Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1.N1C2C=NC=NC=2C=N1>O1CCOCC1.CN1C(=O)N(C)CC1.C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)=[O:28])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: c1ncc2[nH]ncc2n1
Solvent: CCO
Solvent: CN1CCN(C)C1=O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Cl)c1)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 137 I (1.1 mmol) of 3-chloro-phenyl isocyanate are added and the reaction mixture is stirred overnight at RT and finally for 16 hours at 60° C. Since, according to HPLC, not all of the pyrazolo-pyrimidine has reacted, a further 40 all of 3chloro-phenyl isocyanate are added and the mixture is stirred for a further 20 hours at 60° C. Working-up analogously to Example 66 and stirring in hot ethanol yield 4-(3-chloro-phenylamino)-3-[(3-chloro-phenyl-amino)-carbonylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=12.4; FARMS: (M+H)+=414.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH3:54])=[C:48]([C:55]#[N:56])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:55]([C:48]1[CH:47]=[CH:46][C:51]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:50][C:49]=1[O:52][CH2:53][CH3:54])#[N:56]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1ccc(OB([O-])[O-])cc1C#N
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 3-cyano-4-ethoxyphenyl borate (205 mg) and potassium carbonate (251 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (48 mg), and the mixture was refluxed for 18 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-cyano-3-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (209 mg).
Reaction SMILES: OC=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O.[NH:15]([CH2:17][CH:18]([OH:20])[CH3:19])[NH2:16].O.[C:22]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5]([CH2:6][CH:7]=1)=[C:4]1[C:3]([N:15]([CH2:17][CH:18]([OH:20])[CH3:19])[N:16]=[CH:22]1)=[CH:11]2
Reactant: COc1ccc2c(c1)CC(=CO)C2=O
Reactant: Cc1ccccc1
Reactant: CC(O)CNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC1=CCC2=c3cnn(CC(C)O)c3=CC2=C1
Yield: 97 %

Procedure:
A solution of 1.4 g (7.36 mmol) of 2-hydroxymethylene-5-methoxy-1-indanone, 0.8 g (8.83 mmol) of (RS)-1-hydrazino-2-propanol and 100 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator for 1.5 hours. After concentration in a vacuum, the reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.74 g (97%) of (RS)-1-(6-methoxy-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol were obtained as a yellow oil which was used directly in the next reaction.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[C:17]([C:40]2[CH:45]=[CH:44][C:43](N)=[CH:42][CH:41]=2)=[N:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1.[CH:47]([NH2:49])=O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.ClCCCl>[Br:15][C:16]1[C:17]([C:40]2[CH:45]=[CH:44][C:43]([N:49]([CH3:47])[CH3:1])=[CH:42][CH:41]=2)=[N:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2Br)cc1
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: CN(C)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2Br)cc1
Reaction time: 72 h

Procedure:
2.54 g sodium triacetoxy borohydride was added little by little at room temperature to a mixture of 1.44 g 4-(4-bromo-1-trityl-1H-pyrazol-3-yl)phenylamine (compound in Production Example 152), 0.61 mL of 37% formamide and 40 mL 1,2-dichloroethane, and the mixture was stirred for 3 days. Ethyl acetate and an aqueous saturated sodium bicarbonate solution were added to the reaction solution and stirred, then water was added thereto, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated, and diisopropyl ether was added to the resulting residues which were then triturated, and the crystals were collected by filtration. The crystals were dried over a vacuum pump, to give 1.18 g of the title compound as pale brown crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10]>O1CCCC1>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH:14][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:10]
Reactant: Cc1nc(CCl)cs1
Reactant: CCOC(CN)OCC
Solvent: C1CCOC1
Product: CCOC(CNCc1csc(C)n1)OCC
Reaction time: 16 h
Yield: 76 %

Procedure:
4-Chloromethyl-2-methylthiazole (0.6 g, 4 mmol) was added to aminoacetaldehyde diethyl acetal (5 mL, 10 equivalents) dissolved in tetrahydrofuran (15 mL) at 25° C., and the mixture was stirred for 16 h. The solvents were evaporated and the excess aldehyde was distilled from the crude mixture. The crude residue was purified using dichloromethane—dichloromethane/10% methanol to give 0.76 g (76%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][NH:58][CH2:57]1)([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][N:58]([C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:2]3([CH3:1])[CH2:3][CH2:4]3)=[O:6])[CH2:12][CH2:11]2)=[O:15])[CH2:57]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reactant: CC(C)(C)OC(=O)NC1CNCC1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 19 h
Yield: 85.7 %

