Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:26][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@@H:16]([CH2:18]CS([O-])(=O)=O)[O:15][C:14]4=[O:24])=[CH:9][C:8]=3[F:25])[CH2:6]1)[CH2:3][O:2]2.[N-:27]=[N+:28]=[N-:29].[Na+].CO.C(Cl)(Cl)Cl>CCOC(C)=O>[C@H:1]12[CH2:26][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][N:27]=[N+:28]=[N-:29])[O:15][C:14]4=[O:24])=[CH:9][C:8]=3[F:25])[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C1O[C@H](CCS(=O)(=O)[O-])CN1c1ccc(N2C[C@@H]3C[C@H]2CO3)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3C[C@@H]4C[C@H]3CO4)c(F)c2)C(=O)O1
Temperature: 65 °C
Yield: 91.9 %

Procedure:
A solution of (R)-[[3-[4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (0.869 g, 2.26 mmol) in dry DMP (10 mL) was treated with solid NaN3 (0.732 g, 11.3 mmol) at ambient temperature under N2. The mixture was then heated to 65° C. and reaction progress monitored by TLC. After 7.5 h at this temperature, TLC analysis (5% MeOH/CHCl3) revealed the reaction to complete. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O (3×15 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.692 g (92%) of the title compound as a tan solid. An analytical sample was prepared by recrystallization from 1:1 EtOc/hexane as an off-white solid with mp 101-102.5° C. and MS(EI) 333 (M+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([O:26][CH2:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][CH2:27][O:26][CH2:24][CH3:25])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: CCOCCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2 g) in 2-propanol (20 mL) were added 4-[(2-ethoxyethyl)amino]-1,3-thiazol-2(5H)-one (1.67 g) and piperidinium acetate (0.856 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:23]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27].C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC=CC=1.CCCCCCC>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[C@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]([O:22][C:31]3[CH:30]=[CH:29][C:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/[C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CCCCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)[C@H]2CC[C@H](/C=C/[C@H]3CC[C@H](CCCCC)CC3)CC2)cc1
Reaction time: 12 h

Procedure:
(E)-trans-4-(2-(trans-4-pentylcyclohexyl)vinyl)cyclohexane carboxylic acid in an amount of 1.1 g (3.6 mmol), 0.7 g (4.3 mmol) of 4-pentylphenol, 0.1 g (1.1 mmol) of DMAP, and 20 ml of dichloromethane were mixed. To this mixture was added dropwise 4 ml of solution of 1.0 g (4.7 mmol) of DCC in dichloromethane while being cooled with ice in 5 min, and stirred as it was for 12 hours. Separated crystals were filtered off. To the filtrate was added 70 ml of toluene, washed with 2N-NaOH five times and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: toluene/heptane=1/1) to obtain 1.5 g of a crude (E)-4-pentylphenyl trans-4-(2-(trans-4-pentylcyclohexyl)vinyl)cyclohexanecarboxylate. This crude product was recrystallized from a mixed solvent of heptane/diethyl ether to obtain 1.2 g of the subjective compound (yield 74.7%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]=O)[CH2:14][CH2:13]1)=[O:10].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[NH2:18][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]2[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=2[Cl:1])=[O:10])[CH2:13][CH2:14]1
Reactant: Cc1[nH]c(C(=O)NC2CCN(N=O)CC2)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(N)CC2)c(Cl)c1Cl
Temperature: 70 °C

