Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH-:23].[Na+].Cl>CN(C)C=O.O>[OH:23][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: [OH-]
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]32)C1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
16α-Bromo-3β-methylandrost-5-en-17-one (1.00 g, 2.74 ,mmol) was dissolved in dimethylformamide (90 mL). Sodium hydroxide (165 mg, 4.1 mmol) in water (10 mL) was added and the solution stirred for 2 h. at room temperature. The solution was poured into 1% HCl (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with 5% sodium biocarbonate, water, then dried over magnesium sulfate and filtered. Evaporation gave a pale yellow solid which was chromatographed on flash silica gel and eluted with ether/hexane (10/90). Recrystallization from ether gave 0.54 g (65%) 16α-hydroxy-3β-methylandrost-5-en-17-one mp 166°-168° C.; NMR (DMSO-d6) δ 5.30 (br s, 1H, H-3), 4.38 (t, 1H, 16β-H), 2.0-1.05 (m, complex), 0.98 (s, 3H, C-19 Me), 0.95 (d, J=8 Hz, 3H, C-3 Me), 0.87 (s, 3H, C-18 Me); IR (KBr) 3440, 2900, 1735, 1445, 1365, 1010; MS 302 (m+, 100), 287(24), 274(7), 259(7), 241(7), 230(72), 215(41), 159(31); Anal. Calcd for C20 H30O2 : C, 79.42; H, 9.99. Found: C, 79.24; H, 10.04.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].O[Li].O>C1COCC1.O>[C:17]([O:16][C:14]([NH:13][C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](CCCCCC(C)=O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-8-oxononanoic acid methyl ester (1 eq.) was dissolved in a 1:1 mixture of THF and water at RT and LiOH hydrate (1.2 eq.) was added and the mixture was stirred for 30 min. The mixture was partitioned between 0.1M HCl and DCM, separated and the organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The colourless oil A1 obtained was used in the next step without purification. MS (ES) C14H25NO5 requires: 287, found: 288 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)[N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Reactant: OCc1cccc(Cl)n1
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(OCc3cccc(Cl)n3)n2)CC1

Procedure:
The title compound (I-5b) was prepared from (6-chloro-pyridin-2-yl)-methanol (I-5a) and 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1 a) according to a procedure analogous to that described in Example 1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:19])[CH2:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:25][C:26]1[CH:27]=[C:28]([S:33]C2C=C(Cl)C=C(Cl)C=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH:13]([S:33][C:28]1[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)cc(Sc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(=O)C(Sc1cc(Cl)cc(Cl)c1)N(C)C(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
In 2 ml of dry tetrahydrofuran was dissolved 100 mg (0.4 mmol )of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)acetamide (18a'), and there was added 223 μl (0.4 mmol)of n-butyllithium (1.7 M hexane solution)with stirring at -78° C. over 10 minutes. After stirring at -78° C. for 1 hour, and a tetrahydrofuran solution (1 ml)of 135 mg (0.4 mmol)of 3,5-dichlorophenylsulfide was added thereto over 10 minutes. After 30 minutes, the temperature was raised up to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 5:1)to give 79 mg of 2-benzyloxy-N-[1-(3,5-dichlorophenylthio)-3-methyl-2-oxobutyl]-N-methylacetamide (20)(yield 47%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH3:3].[OH-].[Na+]>CO.O>[CH3:15][CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:14]
Reactant: COC(=O)CCc1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(CCC(=O)O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
3-[2,4,6-Tris(1-methylethyl)phenyl]propionic acid, methyl ester (2.12 g, 7.3 mmol) was dissolved in 100 mL methanol and 10 mL water. Sodium hydroxide (0.32 g, 8.0 mmol) was added and the resulting solution was stirred at room temperature for 4 hours. Concentrated in vacuo and partitioned the residue between water and diethyl ether. The aqueous layer was acidified with concentrated HC1 and extracted with dichloromethane. The organic extract was dried over MgSO4, filtered, and concentrated to give 1.87 g of 3-[2,4,6-tris(1-methyl-ethyl)phenyl]propionic acid as a white solid, mp 194°-196° C.
Reaction SMILES: [NH:1]([C:37](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:32](=[O:33])[CH2:31][C:28]([CH3:30])([CH3:29])[CH2:27][C:25]1=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCC[CH2:55]1.N[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C=O)C>[NH:1]([C:37]([CH3:55])=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:25](=[O:26])[CH2:27][C:28]([CH3:29])([CH3:30])[CH2:31][C:32]1=[O:33])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Agent: CC(C)CC(NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O

