Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[CH2:42]([O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:14](=[O:16])[NH:54][C:53]1[CH:52]=[CH:51][C:50]([O:49][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:56][CH:55]=1)[CH2:10][CH2:11][S:12][CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 0.57 g (2.3 mmol) of (S)-Boc-methionine in 5 ml of dichloromethane is treated at RT consecutively with 0.87 g (2.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HBTU), 0.50 g (2.1 mmol) of 4-benzyloxyaniline hydrochloride and 0.98 ml (5.7 mmol) of N-ethyl-diisopropylamine. The reaction mixture is stirred during 1 h at RT. For the working-up, the reaction mixture is diluted with dichloromethane and treated with 20 ml of an aqueous solution of citric acid (10%). The aqueous phase is re-extracted with dichloromethane, the organic phases combined, dried over sodium sulfate and evaporated under reduced pressure. For purification, the crude material obtained is chromatographed on silica gel using a 3:1 mixture of n-hexane and ethyl acetate as the eluent. There are obtained 0.74 g (82.5% of theory) of (S)-[1-(4-benzyloxy-phenylcarbamoyl)-3-methylsulfanyl-propyl]-carbamic acid tert-butyl ester as a white solid. MS: m/e=431 (M+H)+.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([N:12]2[C:16]([C:17]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:18]=3[O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:30][C:31]4[S:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[C:22]([F:36])[CH:21]=3)=[CH:15][CH:14]=[N:13]2)[CH2:9]1.C(O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO.C(O)C.O>[Cl:41][C:39]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:30][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:28])=[O:29])=[C:22]([F:36])[CH:21]=2)=[C:17]([C:16]2[N:12]([CH:10]3[CH2:9][N:8]([CH3:2])[CH2:11]3)[N:13]=[CH:14][CH:15]=2)[CH:40]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CN1CC(n2nccc2-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An alternative method of preparing Example 811 is as follows: 4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trifluoroacetate salt, (Example 801, 110.45 g, 0.1558 mol) was dissolved in dichloromethane (1050 mL) and methanol (110.45 mL). Acetic acid (17.86 mL, 2.73 mol) was added followed by aqueous formaldehyde solution (58.54 mL of 37 wt % in water, 0.779 mol), stirred at room temperature for 30 minutes. The solution was then cooled in an ice bath and sodium triacetoxyborohydride (82.56 g, 0.3895 mol) was added, stirred whilst warming to room temperature over 1.5 hours. Aqueous formaldehyde solution (29.27 mL of 37 wt % in water, 0.3895 mol) was added, stirred for 30 minutes then sodium triacetoxyborohydride (82.56 g, 0.3895 mol) was added and stirred at room temperature for 1.5 hours. The reaction was quenched by adding water (552.25 mL) and stirred for 30 minutes then 0.880 aqueous ammonia solution (100 mL) was added in two equal portions and stirred for a further 30 minutes. The resulting solid was filtered off and dried to give the crude title compound as a white solid, (135 g). The crude product was suspended in ethanol (405 mL) and heated to reflux for 1 hour then water (405 mL) was added and the resulting slurry was stirred at 90° C. for 30 minutes before being allowed to cool to 35° C. The solid was filtered off and dried to give the title compound as a white solid, (67.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([Cl:17])=[CH:12][C:11]=3[O:18][CH3:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: COc1cc(Cl)c(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)c(Cl)cc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone (Example 47) and ethyl4-amino-1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 451.1545, Calcd for (M+H)+: 451.1543.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10](Cl)=[O:11])[CH2:3]1.[NH2:14]C(C)(C)CO>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10]([NH2:14])=[O:11])[CH2:3]1
Reactant: CC(C)(N)CO
Reactant: CC1CCCC(C)(C)CC1C(=O)Cl
Solvent: ClCCl
Product: CC1CCCC(C)(C)CC1C(N)=O

Procedure:
3,3,7-Trimethylcycloheptanecarbonyl chloride, prepared from the product of Part A by the method of Example 26 Part B, (0.5 g. 0.0025 mole) in 10 ml methylene dichloride was added to a stirred solution of 2-amino-2,2-dimethylethanol (0.5 g) in 50 ml methylene dichloride. After 3 hours the solution was washed with 2 N HCl, then with NaHCO3 solution and then dried (MgSO4). Removal of the solvent left an oil which was distilled to yield N-1',1'-dimethyl-2'-hydroxyethyl)-3,3,7-trimethylcycloheptanecarboxamide, bp. 135°/0.015 mm.
