Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][C@H:19]([CH2:54][O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:20][S:21][CH2:22][CH2:23][S:24]([N:27]([CH2:35][C:36]1[CH:53]=[CH:52][C:39]([C:40]([NH:42][C@H:43]([C:49]([OH:51])=[O:50])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[O:41])=[CH:38][CH:37]=1)C(OC(C)(C)C)=O)(=[O:26])=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>FC(F)(F)C(O)=O>[C:1]([O:18][C@H:19]([CH2:54][O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:20][S:21][CH2:22][CH2:23][S:24]([NH:27][CH2:35][C:36]1[CH:53]=[CH:52][C:39]([C:40]([NH:42][C@H:43]([C:49]([OH:51])=[O:50])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[O:41])=[CH:38][CH:37]=1)(=[O:26])=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCCS(=O)(=O)N(Cc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCCS(=O)(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-(N-(2-((2R)-2,3-bis(palmitoyloxy)propylthio)-ethylsulfonyl)-N-t-butyloxycarbonylaminomethyl)benzoyl -glutamic acid de-t-butyl ester as obtained in Example 56 (108 mg) in trifiuoroacetic acid (1 ml) was stirred at room temperature for 1 hour, followed by concentration to dryness under reduced pressure, to yield the title compound (89 mg, yield 100%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 26.5 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in ethanol (15 ml), and sodium hydroxide (600 mg, 17 mmol) was added. The mixture was heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 0.53 g (yield 26.5%) of the title compound.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([N:9]=O)[N:6]=[C:5]([NH2:11])[C:4]=1[NH2:12].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1>C(OCCO)C>[NH2:9][C:7]1[N:6]=[C:5]([NH2:11])[C:4]2[C:3](=[N:2][C:24]([NH2:25])=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:22][CH:21]=3)[N:12]=2)[N:8]=1
Reactant: Nc1nc(N=O)nc(N)c1N
Reactant: N#CCc1ccc(OCCO)cc1
Agent: [Na]
Solvent: CCOCCO
Product: Nc1nc(N)c2nc(-c3ccc(OCCO)cc3)c(N)nc2n1

Procedure:
460 mg of metallic sodium are dissolved with stirring in 150 ml of 2-ethoxy-ethanol. 3.1 g (0.02 mol) of triaminonitroso-pyrimidine and 3.5 g (0.02 mol) of p-(2-hydroxyethoxy)phenyl-acetonitrile are added one after the other with stirring and the mixture is heated with stirring in a water bath at 60° C. The color of the mixture changes from violet to bright brown. After stirring for 14 hours, the reaction is over. The mixture is left to cool. Unreacted 2,4,6-triamino-nitrosopyrimidine is filtered off and the clear solution is concentrated to dryness. The precipitate is taken up in hot acetone and the crude product is precipitated by admixture with petroleum ether. Purification follows first by recrystallization from butanol and then by separation on a silica gel-dry column (silica gel 60 Merck). The compound mentioned in the title is obtained as yellow-brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[CH2:13][N+:14]([O-])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].[ClH:22]>C(O)(=O)C.[Pd]>[ClH:22].[NH2:14][CH2:13][C:12](=[O:17])[C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(C(C)(C)C(=O)C[N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C(C)(C)C(=O)CN)cc1OC
Yield: 75 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-one (400 mg, 1.50 mmol) in acetic acid (6 mL) and conc HCl (2 mL) was added 10% Pd/C (400 mg) in a pressure vessel. The mixture was hydrogenated under 60 psi hydrogen for 48 h and then filtered. The residue was concentrated and triturated with Et2O to give 1-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride (306 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (brs, 2H), 6.90 (d, 1H), 6.80 (dd, 1H), 6.72 (d, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.68 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH:30]([CH3:32])[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:32])[CH3:31]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)N1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a suspension of NaH (60% in mineral oil, 142 mg, 3.56 mmol) in DMF (2.00 mL) was added (1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol Intermediate A (145 mg, 0.88 mmol) and the reaction stirred for 20 min. A solution of Intermediate 58b (220 mg, 0.88 mmol) in DMF (2.00 mL) was added and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (145 mg, 44%). LCMS (Method 4): Rt 0.29 min, m/z 392.2 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methyl 4-hydroxybenzoate (609 mg, 4.00 mmol), 1-(4-bromophenyl)-3-methylbutan-1-ol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1M HCl (3×100 mL) and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-(4-bromophenyl)-3-methylbutoxy)benzoate (1.4 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.89-7.83 (m, 2H), 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 6.83-6.78 (m, 2H), 5.16 (dd, J=9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.75 (m, 1H), 1.58-1.51 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Na].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[CH2:12]([O:19][N:20]=[C:21](Br)[CH:22]=[CH:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][N:20]=[C:21]([S:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:22]=[CH:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(C=CSc1ccccc1)=NOCc1ccccc1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C(=CC(=NOCc1ccccc1)Sc1ccccc1)Sc1ccccc1
Yield: 43 %

