Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
Add (R)-2-methylpropane-2-sulfinamide (40.5 g, 0.33 mol) portionwise to a solution of 4-bromobenzaldehyde (65.57 g, 0.35 mol) in toluene (283 mL). Stir the mixture at ambient temperature for 15 minutes and then add sodium hydroxide (1.34 g, 0.33 mol). Stir the suspension at ambient temperature for 12 hours. Add sodium sulphate (16 g) and Celite® (16 g) and stir the suspension for 15 minutes. Filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography eluting with hexane/EtOAc (100% to 70% hexane) to afford the title compound as a white solid (85.5 g, 88% yield). MS (m/z): 288 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-chloro-4-fluorophenylboronic acid (150 mg, 0.85 mmol) the subtitle compound was obtained (163 mg, 72%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.45(dd, 1H), 7.87(d, 1H), 7.64(m, 2H), 7.52(dd, 1H), 7.49–7.44(m, 1H), 7.28–7.21(m, 2H), 4.08(s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Product: CC1(C)CC(=O)N(C(=O)Nc2ccc(Cl)cc2)CC(C)(C)N1

Procedure:
Using conditions similar to Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 17 parts of p-chlorophenylisocyanate afforded 20 parts of 4-p-chlorophenylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid of melting point 119° -121°C. This material had the following elemental analysis by weight:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:23][NH2:24]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=1[NH:23][NH2:24])#[N:2]
Reactant: NN
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1N1CCCCC1
Solvent: CO
Solvent: O
Product: C=C1NC(N2CCCCC2)=C(C(=O)OCC)C(NN)=C1C#N
Temperature: 25 °C

Procedure:
28.7 g of 5-cyano-6-formyl-2-piperidinyl-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) are dissolved in 100 ml of methanol. 5.5 g of hydrazine hydrate are added and the solution is stirred at room temperature over night. The title compound is filtered off and recrystallized from methanol. Yield 20.5 g (68%); m.p. 168°-170° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[CH:35]=[CH:34][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:34][CH:35]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-propyl-nicotinamide (Intermediate 31, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-propyl-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:16])[C:13]#[N:14].C(#N)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].OS(O)(=O)=O>O>[C:20]([O:16][CH2:15][CH:12]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:13]#[N:14])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1cc(OC(F)F)ccc1Cl
Yield: 80.4 %

Procedure:
A 5 mL screw-capped test tube was charged with 250 mg (1.00 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile, 0.4 mL of acetonitrile and 122 μL (1.3 mmol) of acetic anhydride. This mixture was stirred briefly with a melting point capillary having the tip wetted with conc. H2SO4 to give an immediate exotherm. After 15 minutes the mixture was diluted with water and extracted with butyl chloride. The extract was washed with water 3 times, dried (Na2SO4), and stripped of solvent under high vacuum to give 233 mg (96%) of the desired ester product, i.e., 3-acetoxy-2-(2-chloro-5-(difluoromethoxy)phenyl)propanenitrile, as a colorless oil.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:35]([O:37]C)=[O:36])[CH2:21][C:22]3[CH:33]=[C:32]([CH3:34])[C:25]4[NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:39]=[CH:40][CH:41]=[CH:42][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:35]([OH:37])=[O:36])[CH2:21][C:22]3[CH:33]=[C:32]([CH3:34])[C:25]4[NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:39]=[CH:40][CH:41]=[CH:42][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(N(C)C)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc(N(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 9.0 mg (0.38 mmol) LiOH in 0.5 mL water was added to a solution of 80 mg (0.15 mmol) (R)-2-(2-dimethylamino-7-methyl-1H-benzimidazol-5-yl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 4 mL THF and the reaction mixture was stirred for 4 h at RT. 100 μL of 4 M HCl was added, the mixture was evaporated down i.vac. and the crude product was dried and then further reacted without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH2:17]([NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[C:24]=1[CH3:34])=[O:22])[CH2:18][CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:17]([NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:29][CH:30]=2)[N:25]([CH3:33])[C:24]=1[CH3:34])=[O:22])[CH2:18][CH3:19]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
This material was prepared from 7-chloro-2-(1-methyl-1H-imidazol-2-yl]thieno[3,2-b]pyridine 1e with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid propylamide 58b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ 8.42 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.37 (1H, d, J=1.8 Hz), 7.30 (1H, s), 7.08 (1H, s), 7.03 (1H, dd, J=1.8, 8.7 Hz), 6.65 (1H, d, J=5.5 Hz), 4.01 (3H, s), 3.70 (3H, s), 3.39 (2H, m), 2.64 (3H, s), 1.70 (2H, m), 1.03 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 460. found 460.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.FC(F)(F)C1C=C(O)C=CC=1.[H-].[Na+].COC(=O)C1C=C(Cl)C=C(Cl)N=1>O1CCOCC1.[Cu](I)I.O>[Cl:10][C:8]1[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[N:5]=[C:4]([C:3]([OH:22])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Agent: I[Cu]I
Agent: COC(=O)c1cc(Cl)cc(Cl)n1
Agent: Oc1cccc(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 125 °C
Reaction time: 10 h

