Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[C:19]([O:23][CH3:24])=[C:18]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C)C.C(OCC)(=O)C>CC(C)=O.O>[CH3:24][O:23][C:19]1[C:20](=[O:22])[O:21][CH:17]([CH2:16][C:15]([OH:3])=[O:14])[C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC1=C(c2ccccc2)C(CCO)OC1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=C(c2ccccc2)C(CC(=O)O)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2N Jones reagent (8 ml) was diluted with acetone (12.5 ml). To this solution was added a solution of 5-(2-hydroxyethyl)-3-methoxy-4-phenyl-2(5H)-furanone (1.25 g) in acetone (12.5 ml) at 0° C. over a period of 50 minutes. The mixture was stirred at ambient temperature for 15 minutes and isopropylalcohol (5 ml) was added thereto. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, and dried. Evaporation of the solvent gave 2-(2,5-dihydro-4-methoxy-5-oxo-3-phenyl-2-furyl)acetic acid (865 mg) which was recrystallized from diethyl ether.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([C:16]#[N:17])([CH3:15])[CH3:14])(=O)=O)=CC=1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=1[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:12][C:13]([CH3:15])([CH3:14])[C:16]#[N:17])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(OCC(C)(C)C#N)cc(C)c1Br
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2-cyano-2-methylpropyl 4-methylbenzenesulfonate (760 mg) and 4-bromo-3,5-dimethylphenol (500 mg) in N,N-dimethylformamide (8 mL) is added Cs2CO3 (2.0 g). The mixture is stirred for 12 hours at 80° C., diluted with diethylether and washed with water and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (petrole ether/ethyl acetate 90:10→60:40) to give the title compound. Yield: 572 mg; Mass spectrum (ESI+): m/z=282 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C(C)=CC=CC=1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]1([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc2ccccc12
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: c1ccc2c(N3CCNCC3)cccc2c1
Reaction time: 10 h
Yield: 41.9 %

Procedure:
83.2 g (966 mM [sic]) of piperazine, 38.0 g (339 mM [sic]) of potassium tert-butoxide and 50.0 g (2.41 mM [sic]) of 1-bromonaphthalene were added to a mixture of 5.4 g (24.2 mM [sic]) of palladium acetate and 14.7 g (48.3 mM [sic]) of tri-o-tolylphosphine in 500 ml of xylene, and the mixture was refluxed while stirring vigorously under a nitrogen atmosphere for 10 h. The mixture was then diluted with methylene chloride, the insoluble residues were filtered off, and the filtrate was concentrated. The crude product was purified by column chromatography (silica gel, eluent, THF/methanol/ammonia 85/13/2). 21.5 g (42%) of product were isolated with melting point 84-86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([C:10](=[O:13])[CH2:11][F:12])=[N:6][C:7]=1[O:8][CH3:9].[CH3:22][N:23]([CH:25](N(C)C)OC(C)(C)C)[CH3:24]>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:25])[CH:24]=[C:11]([F:12])[C:10]([C:5]1[C:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:3][C:2]([F:1])=[C:7]([O:8][CH3:9])[N:6]=1)=[O:13]
Reactant: COc1nc(C(=O)CF)c(NC(=O)OC(C)(C)C)cc1F
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COc1nc(C(=O)C(F)=CN(C)C)c(NC(=O)OC(C)(C)C)cc1F
Temperature: 40 °C
Yield: 48.8 %

Procedure:
A solution of 1,1-dimethylethyl [5-fluoro-2-(fluoroacetyl)-6-(methyloxy)-3-pyridinyl]carbamate (3.72 g, 12.32 mmol) in dry toluene (20 ml) was treated with {(dimethylamino)[(1,1-dimethylethyl)oxy]methyl}dimethylamine (Bredereck's reagent) (3.05 ml, 14.78 mmol) and heated at 40° C. for 2 hours. The mixture was evaporated and the residue triturated with 3×200 ml hexane and the remaining solid dried in vacuo to afford the product (2.15 g, 49%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18](=[O:36])[C@H:19]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:20][C:21]([O:23][CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[O:22])[C@H:15]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:14]2)=[CH:4][CH:3]=1.[CH:42]([B-](F)(F)F)=[CH2:43].[K+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:31]1([C@H:19]([NH:20][C:21]([O:23][CH2:24][C:25]([CH3:29])([CH3:30])[CH2:26][CH:27]=[CH2:28])=[O:22])[C:18]([N:16]2[CH2:17][C@H:13]([O:12][C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[C:2]([CH:42]=[CH2:43])[CH:11]=4)[CH:6]=[CH:7][N:8]=3)[CH2:14][C@H:15]2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3ccc(Br)cc23)C[C@H]1C(=O)OCC)C1CCCC1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3ccc(C=C)cc23)C[C@H]1C(=O)OCC)C1CCCC1
Reaction time: 15 h

