:50]>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([OH:48])[CH2:47][NH:53][C:49]([CH3:52])([CH3:51])[CH3:50])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(C)N
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C2CO2)c1)OCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C(O)CNC(C)(C)C)c1)OCCCCCCCCCCCCCCCC
Temperature: 100 °C
Yield: 27 %

Procedure:
t-Butylamine (30 ml) and 1,2-di-O-(n-hexadecyl)-3-O-[3-(1,2-epoxyethyl)-benzyl]-glycerol (2.0 g, 2.97 mmol) were placed in a steel bomb and heated to 100° C. for 9 hours. After cooling the reaction mixture, t-butylamine was removed under reduced pressure and the resulting oil purified by silica gel chromatography, eluted with benzene/ethanol. The desired fractions were saturated with gaseous hydrochloric acid, concentrated under reduced pressure, and recrystallized from ethyl acetate to give pure 1,2-di-O-(n-hexadecyl)-3-O-[3-(1-hydroxy-2-t-butylaminoethyl)-benzyl]-glycerol (630 mg, 27%): mp 49°-51° C.; NMR (CDCl3) δ 1.47 [s, 9, --C(CH3)3 ].