Procedure:
A 20% solution of TiCl3 (36 ml, 27 mmol) in water was added to a solution of 3,4-dichloro-5-methyl-N-(1-nitrosopiperidin-4-yl)-1H-pyrrole-2-carboxamide (Intermediate 87, 2.8 g, 9.2 mmol) in 60 ml of MeOH. The mixture was heated to 70° C. for 1 hour. Aqueous Na2CO3 was added to basify the mixture, which was filtered through Celite rinsing through with MeOH until no more material eluted. The filtrate was concentrated and the residual aqueous solution was saturated with NaCl before being extracted 6 times with DCM. The combined organic layers were dried (MgSO4) and solvent was removed to give product as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=2[CH3:21])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(Cl)nnc2N)c(C)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
4-Bromo-6-chloro-3-pyridazineamine (12 g) and 4-methoxy-2-methylphenylboronic acid (10.5 g) were dissolved in a mixed solvent of toluene (240 mL) and ethanol (45 mL), then tetrakistriphenylphosphine palladium complex (6.7 g) and a 2M aqueous sodium carbonate solution (24 mL) were added thereto, and the mixture was heated under stirring at 100° C. for 12 hours. After completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4) to give the title compound (7.89 g) as brown crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[C:7](Cl)[C:6]=1[N+:19]([O-:21])=[O:20])[CH2:2][CH3:3].[NH3:25]>C(O)C>[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]([NH2:25])[C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:2][CH3:3]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: CCO
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A glass reaction tube was charged with 4.0 grams (0.0108 mole) of N,N-di-n-propyl-3-chloro-2,6-dinitro-4-trifluoromethylaniline, 5.82 grams (0.0237 mole) of 6.95% ethanolic ammonia and 35 ml. of ethanol. The tube was sealed and heated in an oven at 100° C. for 68 hours. The contents of the tube were cooled and the ethanol removed by evaporation. Water was added to the solid orange residue to dissolve the ammonium chloride and the insoluble produced was separated by filtration. The product was dissolved in refluxing 95% ethanol. Upon cooling, orange needles and a yellow powder crystallized. The yellow powder was identified as 2,4-dinitro-6-trifluoromethyl-1,3-phenylenediamine and was separated from the desired product by filtration after extracting with boiling hexane. The desired product dissolved in the hexane and was isolated from the filtrate by evaporation of the hexane. The residue was recrystallized from 95% ethanol to give orange needles, m.p. 124°-125° C.
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:15])C=CC=CC=1.Cl.C([O:29][CH2:30][CH3:31])(=O)C.[C:32]1([CH3:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.O>[O:15]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:38][C:30](=[O:29])[CH2:31]1
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1COc2ccccc2C1
Temperature: 25 °C