Reaction SMILES: [PH2](O)=O.C(N1CCCCC1)C.[CH2:12]=[CH:13][S:14]([O:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28])(=[O:16])=[O:15].I[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[S:37]([C:40]1[C:45]([CH3:46])=[CH:44][C:43]([O:47][CH3:48])=[CH:42][C:41]=1[CH3:49])(=[O:39])=[O:38].C(B(CC)CC)C>C(Cl)Cl>[CH3:48][O:47][C:43]1[CH:44]=[C:45]([CH3:46])[C:40]([S:37]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]2[CH2:30][CH2:12][CH2:13][S:14]([O:17][C:18]2[C:19]([F:28])=[C:20]([F:27])[C:21]([F:26])=[C:22]([F:25])[C:23]=2[F:24])(=[O:16])=[O:15])(=[O:38])=[O:39])=[C:41]([CH3:49])[CH:42]=1
Reactant: C=CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CI)c(C)c1
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(C)c1
Temperature: 0 °C
Reaction time: 0 h

Procedure:
1-Ethylpiperidine hypophosphite (1.184 g, 6.614 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (10 ml) was added. The solution was cooled with ice-water, and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (0.218 g, 0.794 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and 2-(iodomethyl)-1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidine (0.28 g, 0.661 mmol) was added at 0° C. Triethylborane solution (0.03 ml, 1 mol/l) was added to the reaction mixture and compressed air was then passed through the mixture for 10 sec. After stirring for 5 min the addition of triethylborane solution-compressed air was repeated with the same amount. After thin layer chromatography control, the addition of triethylborane soln.-compressed air was repeated again with the same amount. The reaction mixture was washed with cooled water (10 ml) and cooled saturated sodium bicarbonate soln. (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether/methylene chloride (6:1:1) Yield: 50 mg (13%)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:38][CH:39]1[O:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:40][CH:39]([CH3:38])[O:44][CH:43]([CH3:45])[CH2:42]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC1CNCC(C)O1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(CCOc2cc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)ccc2CS(C)(=O)=O)CC(C)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and 2,6-dimethylmorpholine (14 μl, 0.11 mmol), and stirred at room temperature for 18 hours. The reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 20 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(2,6-dimethylmorpholino)ethoxy)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 571 (M)+.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.C1COCC1.Cl.[OH-].[Na+]>ClCCl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 32.5 °C

Procedure:
4-(N—BOC amino)-CBz piperidine (24.4 kg 73.42 mol), THF (65 kg) and 5 M HCl (23.0 kg, 110.13 mol) were combined and heated to 30-35° C. for ˜2 hours, and then at 55° C. overnight. After cooling the reaction mixture to 10° C., dichloromethane (97 kg) and 10M NaOH (7.97 kg, 145.12 mol) were added, while keeping the temperature at <25° C. The phases were separated and the organic phase was washed with 25 wt % NaCl solution (27.5 kg). The washed organic phase was distilled at atmospheric pressure to a volume of 70 L. Dichloromethane (162 kg) was then added, and the mixture was concentrated by distillation to a volume of 120 L to give the title product as a solution in DCM (17.2 kg. 100%.). 1H NMR (CDCl3) 7.33 (5H, m), 5.14 (2H, s), 4.14 (2H, br s), 2.87 (3H, m), 1.83 (2H, m), 1.66 (3H, m) and 1.28 (2H, m).