Procedure:
To the deprotected Lys-resin sample was added Fmoc-Phe (8.8 mg, 33.2 μmol) in DCM/DMF and 1,3-diisopropylcarbodiimide (DIC) (3 μL, 20 μmol). The coupling reaction was continued for 2 h and ninhydrin tests gave negative amino group readings. The Fmoc-Phe-Lys(ivDde) on resin was then treated with photogenerated piperidine as described above. Upon completion of the reaction, the resin was washed with DCM/DMF. Capping of the NH2-Phe-Lys(ivDde)-resin was carried out for 1 h with acetic anhydride (470 μL, 5 mmol) and TEA (700 μL, 5 μmmol) in 1.5 mL DMF to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([NH:38][S:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][S:39]([C:42]1[CH:47]=[C:46]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=4)[CH:11]=[C:10]([C:30]([F:32])([F:31])[F:33])[N:9]=3)[CH:3]=2)[CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-{4-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.38 g, 0.69 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.23 g, 0.89 mmol) according to the general procedure VI. Obtained as light yellow solid (0.45 g), which was subsequently deprotected.
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:6]1.[OH:29][C:30]1(C(C2C=CC3C(=CC=CC=3)C=2)C(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[CH3:3][NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]2[OH:29])[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:6]1
Reactant: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2CCCCC2O)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-[2-[(3R)-3-(methylamino]pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3R)-1-[(1-hydroxycyclohexyl)(2-naphthyl)acetyl]pyrrolidin-3-yl}carbamate. MS m/z 353; HRMS: calcd for C23H32N2O+H+, 353.25874; found (ESI, [M+H]+), 353.2583.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.C(Cl)Cl>[N:18]([C@@H:6]1[CH2:11][CH2:10][O:9][C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](c2ccccc2)C1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
A solution of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate (0.8 g) in DMF (10 mL) was treated with sodium azide (0.8 g) and heated at 100° C. for 4 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.5 g of trans-4-azido-2-phenyl-tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[N:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[N:14]([CH3:17])[CH2:15]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured into water (150 ml) and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 1-acetyl-6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.22 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]([O:32][CH3:33])[CH:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([O:32][CH3:33])[CH:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [H][H]
Reactant: CCCCC(C)C(C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(C)C(CCc1ccc(O)c(O)c1)OC
Yield: 98.4 %

Procedure:
Using 0.1 g of 10% palladium-carbon as catalyst, 560 mg of 1-(3,4-dibenzyloxyphenyl)-3-methoxy-4-methyl-1-octene was catalytically reduced in a mixture of 5 ml of methanol and 5 ml of ethyl acetate until the absorption of hydrogen stopped. Thereafter, the catalyst was filtered off and the filtrate was concentrated under reduced perssure to provide 330 mg of oily 1-(3,4-dihydroxyphenyl)-3-methoxy-4-methyl-octane.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:20][CH2:19][CH2:18][C:17]4[S:16][C:15]([C:21]5[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=5)=[N:14][C:13]=4[C:12]=3[CH:29]=2)=[CH:6][C:5]([CH3:30])=[CH:4][N:3]=1.Cl.C[O:33]CCOC>>[CH:26]([N:22]1[C:21]([C:15]2[S:16][C:17]3[CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([C:7]5[C:2](=[O:33])[NH:3][CH:4]=[C:5]([CH3:30])[CH:6]=5)=[CH:29][C:12]=4[C:13]=3[N:14]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: COCCOC
Reactant: Cc1cnc(F)c(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Agent: Cl
Product: Cc1c[nH]c(=O)c(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 93 %

Procedure:
Following the procedure for Example 330, 9-(2-Fluoro-5-methyl-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 402 was treated with aqueous HCl in DME to give 415 (0.038 g, 93%). 1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.94 (d, J=2.3, 1H), 8.10 (s, 1H), 7.75 (dd, J=8.4, 2.3, 1H), 7.58 (d, J=2.5, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 7.07 (d, J=8.5, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.40 (t, J=4.9, 2H), 3.46 (t, J=4.9, 2H), 2.09 (s, 3H), 1.56 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:12]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.4 %