Procedure:
Example 1B (3.472 g, 19.7 mmol) was dissolved in dichloromethane (45 mL) to which was added triethylamine (3.5 mL) and diphenylphosphoryl azide (5.97 g, 21.7 mmol) in toluene (20 mL). The flask was equipped with a Dean-Stark trap and the mixture was heated to reflux. Toluene (45 mL) was added after one hour and the mixture was reflux for an 2 additional hours after which it was cooled to ambient temperature. 6N hydrochloric acid (50 mL) and toluene (20 mL) were added and the biphasic mixture refluxed for 3.5 hours followed by cooling to ambient temperature. Ethyl acetate (100 mL) and water (100 mL) were added, and the separated organic layer was washed sequentially with saturated sodium bicarbonate (2×100 mL), brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and chromatographed on silica gel eluting with 0-to-40% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.68 (s, 2H), 4.46 (s, 2H), 7.04 (m, 2H), 7.23 (m, 2H). MS (DCI) m/z 148.04 (M+NH4—H2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:34])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:34])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as a white solid (35 mg, 26%). MP 178-180, LCMS 506.06 (M+H). 1H-NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.23 (s, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.71-7.69 (m, 1H), 7.30 (s, 1H), 7.27-7.25 (m, 1H), 6.54 (d, J=8.6 Hz, 1H), 3.22 (s, 3H), 2.11-2.07 (m, 2H), 1.92-1.89 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:39])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)(C)(C)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:6]([OH:40])=[O:5])=[C:10]2[C:15]=1[N:14]=[C:13]([O:20][CH:21]([F:22])[F:23])[C:12]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)=[CH:29][CH:30]=1)=[C:11]2[CH3:39]
Reactant: Cc1c(Cc2ccc(-c3ccn(C(C)C)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-c3ccn(C(C)C)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
A solution of {8-chloro-2-difluoromethoxy-3-[4-(1-isopropyl-1H-pyrazol-3-yl)benzyl]-4-methylquinolin-5-yloxy}acetic acid tert-butyl ester (0.24 g) in tetrahydrofuran (5.0 mL) was treated with 1.0M aqueous sodium hydroxide solution (0.64 mL), and the resulting mixture was stirred at room temperature for 16 hour. The mixture was neutralised by the addition of 1.0M aqueous hydrochloric acid solution (0.64 mL) and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave the title compound as a white solid (0.051 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](C)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClCl.Cl=O.[Cl-].[C:17]([Cl:21])(Cl)([Cl:19])[Cl:18]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:17]([Cl:21])([Cl:19])[Cl:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: ClCl
Agent: [Cl-]
Product: CS(=O)(=O)c1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
Methyl p-tolylsulfone (100 g, 0.59 mole), carbon tetrachloride (1500 ml) and mercuric oxide (211 g) were added to a 3-necked flask equipped with a mechanical stirrer, gas inlet, dry-ice condenser and thermometer. The mixture was stirred and maintained at 50°-60° while adding chlorine gas (scrubbed through sulfuric acid) at a rate of approximately 1600 cc/min for 35 minutes (155 g). At this point chlorine monoxide started refluxing and chloride addition was discontinued. The mixture was stirred and heated for a total of 7 hours and additional chlorine (65 g) and mercuric oxide (100 g) were added as needed to complete the reaction which can be readily monitored by N-nmr.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:10])([CH2:8][CH3:9])[CH2:6][CH:5]([OH:11])[CH:4]([CH3:12])[C:3]1([CH3:15])[CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>O1CCOCC1>[CH3:1][N:2]1[C:7]([CH3:10])([CH2:8][CH3:9])[CH2:6][CH:5]([O:11][Si:24]([CH3:27])([CH3:26])[CH3:23])[CH:4]([CH3:12])[C:3]1([CH3:15])[CH2:13][CH3:14]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1C
Reactant: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC1(C)CC(O[Si](C)(C)C)C(C)C(C)(CC)N1C

Procedure:
21.1 g of 1,2,3,6-tetramethyl-2,6-diethyl-4-hydroxypiperidine and 20 g of triethylamine are dissolved in 250 ml of dioxane. By addition of 10.9 g of trimethylchlorosilane and using the same procedure of reaction and isolation as described in the previous examples there is obtained 1,2,3,6-tetramethyl-2,6-diethyl-4-(trimethylsiloxy)-piperidine (Compound No. 6), b.p. 78°-79° C./0.35 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O:32]C)=[O:31])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:34][CH:35]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
In 150 ml of methanol, was dissolved 30 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate. After addition of 145 ml of 1 N sodium hydroxide, the mixture was stirred at 50° C for 2 hours. The reaction mixture was neutralized with hydrochloric acid, concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 23.9 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine with a mp. 198°-200° C in a yield of 82%. Analysis, calculated for C26H26O6N2C 67.52, H 5.67, N 6.06, found C 67.17, H 5.69, N 5.95.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:19][NH2:20]>ClCCl.CO>[CH3:19][NH:20][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Reaction time: 0.03 h

