Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([CH3:27])[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1.O.[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:4])[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[CH:7]=3)([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=2)=[CH:19][C:20]=1[CH3:27]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: CN(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN(C)C
Yield: 71.1 %

Procedure:
To a solution of N,N-dimethyl hydrazine (0.55 g) in ether (46 mL) was added 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoyl chloride (2.00 g) in small portions at 0° C. After 50 min at this temperature, water was added and the pH was adjusted to 7 by addition of NaOH (2 M). The organic layer was separated and the aqueous layer was extracted with ether. Combined organic layers were washed with NaHCO3 solution, dried over Na2SO4 and evaporated to give the title compound (1.50 g, 71%).
Reaction SMILES: [OH:1]O.[Br:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1(B(O)O)[F:10].O>COC(C)(C)C>[Br:3][C:4]1[C:5]([F:10])=[C:6]([OH:1])[CH:7]=[CH:8][CH:9]=1
Reactant: OO
Reactant: OB(O)C1(F)C=CC=CC1Br
Solvent: O
Solvent: COC(C)(C)C
Product: Oc1cccc(Br)c1F

Procedure:
125 ml of a 35% strength aqueous solution of hydrogen peroxide are added dropwise at room temperature to the crude 2-bromo-1-fluorophenylboronic acid (80 g) dissolved in 300 ml of tert-butyl methyl ether; during this addition, the temperature rises to 55° C. When the addition is complete, the mixture is refluxed for a further 2 hours. After the mixture has been cooled, 100 ml of water are added, and the organic phase is extracted by shaking twice with saturated sodium sulfite solution. After the solvent has been removed by distillation under reduced pressure, vacuum distillation (90° C.; 4 mbar) gives 54 g of 3-bromo-2-fluorophenol as an oil which soon crystallizes. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 5.1 (br; 1H), 19F-NMR (CDCl3): −135 ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([O:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.[C:20](O)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:18]([O:17][C@@H:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:5][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(CCN)cc1)OCC
Reactant: CCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCC(=O)NCCc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Ethyl (2S)-3-[4-(2-aminoethyl)phenyl]-2-ethoxypropanoate (320 mg 1.206 mmol) and heptanoic acid (157 mg, 1.206 mmol) were mixed in DCM (10 ml). EDC (243 mg, 1.266 mmol) was added and then DMAP (147 mg, 1.206 mmol) was added. The mixture was stirred at room temperature overnight. It was then washed with 1% hydrochloric acid, water, 1% sodium hydrogencarbonate aqueous solution, water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. Chromatography of the residue on a column (ISOLUTE, SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99) as eluant gave 166 mg desired product, yield 37%.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CCC(=O)O)cc1
Yield: 99.9 %

Procedure:
An ethanol (250 ml) solution of 4-ethyl cinnamic acid (34.0 g, 0.191 mol) was hydrogenareal at 60 psi over 10% Pd/C (2 g) for 2 hr. The mixture was filtered and concentrated in vacuo to give 3-(4-ethylphenyl)propionic acid as a white solid (34 g, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]O)=[CH:26][C:25]=1[O:34][CH3:35])(=[O:22])[CH3:21].C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][Br:37])=[CH:26][C:25]=1[O:34][CH3:35])(=[O:22])[CH3:21]
Reactant: COc1cc(OCCO)ccc1OC(C)=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OCCBr)ccc1OC(C)=O
Reaction time: 5 h