Procedure:
<Production of 4-chloro-6-[3-(trifluoromethyl)phenoxy] picolinic acid methyl ester as an intermediate product>3-(trifluoromethyl) phenol (3.15 g, 0.0019 mol) was dissolved in 50 ml of dried dioxane. Sodium hydride (0.8 g (ca. 60% in mineral oil), 0.0019×1.05 mol) was added to the obtained solution at room temperature. After completion of the foaming, a solution obtained by dissolving 4,6-dichloro picolinic acid methyl ester (4.0 g, 0.0019 mol) in 5 ml of dried dioxane, was dropped into the above solution. Successively, copper iodide (3.7 g, 0.0019×1.0 mol) was added to the obtained solution. The resultant mixture was heated and stirred at a temperature of 120 to 130° C. for 10 hours. Thereafter, the obtained reaction solution was cooled, mixed with 10 ml of water, and then filtered through a glass filter provided with Hyflo Super-Cell. The obtained filtrate was extracted with 100 ml of ethyl acetate two times, thereby separating an organic phase therefrom. The obtained organic phase was dried with sodium anhydride. After the dried organic phase was subjected to distillation to remove the solvent therefrom, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]#[N:7].C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([N:29]1[CH2:30][C:2]2([C:6]#[N:7])[CH:3]([CH2:4][CH2:5][O:1]2)[CH2:35]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#CC1=CCCO1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC12CN(Cc3ccccc3)CC1CCO2
Temperature: 40 °C
Reaction time: 15 h

Procedure:
14.4 g (0.15 mol) of 4,5-dihydrofuran-2-carbonitrile are introduced in 300 ml of absolute methylene chloride, 1.8 g of triethylamine and 1.8 g of trifluoroacetic acid are added, and the mixture is warmed to 40° C. 42.6 g (0.15 mol) of N-benzyl-N-methoxymethyl-N-trimethylsilylmethylamine are added dropwise to this mixture which is then stirred at 40° C. for 15 hours. It is then washed with 50 ml of saturated sodium hydrogen carbonate solution, dried over MgSO4, concentrated and distilled twice.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([OH:20])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([N:23]([O:24][CH3:25])[CH3:22])=[O:20])[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2c(C(=O)O)cnn2C(C)(C)C)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(=O)N(C)OC)cnn2C(C)(C)C)cc1
Yield: 92.5 %