Procedure:
To a solution of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (4.48 g, 0.02 mol) in DMF (40 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (9.54 g, 0.03 mol). After stirring for 10 min at ambient temperature N,N-diisopropyl ethyl amine (19.82 ml, 0.116 mol) and a solution of rac-(3S,4R)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.39 g, 67% purity, 0.013 mol) in DMF (45 ml) were added and the reaction mixture was stirred for 19 h at this temperature. It was diluted with ethyl acetate (80 mL) and the organic layer was washed with water (80 mL), aqueous sodium carbonate (1M, 40 mL) and brine (40 mL). The aqueous layers were extracted with ethyl acetate (160 mL). the combined organic layers were dried over sodium sulfate and concentrated. Purification by flash chromatography (SiO2, EtOAc/methanol 100:0 to 80:20) afforded 5.84 g (87%) of the title compound as a light brown foam. ES-MS m/e: 524.1 (M+H+).
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:34]=2)[CH:32]=O)[O:22][C:21]1=[O:38])[CH3:19]>C(O)C.O>[CH3:19][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:32]=[C:5]3[NH:4][C:3](=[O:2])[NH:7][C:6]3=[O:8])[CH:34]=2)[O:22][C:21]1=[O:38])[CH3:17]
Reactant: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=O)c2)OC1=O
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)OC1=O
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium (0.9 g, 0.04 g atom) was dissolved in ethanol (150 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (9.19 g, 40 mmol) added. After 30 minutes solid 5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrobenzaldehyde (10.0 g, 32 mmol) was added and the mixture stirred vigorously. After 30 minutes, the mixture was diluted with water (150 mL) filtered and the solid washed with water and air dried to give 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (9.80 g, 77%). An analytical sample was prepared by crystallization from dimethylformamide and wate and had an m.p. 285°-287° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](O)=[O:32])[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:31]([CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:20][CH:19]=2)[CH2:25]1)=[O:32]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NCCO)C2)cn1
Yield: 67 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using ethanolamine instead of methylamine, to the title compound (52 mg, 67%) which was obtained as an off white solid. MS: m/e=494.3 [M+H]+.
Reaction SMILES: CC(C)(C)[C@@H](C(O)=O)N[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[NH2:18][C@@H:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:20]([OH:22])=[O:21].[CH2:28](O)CCCC=C>>[F:25][C:24]([F:27])([F:26])[CH2:23][C@H:19]([NH:18][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:28])=[O:6])[C:20]([OH:22])=[O:21]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=CCCCCO
Reactant: N[C@@H](CC(F)(F)F)C(=O)O
Product: C=CCCCCOC(=O)N[C@@H](CC(F)(F)F)C(=O)O

