Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:47][CH2:48][CH3:49])[C:13]([C:15]1=[CH:16][C:17]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:36][CH:35]=3)=[CH:30][C:18]=2[N:19]=[C:20]([NH:22]C(=O)OC(C)(C)C)[CH2:21]1)=[O:14])(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.N.CO>C(Cl)Cl>[NH2:22][C:20]1[CH2:21][C:15]([C:13]([N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:47][CH2:48][CH3:49])=[O:14])=[CH:16][C:17]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:38][CH:39]=3)=[CH:30][C:18]=2[N:19]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of tert-butyl (1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate (459 mg, 0.37 mmol) in CH2Cl2 (4 mL) at 0° C. was added TFA (1.00 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude material that was azeotroped with toluene-EtOH (3 mL/1 mL) twice. The crude material was dried under reduced pressure for 30 min. The crude material was dissolved into CH2Cl2 (˜3 mL) again and treated with NH3 in MeOH (0.30 mL, 2.1 mmol, 7 N solution in MeOH) at room temperature. The resulting mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (3 to 7% MeOH in CH2Cl2, gradient) to afford 105 mg (59%) of (1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide. MS APCI (+) m/z 475 detected; 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, 2H), 7.60 (d, 2H), 7.51 (br s, 1H), 7.30-7.37 (m, 2H), 6.88 (s, 1H), 3.60-3.69 (m, 6H), 3.48-3.52 (m, 4H), 2.83 (s, 2H), 1.82-2.00 (m, 6H), 1.68-1.74 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.CN(C)CCN(C)C.C([Li])CCC.CN(C)[C:23](=[O:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[CH3:37]>C1COCC1>[CH:32]1[C:31]2[NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23](=[O:38])[CH2:37][C:36]=2[CH:35]=[CH:34][N:33]=1
Reactant: Cc1ccncc1Nc1ccccc1C(=O)N(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1Cc2ccncc2Nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.61 mL, 53.89 mmol) and tetramethylethylenediamine (8.13 mL, 53.89 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 34.2 mL, 54.77 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min., then 0° C. for 10 min. This solution was transferred into a solution of N,N-dimethyl-2-((4-methylpyridin-3-yl)amino)benzamide in THF (100 mL) at 0° C. The resulting solution was stirred overnight and quenched by adding saturated ammonium chloride solution (20 mL). The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the pure desired product, 5H-benzo[b]pyrido[4,3-f]azepin-6(11H)-one (2.2 g) as a yellow solid. 400 MHz 1H NMR (DMSO-d6) δ 9.68 1H), 8.53 (s, 1H), 8.27 (d, J=4.4 Hz, 1H), 7.79 (m, 1H), 7.53-7.49 (m, 1H), 7.38-6.89 (m, 2H), 6.93-6.89 (m, 1H), 3.78 (s, 2H); LCMS (M+H)=211.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]
Reactant: CC(C)CC(=O)N1CCC[C@H](CO)C1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A solution of (S)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 5d) (42 g, 210.75 mmol, 1.2 eq.) in anhydrous THF (300 mL) was added dropwise at 0° C. to a suspension of NaH (60% in mineral oil, 8.43 g, 273.97 mmol, 1.63 eq.) in anhydrous THF (600 mL). The mixture was warmed up to about 25° C. and stirred for 1 h while keeping the temperature below 25° C. A solution of 2-amino-6-fluorobenzonitrile (22.95 g, 168.6 mmol, 1 eq.) in THF (300 mL) was added dropwise. The reaction was heated slowly to reflux and stirred overnight. The mixture was cooled down to room temperature, concentrated to about 400 mL of residual material. Saturated ammonium chloride (200 mL) was added. After stirring vigorously for 15 minutes, EtOAc (800 mL) was added and stirring continued for additional 30 minutes. The organic phase was washed subsequently with water, brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was chromatographed on silica gel (Hex/EtOAc to provide the desired product (44.6 g, 141.40 mmol, 83.87%). 1H NMR (400 MHz, DMSO-d6, 20° C.) δ0.79-0.92 (3×d, J=6.4 Hz/each, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J=10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 & 6.00 (s & s, 2H), 6.18 (pseudo t, J=8.4 & 9.2 Hz, 1H), 6.32 (pseudo d, J=8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (MH+)