Procedure:
Ethyl(4R)-4-[(7-bromoisoquinolin-1-yl)oxy]-1-[(2S)-2-cyclopentyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-L-prolinate (526 mg, 0.83 mmol) was dissolved in ethanol (10 mL) and nitrogen was bubbled through for 15 min. Potassium vinyltrifluoroborate (168 mg, 1.25 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) DCM adduct (34 mg, 0.04 mmol) were added and the reaction mixture heated to reflux under nitrogen. After 15 h, the reaction was complete and the volatiles were evaporated and the residue purified by silica gel chromatography (gradient elution, 10-75% EtOAc/hexane) to give a clear oil. LRMS (ESI) m/z 578.4 [(M+H)+; calcd for C33H44N3O6: 578.3].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:30]2[CH2:31][C:28]([F:32])([F:27])[CH2:29]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 69 a, using ethyl 2-(5-bromo-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoate (Example 265) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e=426.0 [M+H]+.
Reaction SMILES: [OH:1][P:2]([CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25](O)=[O:26])([CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[OH:3][P:2]([CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:26])([CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)CC(CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(CC(C)C)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 65 %

Procedure:
The process is performed according to the procedure described in 1.8., starting with 250 mg (0.58 mol) of 2-[[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]methyl]-4-methylpentanoic acid and 124.5 mg (0.58 mmol) of methyl phenylalaninate hydrochloride. 228 mg of product are recovered (yield=65%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH2:1]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)CCOc1ccc(C=O)c2ccccc12
Product: CC(C)CCOc1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc12

Procedure:
Prepared by Procedure F and Scheme R using 4-(isopentyloxy)-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15](=[O:40])[N:16]([CH3:39])[CH2:17][CH2:18][NH:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>CO>[CH3:39][N:16]([CH2:17][CH2:18][NH:19][C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)=[O:40]
Reactant: CCOC(=O)c1cc2cc(C(=O)N(C)CCNC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
1.3 g (2.4 mmol) 198 was saponified with 5 mL 1M NaOH in 50 mL methanol at room temperature overnight. The methanol was evaporated, the solution was diluted to about 100 mL with cold icy water and was acidified to pH 2 using cold 1 M HCl. The product formed a gel which was extracted with 100 mL ethylacetate, the organic phase was washed once with water and twice with brine, was dried with sodium sulfate and was evaporated to dryness to give a brownish solid foam in quantitative yield. MS: 502.25 (M−H+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC[C:22]([O:24][CH2:25]OC)=C.C(N(CC)CC)C>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:22][O:24][CH2:25][O:1][C@@H:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(CCl)OCOC
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](CC(=O)OCC)OCOC
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
Ethyl (S)-3-hydroxytetradecanoate (2.00 g, 7.3 mmol) and 2-(chloromethyl)-3,5-dioxahexa-1-ene (manufactured by Tokyo Kasei Co., Ltd., 1.20 g, 8.8 mmol) were dissolved in THF (10 mL), p-toluenesulfonic acid (p-TsOH, 10 mg) was added, and the mixture was stirred at room temperature for 15 hr. Triethylamine (1 mL) was poured into the reaction mixture and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate (0.5 g) and filtered. The solvent was evaporated to give the corresponding ethyl (S)-3-methoxymethoxytetradecanoate (2.20 g, yield 95%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[O-:26][CH2:27][CH2:28][CH3:29].[Na+]>>[CH2:27]([O:26][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH2:28][CH3:29]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCC[O-]
Agent: [Na+]
Product: CCCOc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 63 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.54 g) and sodium propoxide solution (from sodium, 0.17 g, and n-propanol, 25 ml) yielded the title compound, 0.19 g, m.p. 157-8° C. (recrystallized from n-propanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=4[CH3:31])[C:24]([O:23][CH3:22])=[O:35])[CH:3]=3)[C:8]2=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reactant: COC(=O)c1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)c1
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (product of step iv)) (1.2 g), intermediate 2 (0.7 g), potassium carbonate (1.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.4 g) in N,N-dimethylformamide (20 mL) was heated to 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered and evaporated. The residue was purified (SiO2, 1:2 ethyl acetate:iso-hexane as eluent) to yield the sub-titled compound (1.03 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2]>C(O)C.[C].[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:16]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(N)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 2-ethoxy-4-nitrobenzoate (550 mg) obtained in Step B of Example 139 in ethanol (10 mL) was added 10% palladium-carbon (42 mg), and the mixture was stirred overnight at room temperature under hydrogen atmosphere (at normal pressures). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (470 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 3.2 g (7.8 mmol) of {2-[3-(3-Methoxy-phenyl)-1-oxo-1,2-dihydro-isoquinolin-4-yloxy]-ethyl}-carbamic acid tert-butyl ester in methanol (10 mL), 4M hydrochloric acid in dioxane (10 mL) was added and the mixture was stirred for 4 hours at room temperature under argon atmosphere. Solvent was evaporated to dryness and the solid residue was treated with methanol and then diethyl ether until precipitation of the hydrochloride salt occurred. The product was collected by filtration, washed with diethyl ether, affording 2.62 g of the title compound (97%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH2:14][C:15]2([CH2:31][CH3:32])[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][C:15]1([CH2:31][CH3:32])[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][CH2:16]1
Reactant: CCC1(CCOc2cc(CC(=O)OC)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(CCOc2cc(CC(=O)O)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
A mixture of [4-Chloro-3-[2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethoxy]phenyl]acetic acid methyl ester (152 mg), 2N aqueous sodium hydroxide (0.45 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (53 mg). Yield: 36%.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.C([O:20][C:21](=O)[CH:22]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])[C:23](OCC)=[O:24])C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:2][O:3][N:4]1[CH2:10][CH2:9][N:8]2[C:21](=[O:20])[CH:22]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[C:23](=[O:24])[N:7]2[CH2:6][CH2:5]1
Reactant: CON1CCNNCC1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C)cc(C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (350 mg, 1.71 mmol) and triethylamine (1.0 ml, 726 mg, 7.17 mmol) in xylene (8 ml) was stirred under argon at 60° C. for one hour. After further addition of 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl ester (482 mg, 1.73 mmol), the reaction mixture was heated at 150° C. (oil bath temperature) for 18 hours. The cooled reaction mixture was poured on ice, the pH made alkaline by addition of 5N aqueous sodium hydroxide, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The base-acidification workup protocol is repeated a second time. Yield: 24 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a beige solid.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:18](N)[CH2:19][NH2:20]>C(O)C>[NH:20]1[CH2:19][CH2:18][N:6]=[C:5]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=N)c1ccc(C(=O)OCC)cc1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=NCCN2)cc1