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[N+:37]([O-:39])=[O:38])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[N+:37]([C:26]1[CH:27]=[CH:28][C:29]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:30][C:25]=1[C:23]1[CH:24]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:20]=[CH:21][N:22]=1)([O-:39])=[O:38]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 160 mg of 3-(trifluoromethyl)phenol in 2 mL of DMF was added 104 mg of potassium carbonate and 160 mg of intermediate 3.1b. After stirring overnight at 50° C. the reaction mixture was partitioned between water and ethyl acetate. The organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated to give a yellow syrup that was used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=4[O:38][CH3:39])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:40])[N:15]=1)=[O:13])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:72][N:73]1[CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]1>CN(C=O)C.O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:37]=[CH:36][C:32]([C:33](=[O:35])[NH:79][CH:76]5[CH2:77][CH2:78][N:73]([CH3:72])[CH2:74][CH2:75]5)=[CH:31][C:30]=4[O:38][CH3:39])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:40])[N:15]=1)=[O:13])[CH3:10]
Reactant: CN1CCC(N)CC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
A solution of 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl}amino)-3-methoxybenzoic acid (50 mg, 0.092 mmol) in anhydrous DMF (0.5 mL) was treated with DIPEA (0.150 mL) and TBTU (50 mg, 0.150 mmol). The mixture was then treated with 1-methylpiperidin-4-amine (18 mg, 1.38 mmol) and was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted twice with DCM. The organic layer was dried over Na2SO4 and the solvent was evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (DCM/MeOH) to afford 43 mg (72% yield) of the title compound.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(C)C(C)=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]1[C:23](=O)[CH2:22][NH:21][C:20]1=[O:25]>O>[NH2:5][C:23]1[CH2:22][NH:21][C:20](=[O:25])[C:19]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CNC(=O)C1c1cccs1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: NC1=C(c2cccs2)C(=O)NC1
Yield: 99 %

Procedure:
To a round bottom flask with a Dean-Stark distilling receiver, ammonium acetate (20.90 g, 271 mmol) and xylene (215 mL) were charged and kept at 60° C. Then 3-thiophen-2-yl-pyrrolidine-2,4-dione (19.0 g, 105 mmol) was added portionwise. The mixture was heated to reflux until there was no more water collected by the receiver (about 15 mL water) and a sticky gel was formed at the bottom. After cooling, toluene was decanted and the sticky gel was further washed by toluene and water and dried under vacuum at 80° C. Finally, a sticky gel was obtained (18.3 g, yield 99%), which can be used directly for the preparation of various compounds having one or more pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione-3,6-diyl units. 1H NMR (d6-DMSO, 500 MHz), δ=7.23 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 7.00 (dd, J=5.0, 4.0 Hz, 1H), 6.77 (s, 2H), 3.82 (s, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC[C@H](N)C(=O)N[C@@H](CCSC)C(N)=O
Reaction time: 1 h
Yield: 89 %

Procedure:
4.5 g (13 mmoles) of BOC-Nva-Met-NH2 are suspended in 20 ml of ethyl acetate, and 20 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, the separated precipitate is filtered off, and dried in vacuo over anhydrous sodium hydroxide. The resulting 4 g of crude product are recrystallized from a mixture of methanol and ether. 3.28 g (89%) of H-Nva-Met-NH2.HCl are obtained; m.p.: 198°-200° C., Rf5 =0.40, [α]D25 =+10.2° (c=1%, in methanol).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[O:29])=[C:23]([F:39])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[C:37]([C:33]1[CH:32]=[C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([C@H:17]3[O:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:22][C:23]=2[F:39])=[O:29])[CH:36]=[CH:35][CH:34]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)Nc3cccc(C#N)c3)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)Nc2ccc([C@@H]3CNCCO3)cc2F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
To a stirred solution of trifluoroacetic acid (216 μl) in water (4.5 ml) was added a solution of (R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (85 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford 1-(3-cyano-phenyl)-3-((R)-2-fluoro-4-morpholin-2-yl-phenyl)-urea (45 mg, 61%) as a white solid. MS (ISP): 341.1 ([M+H]+).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
