Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]([CH:12]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13]1)[CH2:10][F:11])C1C=CC=CC=1.[H][H]>CO.[Pd].S(=O)(=O)(O)O>[F:11][CH2:10][CH:9]([NH2:8])[CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: [H][H]
Reactant: FCC(NCc1ccccc1)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC(CF)C1CCNC1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of benzyl[1-(1-benzylpyrrolidin-3-yl)-2-fluoroethyl]amine (2.5 g, 8.0 mmol, Example 17) in methanol (50 mL) was added 20% palladium on carbon (200 mg). Hydrogen was introduced to the reaction mixture at high pressure (48 psi) for 24 hours, at which time sulfuric acid (3 drops) was added. After an additional 24 hours, the reaction mixture was filtered through Celite, washed with methanol, and the combined filtrates concentrated under vacuum to afford the title compound (1.0 g): MSCI: m/z 133 (MH+).
Reaction SMILES: [S:1](=[O:11])(=[O:10])([O:3][CH2:4][CH2:5][CH:6]([CH3:9])[CH2:7][CH3:8])[NH2:2].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[CH2:7]([C:6]1([CH3:9])[CH2:5][CH2:4][O:3][S:1](=[O:10])(=[O:11])[NH:2]1)[CH3:8]
Reactant: CCC(C)CCOS(N)(=O)=O
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Product: CCC1(C)CCOS(=O)(=O)N1
Temperature: 40 °C

Procedure:
To a solution of 3-methylpentyl sulfamate from Step 1 (1.25 mmol) in 8 mL of dichloromethane was added sequentially MgO (116 mg, 30 mmol), PhI(OAc)2 (443 mg 1.4 mmol), and Rh2(oct)4 (20 mg, 0.025 mmol). The suspension was stirred vigorously and heated at 40° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with 20 mL of dichloromethane, and filtered through a pad of Celite then concentrated. The crude product was purified by multiple flash chromatographies (5% ethyl acetate/dichloromethane) to give 4-ethyl-4-methyltetrahydro-1,2,3-oxathiazine 2,2-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-fluoroaniline (108 mg, 0.972 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.49 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (50 mg, 0.194 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 15 min. and then extracted three times with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded 45 mg (72%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid (2-fluoro-phenyl)-amide as a light yellow solid. Electrospray mass spectrum: m/z 321 [M−1].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Br[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[S:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[S:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 4-bromomethyl-2-(4-chloro-phenyl)-5-methyl-thiazole (JP 62178590 A2) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as light yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
Firstly, 24.3 g (100 mmol) of N-phenylcarbazole was dissolved in 600 ml of glacial acetic acid, and 17.8 g (100 mmol) of N-bromo succinic acid imide was slowly added thereto. The mixture was stirred for about 12 hours at a room temperature. This glacial acetic acid solution was dropped in one litter of ice water while stirring them. A precipitated white solid was washed three times with water. This solid was dissolved in 150 ml of diethyl ether, and washed with a saturated sodium hydrogencarbonate solution and water. This organic layer was dried with magnesium sulfate, and filtered. The obtained filtrate was concentrated. The thus obtained residue was recrystallized with methanol to obtain 28.4 g (the yield: 88%) of 3-bromo-9-phenylcarbazole, which was a white powder (Synthesis scheme (c-1)).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[C:17]([Si](C)(C)C)#[CH:18]>CCN(CC)CC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)#[CH:18]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1cccc2c1CCOC2C1=NCCN1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (300 mg) in Et3N (10 ml) and ethynyltrimethylsilane (210 mg) was added tetrakis(triphenylphosphine)-palladium (37 mg). The mixture was degassed with N2 and heated in a microwave oven for 60 min at 120° C. The reaction mixture was concentrated under vacuum and purified by separation method K. K2CO3 was added to the reaction crude (in MeOH) and the mixture was stirred 4 h at it. The title compound was isolated by a separation method G. (Yield 6.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CO.C(OCC)C>[Si:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)O)cc1
Reaction time: 10 h
Yield: 63.1 %

Procedure:
4-Hydroxybenzoic acid (4.009 g, 28.96 mmol) and tert-butyldimethylsilyl chloride (9.984 g, 66.24 mmol) were dissolved in dry N,N-dimethylformamide (21 ml) containing imidazole (8.653 g, 127.1 mmol). Upon stirring for 10 hours under argon, the reaction mixture was shaken with diethyl ether (130 ml) and water (130 ml). The organic portion was washed with water (60 ml×2). The crude product resulting from evaporating to dryness was dissolved in tetrahydrofuran (32 ml). Methanol (96 ml) and a solution of potassium carbonate (6.40 g, 46.31 mmol) in water (50 ml) were added. The mixture was then stirred for 1 hour. The volume was reduced by half by evaporation before adding a saturated brine (96 ml) followed by acidification with 1M KHSO4. The aqueous portion was washed times with diethyl ether (100 ml×3), and the organic portion was evaporated to dryness. Recrystallization from a mixed solvent of water (200 ml), ethanol (75 ml) and acetone (20 ml) yielded (o) (4.61 g, 63%). Proton-NMR spectral data (acetone-d6), δ (ppm): 0.10 (s, Si(CH3)2, 6H), 1.02 (s, Si(C(CH3)3, 9H), 6.99 (d, aromatic, 2H), 7.95 (d, aromatic, 2H)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=2)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[CH:23][C:24]([C:25]([N:10]3[C:11]4[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:26])=[CH:28][CH:29]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cn2)cc1
Reactant: CC(=O)c1ccc2c(c1)CCCN2
Product: CC(=O)c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(C)cc2)nc1