Procedure:
(2S)-4,4,4-trifluoro-2-{[(hex-5-en-1-yloxy)carbonyl]amino}butanoic acid was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using (2S)-2-amino-4,4,4-trifluorobutanoic acid and 5-hexenol. LRMS (ESI) m/z 284.3 [(M+H)+; calcd for C11H17F3NO4: 284.1].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@:25]2([C:43]3[C:34](=CC4OCCO[C:37]=4[CH:42]=3)OC2)C1=O.CC1C=CC(S([O:55][CH2:56]CC2CC2)(=O)=O)=CC=1.BrCCCCC>>[CH:43]1([CH2:42][CH2:37][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:56][O:55][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH2:34][CH2:25]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Solvent: CCCCCBr
Product: O=C1N(CCC2CC2)c2ccccc2C12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-cyclopropylethyl 4-methylbenzenesulfonate to replace 1-bromopentane, 1′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (59%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=7.4 Hz, 2H), 6.96-7.04 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.19 (s, 1H), 4.72 (ABq, 2H), 4.19-4.03 (m, 4H), 3.94-3.71 (m, 2H), 0.79-0.64 (m, 1H), 0.50-0.37 (m, 2H), 0.11-0.04 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.6, 138.2, 132.4, 128.7, 123.9, 123.0, 121.1, 111.5, 108.5, 99.3, 80.1, 64.5, 63.9, 57.9, 40.4, 32.4, 8.6, 4.4; MS (ES+) m/z 364.0 (M+1).
Reaction SMILES: C([O:4][C:5]1(/[CH:18]=[CH:19]/[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].CC(=O)OCC>CO>[OH:4][C:5]1(/[CH:18]=[CH:19]/[CH2:20][C:21]([F:24])([F:22])[F:23])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(=O)OC1(/C=C/CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (E)-tert-butyl 4-acetoxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (200 mg, 0.57 mmol) in methanol (5 mL) was added 2M NaOH (2 mL, 4 mmol), the mixture was held stirring at r.t. for 16 hrs, when TLC (20% EA/PE) indicated completion of the reaction. The mixture was concentrated in vacuo, the residue was diluted with brine and extracted with EtOAc, and the organic layer was concentrated in vacuo to get the crude product, which was used directly for the next step.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:22]>>[ClH:22].[ClH:22].[CH3:20][N:18]([CH3:19])[C:15]1[CH:14]=[CH:13][C:12]([C:11]([CH2:10][CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:21])=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Agent: Cl
Product: CN(C)c1ccc(C(=O)CC2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
In 30 mi of concentrated hydrochloric acid was dissolved 1.73 g of the 1-acetyl-4-(4-dimethylaminobenzoylmethyl)piperidine prepared in Example 39 and the mixture was stirred at 100° C. for 15 hours. The solvent was then distilled off and the residue was recrystallized from ethanol-ethyl acetate to give 1.7 g of colorless crystals melting at 251°-255° C.
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[CH:44]1([NH:47][CH2:48][C:49]2[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[CH:50]=2)[CH2:46][CH2:45]1>>[CH:7]([OH:8])=[O:6].[CH:44]1([N:47]([CH2:48][C:49]2[CH:50]=[C:51]([O:57][CH3:58])[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=2)[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])[CH2:45][CH2:46]1
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Product: COc1cc(CN(C(=O)C2=C(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)C[C@@H]3CN(C(C)=O)C[C@H]2N3)C2CC2)cc(OC)c1
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and cyclopropyl-(3,5-dimethoxybenzyl)amine. LC-MS: Rt=0.88; ES+: 664.27.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:21]=[O:22]>C(#N)C.O>[OH:22][C:21]1[C:3]([CH3:10])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH:2]=[O:1]
Reactant: Cc1cc(C=O)ccc1O
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc(C=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
The 4-hydroxy-3-methylbenzaldehyde (7.0 g, 51.41 mmole) and magnesium chloride (7.3 g, 77.12 mmole) were mixed in acetonitrile (100 mL) and cooled to 0° C. (ice bath). Triethylamine (19.51 g, 192.79 mmole) followed by para-formaldehyde (10.41 g, 347 mmole) were added to above mixture, which was stirred for 1 hour. The mixture was warmed to room temperature and then heated to 90° C. for 18 hours. The contents were poured into water (100 mL) and extracted with EtOAc (2 X 100 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give an off-white solid (2.2 g, 26%). GCMS m/z 164.0 (M+). 1H NMR (CDCl3/400 MHz) 11.82 (s, 1H), 9.96 (s, 1H), 9.89 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[N:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH3:50][C:49]1([CH3:51])[CH:48]([OH:52])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:11]=2)[NH:8][CH:7]1[C:6]1[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
To a mixture of (3-nitro-benzylidene)-(4-trifluoromethyl-phenyl)-amine (5.88 g, 20 mmol) and ytterbium(III) triflate hydrate (1.24 g, 2 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (2 mL, 22 mmol) and water (0.36 mL, 20 mmol) dropwise. The reaction mixture was stirred at 25° C. for 72 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-ol (7.1 g, 96%) as a light yellow oil: LC/MS m/e calcd for C18H17F3N2O3 (M+H)+: 367.34, observed: 349.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:6]=1[O:23][CH2:24][CH3:25])=[O:4].[OH-].[Na+].C(O)(=O)C.O>CO>[CH2:24]([O:23][C:6]1[C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2])[CH3:25]
Reactant: CCOc1c(C(=O)OC)oc2c3ccccc3n(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c(C(=O)O)oc2c3ccccc3n(-c3ccccc3)c12
Temperature: 0 °C
Yield: 15.6 %

Procedure:
A suspension of 12.0 g (0.036 mole) of 3-ethoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 100 ml of methanol was treated with 60 ml of 1.0N aqueous sodium hydroxide. After stirring at reflux for 20 hours, the cooled reaction mixture was added to 1.2 kg ice/water, and the mixture was acidified with acetic acid. The crude product was filtered, stirred in 600 ml water, and refiltered. Recrystallization from ethanol yielded 5.1 g of analytically pure acid containing 0.35 mole of water of hydration, mp 146°-147° C. An additional 1.8 g of product was obtained from the recrystallization filtrate, for a total yield of 6.9 g (59% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH2:36][CH2:37][NH2:38])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][CH2:37][CH2:36][CH2:35][C@H:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:41])[CH2:39][OH:40])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.155 g (0.42 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.12 g (0.55 mmol) of tert-butyl[(1S)-4-amino-1-(hydroxymethyl)butyl]carbamate (Example 247A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.105 g (0.55 mmol) of EDC and 0.017 g (0.13 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).