10.2 mL benzylchloride was added to 10 g piperidine-4-carboxylic acid amide and 21.6 g potassiumcarbonate in 280 mL DMF at 5° C. The reaction was stirred over night at RT. The solvent was removed and the residue was dissolved in water and dichlormethane. The organic layer was separated and evaporated. The residue was purified by column chromatographie (silica gel, eluent: dichlormethane/methanol 95:5 to 90:10) to give 9.8 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:5]=[O:6]
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(Br)cc(C=O)cc2Br)cc1
Temperature: 60 °C
Reaction time: 0.21 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-dibromo-4-hydroxybenzaldehyde (5.30 g, 18.9 mmol) in anhydrous DMF (15 mL) under nitrogen was added potassium carbonate (5.50 g, 19.9 mmol) and the mixture was stirred for 10-15 min during which time vigorous effervescence was observed. 4-methoxybenzyl chloride (2.70 mL, 19.9 mL) was then added and the mixture was heated at 60° C. for 20 h. The mixture was filtered and the filtrate was evaporated. The residual oil was then poured into water (100 mL) and the mixture was stirred for 1-2 h. The resulting solid was collected by filtration, washed with water and dried under vacuum at 60° C. to leave 6.63 g (88%) of the title compound as a pale brown solid. 1H NMR (DMSO-d6) 3.82 (3 H, s), 5.06 (2 H, s), 7.02 (2 H, d), 7.53 (2 H, d), 8.24 (2 H, s), 9.95 (1 H, s).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][C@@:13]12[C:22]3[CH:23]=[CH:24][C:25]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:21]=3[CH2:20][CH2:19][C@H:18]1[NH:17][C:16](=[O:34])[CH2:15][CH2:14]2.CI>C(OCC)(=O)C>[CH3:1][N:17]1[C@H:18]2[C@@:13]([CH3:12])([C:22]3[CH:23]=[CH:24][C:25]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:21]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:34]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3ccccc3)ccc12
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccccc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 471.2 %

Procedure:
Potassium t-butoxide (0.22 g, 1.9 mmol) was added to 5 mL of t-butanol in a 25 mg round bottom flask. The (4aR)-(10bR)-10b-methyl-8-phenylthio-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one, (0.183 g, 0.566 mmol) was added followed by methyl iodide while cooling briefly in an ice bath. The mixture was allowed to stir at room temperature for 18 h before diluting with ethyl acetate and filtering to remove inorganics. Filtrate was concentrated in vacuo to give a oil which was triturated in hexane/diethyl ether to facilitate crystallization. Recrystallization from ethyl acetate/hexane gave 0.90 g of white crystals: mp 109°-112°; FD MS 337M+; Calcd for C21H23N1O1S1.
Reaction SMILES: [C:1]([O:9]CC1C=CC([N+]([O-])=O)=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.P([O-])([O-])([O-])=O.[Zn]>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a solution of 160 mg of p-nitrobenzyl benzoate in 5 ml of tetrahydrofuran and 5 ml of 0.35M phosphate buffer (pH 6.1) was added 1.6 g of zinc powder and the mixture was stirred for 3 hours at room temperature. After the reaction, the reaction mixture was filtered using Celite, and the pH of the filtrate was adjusted to an alkaline side by adding sodium carbonate. It was then washed with 10 ml of ethyl acetate twice. The aqueous layer was acidified and then extracted with ethyl acetate (10 ml×3). The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 58 mg (76.4%) of benzoic acid. m.p. 121°-122° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:34][CH2:35]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
74 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg, 0.199 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.166 mmol), DIPEA (0.035 mL, 0.199 mmol) and NaBH(OAc)3 (148 mg, 0.697 mmol).