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.[CH3:37][C:38]([CH:40]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:39]>C1C=CC=CC=1>[CH3:37][C:38](/[CH:40]=[CH:1]/[C:3]1[CH:8]([C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=[O:39]
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)/C=C/C1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 25.6 %

Procedure:
A solution of diphenylmethyl 3-formyl-7β-(2-thienylacetamido)ceph-2-em-4-carboxylate (116 mg.) in benzene (3 ml.) was treated with a solution of methylcarbonylmethylenetriphenylphosphorane (150 mg.) in benzene (4 ml.) and the mixture refluxed for 5.75 hours. The organic solution was washed with 2-N-hydrochloric acid and water, dried and evaporated in vacuo. The residual gum (186 mg.) was purified by preparative T.L.C. (Kieselgel HF254+366, developed five times with benzene-ethyl acetate = 8:1) to give the title compound (32 mg, 27%) as a gum, λmax. (CHCl3) 318 nm. (qualitative, τ (CDCl3) 3.00 and 3.86 (CH=CH, two d, J 16 Hz), 3.12 (CHPh2), 3.27 (C(2) -H, broad s), 4.47 (C(7) -H), dd, J 8 and 4 Hz), 4.73 (C(6) -H, d, J 4 Hz), 4.69 (C(4) -H, broad s), 6.16 (CH 2 CONH) and 7.91 (COCH3).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]1)[CH3:2].C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:11]=[CH:10][CH:9]=[CH:14]2)[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOCCn1c(CN2CCCN(CCCCN)CC2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOCCn1c(CN2CCCN(CCCCn3cccc3)CC2)nc2ccccc21
Yield: 188.9 %

Procedure:
A solution of 2.98 g (8 mmol) of 1-(2-ethoxyethyl)-2-{4-(4-aminobutyl)homopiperazin-1-yl-methyl}benzimidazole and 1.06 g (8 mmol) of 2,5-dimethoxytetrahydrofuran hydrofuran in 30 ml of acetic acid is refluxed for 25 minutes. The mixture is cooled, poured into ice cold water, neutralised with NaHCO3 and extracted with chloroform. It is dried using Na2SO4 and evaporated to dryness under vacuum. 3.2 g of the crude compound are thus obtained which are purified on a silica chromatography column (eluent: chloroform-methanol 92:8). Yield 51%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:18])[CH3:2].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][Br:27])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1CBr
Yield: 123.7 %

Procedure:
A mixture of 2-methyl-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (529 mg), NBS (440 mg), and BzOOBz (25 mg) in CCl4 (10 mL) was refluxed for 6 h; then cooled, solids were filtered off, filtrate was concentrated to give crude product (855 mg). 1H NMR in CDCl3, δ in ppm: 8.2-7.6 (m, 4H), 7.1-6.95 (m, 3H), 4.94 (s, 2H), 4.39 (q, 2H, J=7.0 Hz), 1.41 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[CH:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH2:10][CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1>[Pd]>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2=CCCCC2C(=O)C2CCCCC12
Agent: [Pd]
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 75 %

Procedure:
The octahydro-anthraquinone (OHAQ) reaction is initially a highly exothermic and is immediately followed by the rapid elimination of hydrogen which has a pronounced cooling effect on the reaction system. Reaction times of less than 1 minute past the exotherm with a rhodium on carbon catalyst provided yields of 62 percent anthraquinone, along with isomerized OHAQ and isomerized THAQ. If the same reaction is conducted with palladium on a carbon support, a 75 percent yield of anthraquinone is obtained along with the isomerized OHAQ and isomerized THAQ. The reaction can be visualized to be the following: ##STR6##
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4C)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3C)c2O1

Procedure:
The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.103 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 178-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: OB(O)c1cccs1
Reactant: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(I)cc1
