Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][S:24]([NH:27][C:28]([N:30]3[CH2:33][C@H:32]([NH:34]C(=O)OCC4C=CC=CC=4)[C:31]3=[O:45])=[O:29])(=[O:26])=[O:25])=[O:22])[C:17]2=[O:46])[CH:12]=[CH:13][C:14]=1[OH:15].[Na]>C1(SC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:34][C@H:32]1[CH2:33][N:30]([C:28]([NH:27][S:24]([NH:23][C:21]([N:18]2[CH2:19][CH2:20][N:16]([C:11]3[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([OH:8])[CH:10]=3)[C:17]2=[O:46])=[O:22])(=[O:25])=[O:26])=[O:29])[C:31]1=[O:45]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Agent: [Na]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 20 ml of thioanisole and 75 ml of trifluoroacetic acid was cooled to 0° C. and 15.25 g of (S)-[1-[[[[[[3-(3,4-dihydroxyphenyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monosodium salt was added. After stirring overnight at room temperature, the excess trifluoroacetic acid was evaporated in vacuo and the residue triturated with ether. The precipitate was filtered off by suction, washed with ether, and dried in vacuo; yield: 15.69 g.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:32])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][N:25]([CH2:27][C:28]([O:30]C)=[O:29])[N:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1>C(#N)C>[ClH:1].[C:28]([CH2:27][N:25]1[N:24]=[N:23][C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:32])[CH2:19][CH2:18][CH:17]\2[SH:20])=[N:26]1)([OH:30])=[O:29]
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Agent: Cl
Solvent: CC#N
Product: O=C(O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 69.9 %

Procedure:
(E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-4-sulfanylpiperidine hydrochloride (135 mg) was subjected to the procedure similar to that described in Example 134. After purification by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v), the title compound (91.6 mg, yield: 70%) was obtained as a colourless amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CCN(CC)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N,N-diethylamine to give a yellow solid. MS m/z: 391.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][S:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCSCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2.5 g, 10.24 mmol) and dihydro-2H-thiopyran-4(3H)-one (1.42 g, 12.29 mmol) in dichloroethane (50 mL), acetic acid (3.6 ml, 61.47 mmol) was added and reaction stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (6.5 g, 30.73 mmol) was added and stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. Column chromatography purification of crude gave methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 71.0%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[O:63]=[C:64]1[NH:69][CH2:68][CH2:67][N:66]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[CH3:14])[N:3]=[C:2]([N:69]1[CH2:68][CH2:67][N:66]([C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])[CH2:65][C:64]1=[O:63])[CH:11]=[CH:10]2)#[N:13]
Reactant: Cc1cc2nc(Cl)ccc2cc1C#N
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)CC3=O)ccc2cc1C#N
Temperature: 100 °C

Procedure:
To a 25 mL flask was added a stir bar, 2-Chloro-7-methylquinoline-6-carbonitrile (0.2 g, 0.98 mmol), Pd2 dba3 (0.11 g, 0.19 mmol), Xantphos (0.090 g, 0.090 mmol), Cesium Carbonate (0.26 g, 0.63 mmol) and tert-Butyl 3-oxopiperazine-1-carboxylate (0.29 g, 1.4 mmol). The resulting mixture was degassed and purged with N2 three times. To the flask was added 1,4-dioxane (4 mL). The reaction mixture was then refluxed at 100° C. overnight. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was then purified by silica gel column chromatography (10% MeOH in DCM) to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)#[N:2]>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[C:1]#[N:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N)CC2)c1