Procedure:
A solution of triphenylphosphine (0.123 mL, 0.530 mmol) in dry CH2Cl2 (1.3 mL) was added dropwise via cannula to a stirred solution of 4-(2-hydroxyethoxy)-2-methoxyphenyl acetate (100 mg, 0.442 mmol) and carbon tetrabromide (0.051 mL, 0.530 mmol) in dry CH2Cl2 (3.0 mL) at 0° C. under N2. After 5 h at 0° C., the reaction mixture was concentrated in vacuo and the residue obtained was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 1125 mL) to afford 4-(2-bromoethoxy)-2-methoxyphenyl acetate, as a colorless oil. Rf=0.78 (50% EtOAc/hexanes). LCMS calc.=289.1; found=288.8 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 6.93 (d, J=8.7 Hz, 1 H); 6.57 (d, J=2.8 Hz, 1 H); 6.42 (dd, J=8.7, 2.8 Hz, 1 H); 4.26 (t, J=6.2 Hz, 2 H); 3.80 (s, 3 H); 3.62 (t, J=6.2 Hz, 2 H); 2.29 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: C1CNCCN1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)N4CCNCC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and piperazine using diethyl cyanophosphonate as a coupling reagent Mass: 577.17 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]1[CH2:8][C@H:7]([N:9]=[N+]=[N-])[CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[C@H:4]1[CH2:8][C@H:7]([NH2:9])[CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A mixture of trans-4-azido-N-tert-butoxycarbonyl-D-proline methyl ester (C, 1.04 g) and 10% palladium on activated carbon (500 mg) in methanol (30 mL) was stirred at room temperature for 1.5 hr under hydrogen. The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo to give the title compound (0.90 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH2:38]([Sn](CCCC)(CCCC)CCCC)[CH:39]=[CH2:40]>>[CH3:22][C:16]([O:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH2:38][CH2:39][CH3:40])=[CH:7][N:6]=2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1)([CH3:23])[C:17]([OH:19])=[O:18]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Product: CCCc1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and allyltributyltin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCNCC2)cn3-c2ccc(F)cc2)n1
Reactant: O=C1NCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCN4CCNC4=O)CC2)cn3-c2ccc(F)cc2)n1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a) (4 g), 1-(2-chloroethyl)imidazolidin-2-one (1.8 g), potassium carbonate (2.1 g) and potassium iodide (0.5 g) in MIBK (80 mL) was boiled at reflux for 20 hours. After cooling, inorganic salts were filtered off and the solvent evaporated in vacuo. The title compound crystallised from ethyl acetate. Yield 3.0 g. Mp 201-203° C. 1H NMR (CDCl3): δ 2.60-2.70 (m, 4H), 2.80 (t, 2H), 3.30 (broad s, 2H), 3.35-3.45 (m, 4H), 3.55 (t, 2H), 4.40 (s, 3H), 4.65 (s, 1H), 6.35 (broad s, 1H), 7.20 (t, 2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.95 (d, 1H), 8.25 (s, 1H); MS m/z (%): 487 (MH+, 12), 142 (49), 113 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 211 mg of ethanesulfonyl chloride was added to the solution, and the mixture was stirred at 0° C. for 20 minutes and then at room temperature for 3 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and brine in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (75:25) as the eluent to give 176 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]ethanesulfonamide.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C@@H:6]([NH:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:24][N:23]=[C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])[N:21]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:20]([NH:19][C@@H:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:41])=[O:3])=[N:21][C:22]([N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[N:23][CH:24]=1
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(OC(=O)N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)Oc1ccc([C@@H](CC(=O)O)Nc2nc(N(C)C3CCCCC3)ncc2-c2ccccc2F)cc1
Temperature: 22 °C
Reaction time: 6 h

Procedure:
To a solution of (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid ethyl ester (1.0 eq) in 3:1 MeOH/H2O was added 1M NaOH (2.5 eq). The mixture was stirred at 22° C. for 6 hr, and then the MeOH and H2O were evaporated. The residue was partitioned between Et2O and H2O, and then the separated aqueous layer was acidified to pH=3 by addition of 0.1 M H3PO4. The aqueous layer was extracted three times with 3:1 CHCl3/iPrOH, and then the CHCl3/iPrOH extracts were treated with MgSO4, filtered and evaporated to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([O:15][CH2:16][CH3:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([N:8]1[C:12]([CH:13]=[O:14])=[CH:11][C:10]([O:15][CH2:16][CH3:17])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(CO)n(Cc2ccccc2)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc(C=O)n(Cc2ccccc2)n1
Reaction time: 20 h
Yield: 47.7 %