Procedure:
Sodium salt of thiophenol (0.14 g) was added to ethanol (5 ml) solution of N-benzyloxy-3-phenylthioacrylimidoyl bromide (0.30 g) at room temperature, then it was heat refluxing for three hours. It was cooled, and chloroform (50 ml) was added to the reaction mixture. It was successively washed with 1N aqueous sodium hydroxide solution, pure water, aqueous saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain phenyl N-benzyloxy-3-(phenylthio)thioacrylimidate (0.14 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[N:16]=[C:17]([CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[O:18][CH:19]=1)=O.NC1C=CC(C(F)(F)F)=CC=1NC(C1N=C(CC2C(Cl)=CC=CC=2Cl)OC=1)=O>>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH2:20][C:17]1[O:18][CH:19]=[C:15]([C:13]2[NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[N:1]=2)[N:16]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NC(=O)c1coc(Cc2c(Cl)cccc2Cl)n1
Agent: Nc1ccc(C(F)(F)F)cc1NC(=O)c1coc(Cc2c(Cl)cccc2Cl)n1
Product: FC(F)(F)c1ccc2[nH]c(-c3coc(Cc4c(Cl)cccc4Cl)n3)nc2c1

Procedure:
N-[2-Amino-4-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)methyl](1,3-oxazol-4-yl)}carboxamide and N-[2-amino-5-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)methyl](1,3-oxazol-4-yl)}carboxamide. According to the procedure described in step (e) of Example 19, the title product was obtained from 2-[(2,6-dichlorophenyl)methyl]-1,3-oxazole-4-carboxylic acid, Example 19 (d), (0.26 g, 0.97 mmol) and 4-(trifluoromethyl)-1,2-phenylenediamine (0.17 g, 0.97 mmol, Lancaster) as a light-brown solid. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH2:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH2:5]2.Cl[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH:21][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:6][CH2:5]2
Reactant: Clc1cnccn1
Reactant: CC(C)(C)C[C@H](N)C(=O)NCCN1CCc2cc(F)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@H](Nc1cnccn1)C(=O)NCCN1CCc2cc(F)ccc21
Temperature: 240 °C
Yield: 30.3 %

Procedure:
(S)-2-Amino-4,4-dimethyl-pentanoic acid [2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-amide (20 mg, 0.066 mmol) was dissolved in DMF (0.7 mL) containing equimolar amounts of 2-chloropyrazine (6 μL, 0.066 mmol), 0.1 equivalents of CuI (1.3 mg, 0.006 mmol), and 1.5 equivalents of potassium carbonate (13.9 mg, 0.099 mmol). The mixture was stirred and heated by microwave to 240° C. for 30 minutes. After completion the mixture was purified by reverse phase LC to afford (S)-4,4-Dimethyl-2-(pyrazin-2-ylamino)-pentanoic acid [2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-amide 2 (8.3 mg, 0.02 mmol, 32%): 1H-NMR (400 MHz, CD3OD) δ=8.37 (m, 2H), 6.82-6.41 (m, 4H), 4.57 (dd, J=9.2, J=3.2, 1H), 3.42 (t, J=6.2, 2H), 3.36 (t, J=8.2, 2H), 3.14 (m, 2H), 2.88 (t, J=8.2, 2H), 1.83-1.62 (m, 2H), 0.96 (s, 9H). MS calcd. for C21H29FN5O (M+H+) 386.23, found 386.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH2:17]([N:19]([CH2:36][CH3:37])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:34]=O)=[C:28]2[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:24])[CH3:18]>>[CH2:36]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[C:28]2[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:24])[CH3:37]
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: CCN(CC)CCNC(=O)c1[nH]c(C=O)c2c1CCCC2
Product: CCN(CC)CCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c2c1CCCC2
Yield: 37.7 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (2-diethylaminoethyl)amide (80 mg) to give 50 mg (38%) of the title compound as a reddish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a suspension containing 3.0 g (15 mmol) of 2-chloro-6-nitrobenzoic acid in 150 ml of dichloromethane was added 2.8 g (22 mmol) of oxalyl chloride followed by 0.055 ml (0.75 mmol) of N,N-dimethylformamide. The reaction was allowed to stir at room temperature for 2 h, quenched with 50 ml of methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% ethyl acetate/hexanes gave 3.1 g (9-7%) of product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21]([O:23][C:24]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[CH:30][CH:31]=2)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)CCOc1ccc(O)cc1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCOc1ccc(Oc2cc(C(F)(F)F)nc(C(F)(F)F)c2C(=O)OCC)cc1
Yield: 68.8 %