Procedure:
A solution of the compound (300 mg, 1.09 mmol) obtained in step 2, N,O-dimethylhydroxylamine monohydrochloride (160 mg, 1.64 mmol), HOBt (222 mg, 1.64 mmol), WSC (314 mg, 1.64 mmol) and TEA (0.228 mL, 1.64 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution and dried, and the solvent was evaporated under reduced pressure to give a crude product 1-tert-butyl-N-methoxy-5-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide (320 mg, 1.008 mmol, 92%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[CH:21]1([CH2:24][NH:25][C:26]2[N:31]([CH3:32])[C:30](=[O:33])[C:29]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=3)=[CH:28][N:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CC([O-])(C)C.[K+]>CN(C=O)C>[CH:21]1([CH2:24][NH:25][C:26]2[N:31]([CH3:32])[C:30](=[O:33])[C:29]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[C:10]([CH3:18])[C:11]=45)=[C:36]([F:41])[CH:35]=3)=[CH:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: Cn1c(NCC2CC2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(NCC6CC6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 15 mL capacity reaction tube were added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (20 mg, 0.07 mmol; prepared according to the procedure of Example 43, Step E) and 2-(cyclopropylmethylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (22.1 mg, 0.077 mmol) and the solids were dissolved in DMF (1 mL) under nitrogen. Potassium carbonate (10.6 mg, 0.0765 mmol) was added, followed by KOtBu (0.077 mL, 0.077 mmol, 1M solution in THF). The reaction tube was sealed and the reaction mixture was stirred at 110° C. for 1 hour. The reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with a second portion of ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate and evaporated to afford 37.5 mg of a red semi-solid. The crude product was purified by silica gel chromatography (Biotage 12M) eluting with 2% MeOH/DCM to afford a red colored glass (23.8 mg, 63%). LRMS (APCI pos) m/e 541.3 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22](O)=[O:23])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]1[CH:16]=[C:15]([CH:14]=[C:13]([O:12][CH3:11])[CH:18]=1)[CH2:21][CH2:22][OH:23]
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCO)cc(OC)c1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
Within 40 minutes, 1.12 liters of a 20% solution of diisobutylaluminum hydride in toluene is added dropwise to a solution, cooled to -40° C., of 132.3 g. of the methyl ester of 3,5-dimethoxyphenylacetic acid in 1.3 l. of absolute toluene, the temperature rising to -10° C. during this step. After another 20 minutes at -10° C., 151 ml. of water is carefully added dropwise so that the temperature does not exceed +10° C. 200 g. of sodium sulfate is then added to the reaction mixture, and the latter is stirred for 2 hours at room temperature. The solids are filtered off and a subsequent washing step is performed with a total of 1 liter of methylene chloride.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]2([CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[C:16](=[O:30])[O:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C>[C:20]1([CH:19]2[C:12]3([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[O:15][C:16](=[O:30])[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]2=3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1OC2(CCNCC2)C(c2ccccc2)c2ccccc21

Procedure:
Prepared by the procedure described in Example 3, Step A from 1'-benzyl-1,4-dihydro-4-phenylspiro(3H-2-benzopyran-3,4'-piperidine)-1-one hydrochloride, (8 mg, 0.019 mmol) and ethanol (5 mL). Reaction time: 45 minutes. Yield 5.5 mg (98.5%).
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:4][C:5]([O:7]CC1C=CC=CC=1)=[O:6]>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:2](=[O:22])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(=O)C(CC(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)C(CC(=O)O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
A suspension of benzyl 4-amino-3-(4-bromophenyl)-4-oxobutanoate (1.14 g, 3.16 mmol) and platinum(IV) oxide (30 mg) in ethanol/ethyl acetate (5:1; 120 mL) was stirred under an hydrogen atmosphere for 2 h. After replacement of hydrogen with nitrogen the crude reaction mixture was filtered through a thin pad of celite and the filtrate evaporated to dryness to give the title compound as a white solid (671 mg, 78%). LC/MS: 2.41 min; z/e 271 and 273, calcd (M+1) 271 and 271. 1H NMR (400 MHz: DMSO-d6): 7.50 (2H), 7.25 (2H), 3.95 (1H), 2.95 (1H), 2.45 (1H).
Reaction SMILES: [C:1](OC1C=CC=CC=1)([O:16]C1C=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(O)C=CC=CC=1.S(=O)(=O)(O)O>>[C:1](=[O:16])([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(OC(Oc2ccccc2)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 2 h