Procedure:
Using 6-acetyl-1,2,3,4-tetrahydroquinoline and 6-(4-methylphenyl)nicotinic acid, 1-[1-[[6-(4-methylphenyl)-3-pyridinyl]carbonyl]-1,2,3,4-tetrahydro-6-quinolinyl]ethanone was obtained as pale yellow powder by the same procedure as in Reference Example 5.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:16].O>CN(C)C=O>[CH3:16][N:12]1[CH2:13][CH2:14][N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: CI
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 2.70 g, 67.8 mmol) was added to a solution of 1-phenylpiperazine (10.0 g, 61.6 mmol) in N,N-dimethylformamide (80 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added Iodomethane (8.74 g, 67.8 mmol), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water (80 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-isopropyl ether to obtain 1-methyl-4-phenylpiperazine (7.40 g). Bromine (7.00 g, 43.8 mmol) was added to a solution of this compound in ethanol (80 mL) at 0° C., and the mixture was stirred for 1 hour at room temperature. Water (80 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was combined, washed with an aqueous saturated sodium hydrogencarbonate and water, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (8.1 g, yield 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1Br

Procedure:
In a similar manner as described for example 49 (step 1), 357 mg of 3-[(1R)-1-(2-bromophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 173 mg of methanesulfonyl chloride, and 153 mg of triethylamine in 7.5 ml dichloromethane give (1-{4-[(1R)-1-(2-bromophenyl)ethoxy]-5-carbamoyl-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[Li+].[OH-]>C1COCC1>[C:26]([O:25][CH:4]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([OH:30])=[O:2])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(F)c(F)c2)c2ccccc2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(F)c(F)c2)c2ccccc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of tert-Butoxy-[4-(3,4-Difluoro-phenyl)-2-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (72 mg, 0.15 mmol) in THF (2.0 ml) was added an aqueous LiOH (1 N, 0.69 ml). The mixture was stirred at 60° C. overnight. LCMS showed SM was consumed, cooled to RT, removed the solvent, added water, extracted with EA to remove impurity, the aqueous layer was adjusted to pH=6 with 1N HCl, extracted with EA, the organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated to dryness, gave the desired product. (m=46 mg, Yield: 66%). 1HNMR: (400 MHz, d6-DMSO) δ 0.91 (s, 5H), 1.00 (s, 4H), 3.56 (s, 1.67H), 3.63 (s, 1.33H), 4.93 (s, 1H), 6.84 (d, J=8.0 Hz, 0.5H), 6.99 (d, J=8.0 Hz, 0.5H), 7.15 (s, 0.5H), 7.30 (m, 1H), 7.44 (m, 0.5H), 7.60 (m, 3H), 8.28 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32]CC1C=CC=CC=1)=[O:31])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([OH:32])=[O:31])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reaction time: 3 h

Procedure:
H-Glu(OtBu)-Val-Val-Pro-OH was prepared by dissolving Z-Glu(OtBu)-Val-Val-Pro-OBzl (2.90 g, 3.89 mmol) in 100 mL methanol containing 1% acetic acid. Pearlman's catalyst, Pd(OH)2, (100 mg) was added and the flask was placed on the Parr hydrogenation apparatus with an initial H2 pressure of 34 psi. After three hours, the catalyst was removed by filtration through a celite pad and the filtrate was evaporated in vacuo to yield a yellow oil (1.30 g, 2.61 mmol. 67%). ESI/MS calculated for C24H42N4O7+H: 499.3 Found: 499.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]1=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.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.C(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27](=[O:41])[N:26]([CH3:25])[CH:31]=4)=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
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: [Cs+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)n(C)c3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (44.2 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-5-(6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)-1-methylpyridin-2(1H)-one as a white solid (15 mg, 34.9%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O1CC[CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].C(Br)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCBr
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 58 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1.66 g, 7.0 mmol) and tetrahydrofuran (16 mL). Sodium tert-butoxide (0.843 g, 8.77 mmol, 1.25 eq) and ethyl bromide (0.78 mL, 10.52 mmol, 1.5 eq) were added and the reactor was capped with a septa. The reaction was stirred at 58° C. for 24 hours, at which point HPLC analysis indicated that only 1.97% starting material remained. The mixture was concentrated to give a brown residue, which was dissolved in water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were concentrated to dryness. The residue was passed through a silica gel plug (40 g silica) and eluted with ethyl acetate (200 mL). The filtrates were concentrated to dryness and further dried under vacuum at 20° C. to afford a yellow solid (1.68 g, 89%). Characterization matched sample prepared by previous method.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 97.7 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5, 7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (83.6 mg, 98%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1.[ClH:17]>CO.Cl>[ClH:17].[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(CCCN(C)C)cc1
Agent: Cl
Solvent: CO
Product: CN(C)CCCc1ccc(N)cc1
Temperature: 56 °C
Reaction time: 72 h

Procedure:
To a solution of N-[4-(3-dimethylamino-propyl)-phenyl]-acetamide (0.50 mmol maximum) in methanol (8 mL) is added 20% aqueous hydrochloric acid solution. After 3½ hours of shaking at 56° C., an additional 2 drops of concentrated hydrochloric acid is added and shaking is continued for 3 days. The mixture is concentrated to give 4-(3-dimethylamino-propyl)-phenylamine hydrochloride, which is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:23][CH:22]=2)=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)Nc1ccc(S(=O)(=O)O)cc1

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.732 g (10 mmol) of 4-aminobenzenesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger, thus obtaining the title compound by freeze-drying of the aqueous solution.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.I[CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: CCCCC(I)CC
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Product: CCCCC(CC)N1C(=Nc2ccc([N+](=O)[O-])cc2C)SC[C@@H]1CC(C)C

Procedure:
(1S)-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-1-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(5-heptyl)-1,3-thiazolidine.