Procedure:
2.96 g (11.5 mmol) of ethyl 4-ethoxycarbonimidoylbenzoate hydrochloride and 690 mg (11.5 mmol) of ethylenediamine were stirred in 100 ml of ethanol at 60° C. for 4 hours. The solvent was evaporated. 1 N aqueous sodium hydroxide solution was added to the residue. After the extraction with dichloromethane followed by the washing with saturated Aqueous NaCl solution and drying over anhydrous magnesium sulfate, the solvent was evaporated to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1>[NH2:8][C@@H:12]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ccc(Cl)cc3)cc2)COC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N[C@H](CO)CCc1ccc(Nc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of (S)-4-{2-[4-(4-chloro-phenylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (220 mg) in THF (3 ml) in a pressure tube was added HCl solution (2.55 ml, 4 M solution in dioxane). The tube was sealed and the reaction mixture was shaken at 60° C. for 2 hours. The mixture was then cooled to room temperature and poured into 1 M aq. NaOH and extracted with EtOAc. The phases were then separated and the organic phase was dried over sodium sulphate and concentrated in vacuo to afford (S)-2-amino-4-[4-(4-chloro-phenylamino)-phenyl]-butan-1-ol (148 mg, quant.) as a yellow oil which was used in the next step without further purification. MS (ISP): 293.0 ([{37Cl}M+H]+), 291.1 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([CH3:20])[CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: Nc1ccc(I)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1-c1ccc(N)cc1Cl
Temperature: 25 °C

Procedure:
3-Chloro-4-iodoaniline (3.0 g, 11.8 mmol), (4-chloro-2-methylphenyl)boronic acid (2.4 g, 14.2 mmol), Pd(dppf)Cl2 (1.0 g, 1.2 mmol), and K2CO3 (3.3 g, 23.7 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=4[CH3:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 0.31 g of 5-(2-chloro-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene -5 chloride is cooled in an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO3, brine and dried (Na2SO4). The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M+ =467.