Procedure:
4 Å molecular sieves are added to a solution of 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol in 0.5 ml of dichloromethane, followed by addition of 43.1 mg of pyridinium chlorochromate. After 20 hours at a temperature in the region of 20° C., the reaction mixture is filtered through Celite. The insoluble material formed is rinsed with ethyl acetate and then with dichloromethane. The filtrate is washed with water. After separation of the phases by settling, the aqueous phase is re-extracted with dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure. 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde are thus obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: CC([O:4][C@@H:5]1[C:19](=[O:20])[C@H:18]2[C@@:8]([CH3:27])([CH2:9][CH2:10][C@@H:11]3[C@:17]2([CH3:21])[CH2:16][C@@H:15]([C:22]2[CH:23]=[CH:24][O:25][CH:26]=2)[O:14][C:12]3=[O:13])[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:27][C@:8]12[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6][C@H:5]([OH:4])[C:19](=[O:20])[C@@H:18]1[C@:17]1([CH3:21])[C@H:11]([C:12]([O:14][C@H:15]([C:22]3[CH:23]=[CH:24][O:25][CH:26]=3)[CH2:16]1)=[O:13])[CH2:10][CH2:9]2
Reactant: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of Salvinorin A (500 mg, 1.15 mM) in methanol (10 ml) was added solid sodium carbonate (490 mg, 4.6 mM) and the mixture stirred at room temperature overnight. Water (20 ml) was added to mixture and the mixture stirred for 30 mins. The solution was filtered and the filter-cake washed with ice-cold water (20 ml) and ice-cold methanol (20 ml) and dried in a dessicator to give Salvinorin B (191 mg, 42%).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:18][CH2:17][C:9]2([O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[CH2:10]2)[CH2:8][CH2:7]1)=O)C.C(O)CO.COCCO[AlH2-]OCCOC.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:14]([CH:12]1[C:11](=[O:16])[CH2:10][C:9]2([CH2:8][CH2:7][N:6]([CH3:4])[CH2:18][CH2:17]2)[O:13]1)[CH3:15]
Reactant: CCOC(=O)N1CCC2(CC1)CC(=O)C(CC)O2
Agent: COCCO[AlH2-]OCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: CCC1OC2(CCN(C)CC2)CC1=O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
The crude 2-ethyl ketone (18.7 g) from step (a) was dissolved in 350 ml of toluene under a nitrogen atmosphere. Ethylene glycol (35 ml) and p-toluenesulfonic acid (0.75 g) were added and the reaction was heated at reflux. A Dean & Stark apparatus was used to remove the water. After 3 hrs. the reaction was cooled with an ice-bath and the toluene layer was washed with cold water. The aqueous layer was back extracted with chloroform and the combined organic layers were dried and evaporated to give the crude ketal as an oil (21.5 g). The ketal (21.5 g, 0.072 mol) was dissolved in THF (220 ml) and added dropwise to Vitride (0.216 mol ) in THF (284 ml) . The reaction was stirred overnight, cooled and then water was added to decompose the complex and excess Vitride. The THF layer was separated, dried and concentrated to give the crude 8-methyl-ketal (20.8 g). A portion of the ketal (18.8 g, 0.078 mol) was heated with 125 ml of 1.25N.HCL at 50° C. for 3 hrs. The cooled solution was neutralized with saturated Na2CO3 solution. The aqueous mixture was extracted twice with chloroform, the chloroform layer was dried and concentrated to give the title ketone as an oil (11.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.Br[CH2:37][C:38]1([CH3:42])[CH2:41][O:40][CH2:39]1>>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:35]=[N:34][N:33]([CH2:37][C:38]4([CH3:42])[CH2:41][O:40][CH2:39]4)[CH:32]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(CBr)COC1
Product: COc1nccc2[nH]nc(-c3cnn(CC4(C)COC4)c3)c12
Yield: 35 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-(bromomethyl)-3-methyloxetane to give the title compound (23.1 mg, 35% over two steps). LC-MS (Method G): m/z=300.0 [M+H]+; 2.54 min. 1H-NMR (400 MHz, DMSO) δ 8.75 (s, 2H), 7.47 (d, J=5.8, 1H), 7.00 (d, J=6.0, 1H), 4.54 (d, J=11.7, 2H), 4.31 (d, J=11.8, 2H), 4.01 (s, 2H), 3.50 (s, 5H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].BrN1C(=O)CCC1=O.BrCC1C=C(C=CC=1CBr)C(OC)=O.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:1][C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH2:12]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(C)c(C)c1
Reactant: NCc1ccccc1
Agent: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 54.4 %

Procedure:
18.1 g of methyl 3,4-dimethylbenzoate, 39.2 g of N-bromosuccinimide, 200 mg of benzoyl peroxide, and 200 ml of carbontetrachloride were processed in a similar manner as in Reference Example 6-(1) to give a mixture containing methyl 3,4-bis-(bromomethyl)benzoate as a major component. (3) The procedure of Reference Example 14-(3) was followed using the whole mixture prepared above, 11.8 g of benzylamine, and 22.9 g of triethylamine to give 16.0 g of 2-benzyl-5-methoxycarbonylisoindoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([NH:20][NH2:21])[CH2:10][N:9]=1.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24]>C1(C)C(C)=CC=CC=1>[CH2:23]([C:24]1[N:12]2[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH2:10][C:11]2=[N:20][N:21]=1)[CH3:22]
Reactant: NNC1=Nc2ccc(I)cc2C(c2ccccc2F)=NC1
Reactant: CCOC(CC)(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Yield: 97 %

Procedure:
A mixture of 1 g of 5-(2-fluorophenyl)-7-iodo-2-hydrazino-7-iodo-3H-1,4-benzodiazepine (see example 3), 5 ml of triethyl orthopropionate and 10 ml of xylene was heated to reflux for 1 hour. The solvents were partially distilled over and the residue was diluted with hexane. The precipitated crystals were collected and recrystallized from methanol/ethyl acetate to leave 1.05 g (97%) of 1-ethyl-6-(2-fluorophenyl)-8-iodo-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with m.p. 209°-211° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C)C=O.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11])#[N:2]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnccn2)cc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.081 mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a mixture of 2-aminopyrazine (89 mg, 0.933 mmol) and triethylamine (0.173 mL, 1.24 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 methylene chloride/methanol) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide as an impure orange foam. Re-purification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide (8 mg, 3%) as a yellow foam: mp 88-93° C. (foam to gel); EI-HRMS m/e calcd for C20H22N4O3S (M+) 398.1413, found 398.1413.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)O)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mL of DMF were added 50.0 g (250 mmol) of 2-amino-α-(methoxyimino)-4-thiazoleacetic acid and 35 g (260 mmol) of N-chlorosuccinimide. The mixture was stirred at room temperature overnight, after which time mass spectral analysis showed no more starting material to be present. The light brown solution was used without further manipulation.