Procedure:
To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL), and the reaction mixture was stirred for 2 minutes after precipitation was complete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL), and the solution was extracted with dichloromethane (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).
Reaction SMILES: Br[CH:2]=[CH:3]Br.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:35])[CH2:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C@H:24]2[C@@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH2:2][CH2:3][N:14]4[CH2:13][CH2:12][N:11]([C:8]5[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=5)[CH2:16][CH2:15]4)[C:27]3=[O:35])[CH2:25]2)=[CH:22][CH:23]=1
Reactant: BrC=CBr
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C1N(CCN2CCN(c3ccncc3)CC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 81 starting from dibromo ethylene, 1-(pyridin-4-yl)piperazine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H27ClN4O: 458, observed (M+H)+: 459.2 1HNMR (400 MHz, MeOD-d4) δppm 1.32 (s, 2 H) 2.02-2.40 (m, 3 H) 3.26 (s, 1 H) 3.47 (d, J=9.09 Hz, 8 H) 4.02 (br. s., 4 H) 4.25 (s, 2 H) 6.11 (d, J=7.33 Hz, 1 H) 6.80 (s, 1 H) 7.12-7.18 (m, 1 H) 7.19-7.27 (m, 3 H) 7.32 (t, J=8.97 Hz, 4 H) 8.27 (d, J=7.83 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[NH:20][CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:26]([N:34]=C=O)(=[O:33])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[N:20]([C:26]([NH2:34])=[O:33])[CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(COc4ccc(F)cc4)c3)cnc21
Temperature: 50 °C
Yield: 71.6 %

Procedure:
6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine (32 mg, 0.096 mmol) and benzoyl isocyanate (24 mg, 0.14 mmol) are mixed in 1.0 mL of DCM and the mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in 1.0 mL of EtOH. K2CO3 (23 mg, 0.16 mmol) is added and the mixture is heated at 80° C. for 45 min. Then the solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (75 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 26 mg of the titled product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[F:17][CH:15]([F:16])[C:8]1([C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[F:18])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]1
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C(F)F)N1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1COCC(c2ccccc2F)(C(F)F)N1
Yield: 99.7 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one (190 g, 586 mmol) [example 42 step e)] and sodium acetate (57.7 g, 703 mmol) were suspended in 1850 mL methanol. 10% Pd on charcoal (18.7 g) was then added and the reaction mixture was shaken in a Parr apparatus in an atmosphere of hydrogen at rt. After 60 minutes the reaction mixture was filtered over celite and evaporated. The residue was dissolved in 2 L TBME and washed with aqueous NaHCO3 and brine. The organic layer was dried over MgSO4.H2O and evaporated to give 143.2 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1>CN(C)C=O>[CH:56]1([O:60][CH:61]2[CH2:66][CH2:65][N:64]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:5])[CH2:63][CH2:62]2)[CH2:59][CH2:58][CH2:57]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CC(OC2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCC2)CC1
Reaction time: 2 h
Yield: 5.8 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.20 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL), and to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-cyclobutoxypiperidine (14) (0.104 g, 0.67 mmol). The reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white solid (0.017 g, 5.82%); 1H NMR (400.132 MHz, CDCl3) δ 1.56-1.44 (2H, m), 1.72-1.64 (2H, m), 2.00-1.84 (4H, m), 2.23-2.14 (2H, m), 3.14-3.04 (1H, m), 3.48-3.41 (2H, m), 3.58-3.52 (1H, m), 4.00 (1H, quintet), 4.10-4.03 (1H, m), 4.26 (2H, s), 7.01 (1H, t), 7.31-7.24 (2H, m), 7.77-7.70 (3H, m), 8.47-8.44 (1H, m), 9.90 (1H, s); m/z (LC-MS, ESI+), RT=2.15 (M+H 436).
Reaction SMILES: C(OC([CH:6]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:23])=O)C.[OH-].[Na+]>CO>[CH2:20]1[CH2:21][CH2:22][CH2:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)C1CCCCCCC=CCCCCCCCC1=O
Agent: O=C1CCCCCCC/C=C\CCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCCCCCC=CCCCCCCC1

Procedure:
2-ethoxycarbonyl-9-cycloheptadecenone will be refluxed with about 10% NaOH in methanol for about 1 hour to give civetone. After completion of the reaction, the reaction mixture will be neutralized using about 10% sulfuric acid. The product will be extracted using ether and can be purified using silica-gel chromatography.