Product: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 126-196. MS (ES−) m/e 476/478 [M−H]−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=O)([O:16]C)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:8](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
A stream 11 essentially containing all the non-reacted phenol, phenyl methyl carbonate and any possible diphenyl carbonate produced, the transesterification catalyst and a fraction of the dimethylcarbonate fed, is extracted from the bottom of the reaction section of column C1 so that the molar ratio, in this stream, between the dimethyl carbonate and the phenol is between 0.5 and 5, normally between 1.0 and 5.0. This fraction usually forms between about 10 and about 60% of the total dimethyl carbonate fed to column C1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccncc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnccc3C)cccc2c1N
Yield: 86 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and (4-methylpyridin-3-yl)boronic acid (274 mg, 2.000 mmol) were reacted to afford the title compound (134 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 8.59-8.45 (m, 3H), 7.98-7.92 (m, 1H), 7.80-7.66 (m, 2H), 7.27 (m, 1H), 3.44 (m, 2H), 2.11 (s, 3H), 1.65 (m, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=322 (M+H). HPLC 1.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:31])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH2:13][F:31])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)nc2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2cc(CF)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-methanol (Example 158) (250 mg, 0.689 mmole) in 5 ml of dichloromethane was added dropwise a solution of diethylamino sulfur trifluoride (DAST) (166 mg, 1.03 mmole) in 1 ml of dichloromethane. As the addition proceeded, the mixture became homogeneous. After stirring for two hours, water was added, the layers separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue over silica gel using 60% ethyl acetate in hexane gave the title compound as a very slightly yellow solid (106 mg): mp (DSC) 165° C. Anal. Calc'd. for C17H14ClFN2O2S.¼ H2O (MW 369.33): C, 55.29; H, 3.82; N, 7.59. Found: C, 55.15; H, 3.82; N, 7.42.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][N:5]1[C@H:9]2[C@H:10]3[N:15]4[C@H:16]([O:17][CH2:18][C@H:14]4[C:13]4[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:12]=4[CH2:11]3)[C@@H:6]1[CH2:7][C@H:8]2[C:25]([O-:27])=[O:26]>P([O-])([O-])([O-])=O>[CH3:4][N:5]1[CH:9]2[CH:10]3[N:15]([CH:16]([C:1]#[N:2])[CH:6]1[CH2:7][CH:8]2[C:25]([OH:27])=[O:26])[CH:14]([CH2:18][OH:17])[C:13]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:12]=1[CH2:11]3
Reactant: [C-]#N
Reactant: COc1cccc2c1[C@@H]1CO[C@@H]3[C@@H]4C[C@@H](C(=O)[O-])[C@H]([C@H](C2)N31)N4C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COc1cccc2c1C(CO)N1C(C#N)C3CC(C(=O)O)C(C1C2)N3C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At first, 2.0 g of sodium cyanide is dissolved in 30 ml of 0.1M phosphate buffer (pH 7.4) and 1 g of crude DC-52-(containing 0.6 g of DC-52) is added thereto. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is passed through a column containing 200 ml of Diaion HP-20SS (made by Mitsubishi Chemical Industries Co., Ltd.), and the column is developed and eluted with 1 l of water (fraction Nos. 1-160; 6 ml each), and then with 1% acetone-99% water (by volume; fraction Nos. 161-224, 6 ml each). Fraction Nos. 125-165 and fraction Nos. 166-199 are joined together separately, and concentrated under reduced pressure, followed by freeze-drying to obtain 161 mg of fraction A and 179 mg of fraction B.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([O:27]C)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 1.3 mmol) was dissolved in methanol and 2N NaOH (3 mL) added. The reaction was stirred at 60° C. for 2 hours then the solution was adjusted to pH 6.5. The product was extracted into ethyl acetate, and the organic phase was dried by MgSO4. The solvent was evaporated to afford 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetic acid (0.30 g). 1H NMR (500 MHz, CDCl3) 1.02 (m, 2H), 1.25 (m, 2H), 1.55 (m, 2H), 1.65 (m, 2H), 2.57 (m, 2H), 3.33 (m, 1H), 3.75 (s, 2H), 3.95 (m, 2H), 6.63 (m, 3H), 6.98 (m, 1H).