Procedure:
The above procedure is repeated except that hydrolysis of the tetraphenyl orthocarbonate is effected by adding to a solution of 10.5 grams of phenol in 4.0 ml. of 0.1N aqueous sulfuric acid. The reaction is complete within two hours. An excellent yield of diphenyl carbonate is obtained and no significant by-products are formed.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:10][C:11]1[C:12]([NH:17][C:18]([C:20]2[O:39][C:23]3=[N:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH:27]=[C:22]3[CH:21]=2)=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:10][C:11]1[C:12]([N:17]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])[C:18]([C:20]2[O:39][C:23]3=[N:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)[CH:27]=[C:22]3[CH:21]=2)=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(COCc2cnc3oc(C(=O)Nc4ncccc4Br)cc3c2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cnc3oc(C(=O)N(COCC[Si](C)(C)C)c4ncccc4Br)cc3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-Trimethylsilylethoxymethyl chloride (0.13 g, 0.81 mmol) was added to a solution of N-(3-bromopyridin-2-yl)-5-(((4-methoxybenzyl)oxy)methyl)furo[2,3-b]pyridine-2-carboxamide (0.29 g, 0.62 mmol) and cesium carbonate (0.61 g, 1.8 mmol) in DMF (6.2 mL) at 0° C. The reaction mixture was gradually warmed to 23° C. and stirred for 2 h, then partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 18% ethyl acetate in petroleum ether to give the title compound. MS: m/z=600.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc(Cl)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 43.9 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-chlorobenzaldehyde 1.03 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 250 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.77 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@H:13](O)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:64]([C@@H:13]1[C@@H:11]2[C@@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[N+:65]=[N-:66]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reaction time: 16 h

Procedure:
(3aR,4R,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (3.00 g, 13.81 mmol, Example 706, Step 1) and triphenylphosphine (4.35 g, 16.57 mmol) were combined in toluene (69 mL). Diisopropyl azodicarboxylate (3.49 g, 17.26 mmol) was added dropwise via addition funnel to the reaction solution at 5° C. Diphenylphosphoryl azide (4.56 g, 16.57 mmol) was then added to the reaction solution. The reaction was allowed to proceed at room temperature for 16 hours and then quenched with saturated aqueous sodium bicarbonate (100 mL). The resulting layers were separated and the product containing phase was extracted with 1.2 M hydrochloric acid (2×40 mL). The acid layer was extracted with ethyl acetate (50 mL) and then basified with 1.9 M potassium hydroxide (68 mL). The aqueous solution was extracted with methyl tert-butyl ether (2×50 mL). The methyl tert-butyl ether was removed under reduced pressure by co-distillation with ethanol and then filtered to provide (3aR,4S,6aS)-4-azido-2-benzyloctahydrocyclopenta-[c]pyrrole in ethanol.
Reaction SMILES: [F:1][C:2]1[C:34]([NH:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:18]([F:21])([F:20])[F:19])=[CH:9][C:8]=1[I:30])=[O:5].[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>>[F:1][C:2]1[C:3]([C:4](=[O:5])[NH:6][C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:18]([F:20])([F:21])[F:19])=[CH:9][C:8]=2[I:30])=[CH:31][CH:32]=[CH:33][C:34]=1[N:35]([CH3:36])[C:41](=[O:42])[O:40][CH2:39][C:38]([Cl:45])([Cl:44])[Cl:37]
Reactant: CNc1cccc(C(=O)Nc2c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2C(F)(F)F)c1F
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CN(C(=O)OCC(Cl)(Cl)Cl)c1cccc(C(=O)Nc2c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2C(F)(F)F)c1F

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 2-fluoro-N-(2-iodo-4-(perfluorobutan-2-yl)-6-(trifluoromethyl)phenyl)-3-(methylamino)benzamide and 2,2,2-trichloroethoxycarbonylchloride.