Procedure:
ethyl 4-cyano-3-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}-amino)cyclohexyl]amino}benzoate (0.37 g, 0.97 mmol) was stirred in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL) at room temperature for 1 hour. The solvent was rotary evaporated, and the residue was dried in vacuo to give ethyl 3-[(trans-4-aminocyclohexyl)amino]-4-cyanobenzoate (0.490 g, 99% yield) as trifluoroacetic acid salt. MS (EI) for C16H21N3O2: 288 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[C:18]1([C:24]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][O:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:25])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: c1ccc(C2(c3ccccc3)CO2)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a solution of 8-chloro 2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole (800 g, 3.6 mmol) in 8 mL DMF, was added sodium hydride [60% dispersion in oil] (436 mg, 10.9 mmol) and the reaction mixture was stirred for 5 min. 2,2-Diphenyl oxirane (1.06 g, 5.4 mmol) was added dropwise at RT and reaction mixture stirred at RT for 16 h. The reaction mixture was poured into ice water and the desired compound extracted with EtOAc (3×200 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was crystallized in ether (50 mL) to obtain 950 mg of white solid product as the free base. 100 mg free base was converted to HCL salt. 1H NMR (DMSO, HCl salt) δ (ppm): 7.50 (m, 2H), 7.40 (s, 1H), 7.30 (m, 3H), 7.22 (m, 5H), 7.14 (d, 1H), 6.82 (d, 1H), 6.15 (bs, 1H), 4.82 (d, 2H), 4.55 (m, 1H), 4.38 (m, 1H), 4.20 (m, 1H), 3.56 (m, 1H), 3.20 (m, 2H), 2.86 (s, 3H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1>C1COCC1.O.[OH-].[Na+]>[CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (10 mg, 0.023 mmol) in THF (0.6 mL) and H2O (0.4 mL) was added NaOH (5N, 2 drops). After stirring for 3 h at room temperature, the reaction mixture was purified by preparative HPLC to yield 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (MS calcd for C21H22N6O3 406.2, found [MH] 407.0; UV 207.5, 304.5 nm).
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].[H-].[Na+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([O:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:6])([F:7])[F:8])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: OCc1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)n1ncc(OCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1.16 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl alcohol (Example 3) and, 15 minutes later, 0.95 g of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone are added to a suspension of 0.2 g of sodium hydride at 50% in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.3 g of pure product is obtained. Melting point 68°-69° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([NH:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH3:13]>ClCCl>[CH:12]([NH:15][CH2:16][CH2:17][NH:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])([CH3:14])[CH3:13]
Reactant: CC(C)NCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCNC(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 65 grams of p-toluenesulfonyl chloride in 125 ml. of dichloromethane was added dropwise with stirring to a solution of 100 grams of N-isopropylethylenediamine in 150 ml. of dichloromethane. Following completion of addition the mixture was stirred one-half hour at room temperature, then heated in a steam bath for 45 minutes. The mixture was evaporated to dryness in vacuo. The residue was triturated with sodium carbonate solution then dissolved in a mixture of ethyl acetate and water. The ethyl acetate portion was extracted with saturated sodium carbonate solution and water. After drying the ethyl acetate portion over magnesium sulfate, the solvent was removed in vacuo. The solid residue was recrystallized from ethyl acetate-hexane to obtain N-[2-(isopropylamino)ethyl]-p-toluenesulfonamide, m.p. 76°-8°C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:20])[N:13]([CH2:17][CH2:18][CH3:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:21])[CH:4]=1.[CH:24]1(C=O)CC1>>[F:23][C:2]([F:1])([F:22])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:20])[N:13]([CH2:17][CH:18]4[CH2:24][CH2:19]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:21])[CH:4]=1
Reactant: CCCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C
Reactant: O=CC1CC1
Product: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 10.91 (br. s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 6.94 (s, 1H), 3.65 (m, 1H), 3.35 (dd, 1H, J=15.0, 5.5), 3.09 (dd, 1H, J=15.0, 6.2), 2.97-2.82 (m, 2H), 2.00-1.94 (m, 1H), 1.84-1.79 (m, 1H), 1.17 (d, 3H, J=6.5), 0.88-0.85 (m, 1H), 0.58 (m, 2H), 0.28 (dd, 2H, J=10.3, 5.0).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1