Reaction SMILES: C(OC([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=O)(C)(C)C.BrC1N=[C:32]([C:34](OC)=[O:35])C(NC(OC(C)(C)C)=O)=NC=1.Cl>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([C:10]1[C:9]([NH:8][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[N:14][CH:13]=[C:12]([C:34](=[O:35])[CH3:32])[N:11]=1)=[O:17]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(Br)cnc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C(C)=O)cnc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a stirred solution of an 1:4 mixture of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate and methyl 6-bromo-3-(tert-butoxycarbonylamino)pyrazine-2-carboxylate (ca. 4.1 g, 11.6 mmol) at rt in toluene (55 ml) under an argon atmosphere were added bis(triphenylpohsphine)palladium(II) chloride (81.1 mg, 0.12 mmol) and 1-ethoxyvinyl tri-N-butyltin (3.0 g, 2.8 ml, 12.7 mmol). The clear yellow solution was heated to reflux and stirring was continued for 18 h. The mixture was cooled to 0° C. 1 N HCl (55 ml) was added dropwise within 15 min. The biphasic mixture was stirred vigourously for 22 h, slowly warming up to rt. The layers were separated. The organic layer was diluted with 150 ml EtOAc (150 ml). Then, a 10% aqueous ammonium fluoride solution (150 ml) was added. The biphasic mixture was then stirred at rt for 5 h and then filtered. The organic phase of the filtrate was washed with 50 ml brine, dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a n-heptane/ethyl acetate gradient. The product-containing fractions were concentrated. The residue was triturated with n-heptane/cyclohexane 9:1 (20 ml). The suspension was stirred for 2 hrs. The solid was filtrated, washed with n-heptane and dried to give the title compound (1.54 g, 45%) as off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])(=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:5]([N:8]1[CH2:13][CH2:12][N:11]([CH2:2][CH2:3][OH:4])[CH2:10][C@H:9]1[CH3:14])(=[O:7])[CH3:6]
Reactant: OCCBr
Reactant: CC(=O)N1CCNC[C@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCO)C[C@H]1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
2-Bromoethanol (7.34 mL, 103.38 mmol) was added to a stirred mixture of (R)-1-acetyl-2-methylpiperazine (2.94 g, 20.68 mmol) and potassium carbonate (8.57 g, 62.03 mmol) in THF (75 mL). The resulting mixture was stirred at 80° C. for 18 hours before, then filtered and evaporated. The residue was purified by ion exchange chromatography, using an SCX column and eluting with 2M ammonia in methanol. Pure fractions were evaporated to dryness to give (R)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (3.74 g, 97%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:28])=O.CN(C)C=O>ClCCl>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([Cl:28])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
(4-Trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid 39 (0.05 mol) was dissolved in dichloromethane (50 mL) and thionyl chloride (5 mL) and dimethylformamide (0.1 mL) were added. After 2 hours, the solvents were removed under vacuum to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetyl chloride, 123. This compound (0.01 mol) was dissolved in ether (25 mL) and the solution was cooled to −80° C. and lithium aluminum tri-tertiarybutoxy hydride (0.01 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was warmed to room temperature and water was added. The organic phase was dried and concentrated and the residue was chromatographed to afford the title compound 124.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:17][C:18]1[N:23]=[N:22][C:21]([NH2:24])=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:2]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:24]=2)[N:23]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccncc1
Reactant: Nc1ccc(Cl)nn1
Solvent: CCO
Product: Clc1ccc2nc(-c3ccccc3)c(-c3ccncc3)n2n1

Procedure:
A mixture of 13 g (36.5 mmol) of 2-bromo-1-phenyl-2-pyrid-4-ylethanone (CAS No.: 741633-76-1) and 18.9 g (146 mmol) of 6-chloropyridazin-3-ylamine in 200 mL of ethanol is maintained at 90° C. for 5 hours 30 minutes. After cooling, the solvent is evaporated off under reduced pressure, the medium is taken up in 50 mL of water and the product is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate and then concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)=[CH:5][C:4]([CH3:18])=[N:3]1>C(Cl)Cl.C1COCC1.[O-2].[Mn+4].[O-2]>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: CSc1ncc(CO)c(Nc2cc(C)nn2C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1ncc(C=O)c(Nc2cc(C)nn2C)n1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To a solution of [4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidin-5-yl]-methanol, 17, (0.97 g, 3.66 mmol) in CH2Cl2/THF (35 mL of 1:1 mixture) is added manganese (IV) oxide (2.54 g, 29.28 mmol). After stirring the suspension at room temperature for 43 hours, the mixture is filtered through celite, and washed with CH2Cl2. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (5% MeOH/chloroform) to afford 0.52 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.22 (s, NH), 10.58 (s, NH), 9,86 (s, 1H), 8.54 (s, 1H), 6.36 (s, 1H), 3.81 (s, 3H), 2.58 (s, 3H), 2.30 (s, 3H); ESI+ MS: m/z (rel intensity) 264.0 (100, M++H).