Procedure:
A 250 ml round bottom flask is charged with 3.54 g (0.011 mol) of product of Example 19, 2.31 g (0.011 mol) of 4-[(1-ethoxycarbonyl)ethoxy]phenol and 1.82 g (0.013 mol) of K2CO3 in 150 ml of methyl isobutyl ketone. This mixture was stirred at reflux for 18 hours, filtered and concentrated. The residue was taken up in ether, washed with 5% NaOH, water, dried (MgSO4) and concentrated in vacuo to afford 3.75 g of an orange oil. Purification by HPLC using 18% ethyl acetate/cyclohexane as eluting solvent gave 2.66 g of an oil which was kugelrohr distilled at 41 Pa, pot temperature 150°-154° C., affording 2.56 g (47.0%) of product as a clear oil, nD25 1.4732.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]2[NH:35][N:36]=[C:32]([O:31][CH2:30][C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:33]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 27 %

Procedure:
4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (0.25 g, 0.96 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.239 g, 0.96 mmol) and 2M trimethylaluminium in toluene (1.2 ml, 2.4 mmol). The crude product was purified by preparative HPLC, 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 title compound (0.124 g, 27%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[OH-:12].[Na+]>O>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [OH-]
Reactant: O=C(O)Cc1ccccc1Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1O
Temperature: 20 °C

Procedure:
(2-Chlorophenyl)acetic acid (3.4 g, 0.02M), crushed sodium hydroxide pellets (4.8 g, 0.12M) and `SOLVESSO` 200 (30 g) were stirred for 0.5 hours. Cupric sulphate pentahydrate (0.2 g, 0.0008M) was added and the mixture heated at 190°-196° C. for about 4 hours. The reaction mass was cooled to 20° C. and treated with water (50 g), transferred to a separator with a further amount of water (50 g) and filtered. The separated aqueous filtrates were acidified to about pH4 using 36% hydrochloric acid and the product was extracted into ethyl acetate (180 g). (2-Hydroxyphenyl)acetic acid (2.62 g) was isolated as a solid by distillation of the ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+].O>[Fe].C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC(=O)CCC2
Yield: 89.6 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (0.20 g), iron powder (218 mg), ammonium chloride (52 mg), water (1.2 ml) and ethanol (4 ml) was refluxed for 2 hours. After cooling, the insoluble material was filtered off and the filtrate was evaporated in vacuo. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (153 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([CH2:10][CH3:11])=[C:4]([Cl:12])[CH:3]=1.Cl[CH2:14][C:15](Cl)=[O:16].C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:4]1[C:5]([CH2:10][CH3:11])=[C:6]([Cl:9])[C:7]2[O:8][CH2:14][C:15](=[O:16])[NH:1][C:2]=2[CH:3]=1
Reactant: CCc1c(Cl)cc(N)c(O)c1Cl
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Yield: 92.1 %

Procedure:
6-Amino-2.4-dichloro-3-etylphenol (95MF2226) (0.293 g, 1.5 mmol), 2-chloroacetyl chloride (0.19 g, 1.7 mmol) and K2CO3 (0.44 g, 3.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF46) (0.34 g).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=S)c1ccccc1
Product: O=C(O)COc1ccc(Br)cc1-c1csc(-c2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and thiobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.69 min, m/z 390 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:34]1[C:33]([CH3:39])=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3C)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M130) (0.33 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (160 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.O=[C:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:27]([O:26][C:24]([N:22]1[CH2:23][CH:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[F:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)[CH2:21]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
A solution of 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.100 g, 0.400 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.171 g, 0.999 mmol) in MeOH (10 mL) and HOAc (1 mL) was stirred at rt for 1 h. Sodium cyanoborohydride (0.176 g, 2.80 mmol) was added and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by column on silica gel (eluting with 0-10% MeOH in DCM to give 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.115 g, 71%) as a crude gum, which was used directly in the next step. LC/MS (Table 1, Method 3) Rt=1.374 min.; MS m/z: 428 [M+23]+.