Procedure:
30 g of 2-amino-4-(4'-nitrophenyl)-1,3-thiazole (prepared in accordance with J. Chem. Soc. 1059, (2365) and 100 ml of acetic anhydride are heated for 3 hours at 140° C. Excess acetic anhydride is removed by vacuum distillation and the residue is treated with 500 ml of warm water, filtered, washed, and dried to constant weight, affording 34 g of 2-acetamido-4-(4'-nitrophenyl)-1,3-thiazole.
Reaction SMILES: N#N.[N+:3]([C:6]1[NH:10][N:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1>C(C#N)(C)=O.CC(=O)OCC.O>[CH3:27][C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][N:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[N:10]2)[O:26][CH2:25][CH2:24][O:23]1
Reactant: CC1(CCCCBr)OCCO1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: CC(=O)C#N
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(CCCCn2ccc([N+](=O)[O-])n2)OCCO1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-nitro-1H-pyrazole (2.97 g, 18.68 mmol) and Cs2CO3 (6.67 g, 26.22 mmol) in AcCN (27.0 mL) was treated with a solution of 2-(4-bromo-butyl)-2-methyl-[1,3]dioxolane (5.85 g, 26.22 mmol) in AcCN (27.0 mL). The reaction mixture was stirred at 80° C. for 2.5 h. Water (100 mL) and EA (200 mL) were added to the cooled reaction mixture. The aq. layer was extracted with EA (100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound. TLC: rf (60:40 hept-EA)=0.17. LC-MS-conditions 02: tR=0.89 min; [M+H]+=256.32. 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H), 1.39-1.50 (m, 2H), 1.67-1.75 (m, 2H), 1.92-2.02 (m, 2H), 3.88-3.94 (m, 2H), 3.94-4.00 (m, 2H), 4.22 (t, J=7.0 Hz, 2H), 6.91 (d, J=2.3 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of 1564 g. (10.2 mole) of methyl 3-hydroxybenzoate, 1407.6 g. (10.2 mole) potassium carbonate and 1285.2 g. (10.2 mole) benzyl chloride in 5 . of acetone is heated at reflux for 22 hours. The reaction mixture is then cooled, filtered and the filtrate evaporated. The residue is crystallized in a small volume of pentane to give a quantitative yield of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].C(N(CC)CC)C.[C:32]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.ClCCl>[Si:36]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (45 g, 124 mmol), DMAP (760 mg, 6 mmol) and triethylamine (25.1 g, 248 mmol) in dichloromethane (300 mL) was added tert-butylchlorodimethylsilane (22.4 g, 149 mmol). After stirred for 6 h at room temperature, the mixture was condensed to provide a residue, which was purified by silica gel column, eluted with 10-30% ethyl acetate in petroleum ether to give compound 17 as a yellow oil (43 g. 65%). (ES, m/z): [M+H]+ 477.1; 1H NMR (300 MHz, CDCl3) δ 6.12-6.14 (d, J=6.3 Hz, 1H), 4.40-4.45 (m, 1H), 3.84-3.96 (m, 4H), 3.64-3.71 (m, 1H), 3.13-3.30 (m, 3H), 1.67-1.74 (m, 2H), 1.53 (s, 9H), 0.93-0.98 (m, 3H), 0.92 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (70 mg, 0.19 mmol) in tetrahydrofuran (2 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 24 hr. 1N Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried in vacuo to give 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (59 mg, yield 85.2%).
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=O)[NH:21][C:20]=2[CH:31]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]([Cl:12])[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH:22]=[N:21][C:20]=2[CH:31]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
N,N-dimethylaniline (5.1 ml, 40 mmol) and phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (2.45 g, 10 mmol) in dry toluene (20 ml). The mixture was shaken at 95° C. for 2 h. The temperature was then decreased and the excess N,N-dimethylaniline and phosphorus oxychloride were removed at reduced pressure using an oil pump. The remaining oil was dissolved in dioxane (20 ml) and aqueous Na2CO3-solution (10 ml, 2 M) was added. The two-phase mixture was shaken at 80° C. for 30 min. The temperature was then decreased and ether was added to the reaction mixture. The ethereal phase was washed with saturated aqueous NaCl-solution, dried (Na2SO4) and finally concentrated at reduced pressure. The obtained oil crystallized upon standing at room temperature. Recrystallization (heptane-ether) gave 1.8 g (69%) of the title compound (160FE64). 1H NMR (CDCl3) δ 7.61 (dd, 1H, J=1.4, 7.8 Hz), 7.31 (dt, 1H, J=1.5, 8.0 Hz), 7.15 (d, 1H, J=2.5 Hz), 7.02 (m 2H), 6.66 (dd, 1H, J=1.0, 7.8 Hz), 6.58 (d, 1H, J=8.4 Hz), 4.94 (bs, 1H). 13C NMR (CDCl3) δ 157.2, 152.4, 140.3, 138.9, 134.0, 131.9, 129.7, 128.5, 128.0, 127.0, 123.5, 121.0, 119.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26]C)=[O:25].[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:13](=[O:15])[C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one from Step E (850 mg, 3.18 mmol) in THF (15 mL) at ambient temperature was added NaH (178 mg of a 60% dispersion in oil, 4.45 mmol). After 15 min, methyl bromoacetate (0.469 mL, 5.09 mmol) was added and the mixture was stirred for 1 h. Sodium hydroxide (9.54 mL of a 1 M solution, 9.54 mmol) was added and the mixture stirred for an additional 16 h at 50° C. The reaction mixture was poured onto 1 M HCl (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=326 (M+1).
Reaction SMILES: C([O-])(=O)C.[NH4+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=O.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH:19]=[CH:10][C:9]1[CH:8]=[C:7]([OH:6])[C:14]([OH:15])=[CH:13][CH:12]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc(O)c(O)c1
Yield: 61 %

Procedure:
Ammonium acetate (5.6 g, 72.73 mmol, 1.00 equiv) was added to a solution of 3,4-dihydroxybenzaldehyde (10 g, 72.41 mmol, 1.00 equiv) and nitromethane (50 mL). The resulting mixture was heated at reflux for about 16 hours, and then concentrated in vacuo. The resulting residue was then purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:5)) to give the title compound as a yellow oil (8 g, yield=61%).