Procedure:
A mixture of methyl-4-(aminomethyl)benzoate (50 g, 0.302 mol) and benzaldehyde (32 g, 0.302 mol) in EtOH (1 L) was refluxed for 5 h. After cooling to r.t, NaBH4 (11.5 g, 0.302 mol) was added portionwise. The reaction mixture was stirred at r.t. for 10 h. The solvent was removed under reduced pressure and the compound was purified by acid-base work up to give N-(4-methoxycarbonylbenzyl)benzylamine (25 g, 33%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)CCC3)cc1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-(5-indanoxy)benzaldehyde (6.2 g) in ethanol (100 mL) was added a solution of semicarbazide hydrochloride (3.2 g) and sodium acetate (2.3 g) in water (50 mL) at room temperature. The mixture was stirred for 1 h, and the resulting solid was collected by filtration, washed with water (3×100 mL) and dried in vacuo to yield the title compound as a pale yellow solid (7.5 g, 97%), mp: 218-220° C. 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 7.24 (d, J=8.1, 1H), 6.94 (d, J=8.7, 2H), 6.92 (s, 1H), 6.82 (d, J=8.1, 1H), 6.45 (s, 2H), 2.84 (t, J=7.5, 4H), 2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])[C:11](O)=[O:12])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:31][O:32][C:33]1[C:34](=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:35][CH3:36].Cl>ClCCCl.[Fe](Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:40]=[C:39]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:10]([C:11]([C@@H:10]([N:14]2[C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:23]2=[O:24])[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:38]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[C:34]([O:35][CH3:36])[CH:37]=2)=[O:12])[N:14]2[C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:23]2=[O:24])[CH:38]=[CH:37][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reactant: COc1ccccc1OC
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(C(c2ccc(OC)c(OC)c2)[C@@H](C(=O)[C@H](C(c2ccc(OC)cc2)c2ccc(OC)c(OC)c2)N2C(=O)c3ccccc3C2=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A solution of 3.25 g (10.0 mmole) N-phthaloyl-0-methyl-(S)-tyrosine in 50 ml 1,2-dichloroethane was combined with 2.29 g (11.0 mmole) phosphorus pentachloride at 0° C. and agitated at first for 30 minutes at 0° C. and then for 16 hours at room temperature. After the addition of another 50 ml 1,2-dichloroethane, a tenth of the solution was rapidly added to an agitated solution of 1.38 g (10.0 mmole) catechol dimethylether and 160 mg iron-(III)-chloride (10 mole percent) in 70 ml 1,2-dichloroethane. The reaction mixture was heated to 50° C. and the remaining solution of acid chloride was added dropwise in a continuous manner over 12 hours. The mixture was agitated 12 hours further at 50° C. and then cooled down to 0° C. 100 ml 1N hydrochloric acid cooled down to 0° C. were added and the mixture was agitated for 24 hours at room temperature. The aqueous phase was separated off and extracted twice with 40 ml methylene chloride per extraction. The combined organic phases were washed with 150 ml saturated, aqueous sodium hydrogen carbonate solution, then with 100 ml water, and dried over sodium sulfate. After removal of the solvent at 40° C. under reduced pressure, the raw product was chromatographed over a silica gel column. 1.93 g (43 % of theory) (S)-3,4-dimethoxyphenyl-[2-(4-methoxyphenyl)-1-phthalimidoethyl]-ketone of reagent purity were obtained as oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]=1[CH3:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:21]1[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]([CH3:36])=[C:17]([Cl:16])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@@H]1COCCN1Cc1ccccc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@@H]2COCCN2Cc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
A solution of [(3R)-4-benzylmorpholinyl]methylamine (preparation 95) (4.2 g, 20.4 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (1 g, 3.06 mmol), and triethylamine (0.7 ml, 5.0 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried over MgSO4 and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to give the title compound as a white solid, (500 mg, 32%). LRMS: m/z=515 (M+18)+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=O)=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]([CH2:34][CH3:35])[CH2:32][CH3:33].CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:15][N:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNCC
Reactant: O=Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Reaction time: 0.5 h

Procedure:
A mixture of Compound 150 (0.2 g, 0.4675 mmol), Et2NH (0.037 mL, 0.360 mmol), and NaOAc (46 mg, 0.561 mmol) was dissolved in DCM:MeOH (20:1, 1 mL) and stirred for 30 min. To this solution was added NaBH3CN (0.056 mg, 0.891 mmol) and the mixture was stirred at RT overnight. The reaction was quenched with aqueous NaHCO3 and extracted into DCM. The organic layer was washed with water and dried over MgSO4. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, MeOD) δ ppm 0.99-1.27 (m, 6H) 1.35 (s, 6H) 1.59-1.89 (m, 5H) 2.06-2.16 (m, 1H) 2.17-2.28 (m, 1H) 3.21 (q, J=7.07 Hz, 4H) 4.59 (s, 2 H) 5.91 (dd, J=11.12, 5.56 Hz, 1H) 7.62-7.70 (m, 2H) 7.80 (dd, J=9.09, 4.80 Hz, 1H) 7.88 (dd, J=8.46, 2.91 Hz, 1H) 8.46 (s, 1H). [M+H] calc'd for C25H32FN5O2S, 486; found, 486.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])[C:3]1=[O:20]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical Product: m.p. 261°-263° C.