Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:37])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:38]>C(O)(=O)C>[ClH:38].[ClH:38].[NH2:8][C@@H:9]([CH3:37])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](C)N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxybutyl]-L-phenylalanyl-L-leucine, t-butyl ester (slower isomer) (0.27 g, 0.52 mmol) in 20 ml of 1.3N hydrogen chloride in acetic acid was allowed to stir for 2 hours at room temperature, during which time a white precipitate separated. The mixture was concentrated under reduced pressure to approximately one third of the original volume, then diluted with ether and filtered yielding 185 mg of the title compound as a white solid, melting point 236°-239° C. (with slow decomposition >210° C.). Analysis by 400 MHz 1H-NMR revealed the presence of a small amount (<5%) of the faster isomer.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])(=O)C.[Na+].O>CN(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]>[O:9]=[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[C:14]2[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=2[NH:12]1
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Reactant: COC(=O)c1ccsc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Temperature: 120 °C
Yield: 49.7 %

Procedure:
In a microwave vessel, methyl 2-bromo-3-thiophene carboxylate (1.0 eq, 260 mg, 1.18 mmol), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (1.1 eq, 300 mg, 1.30 mmol), sodium acetate (3.0 eq, 292 mg, 3.56 mmol) and PdCl2(dppf) (0.05 eq, 31 mg, 0.059 mmol) were mixed together in anhydrous DMF (2 ml). The mixture was heated in a microwave oven at 120° C. for 10 nm. Water was added and the solid filtered and dried. The material was suspended in CH2Cl2, filtered and dried to afford methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate as a yellow solid (152 mg, 50% yield). LCMS (ES): 95% pure, m/z 260 [M+1]+;
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20][CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7].O>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:4]([Cl:3])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20](=[O:1])[CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: OO
Reactant: O=C(Nc1cccc2c3c(oc12)CCSC3)c1c(Cl)cccc1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c3c(oc12)CCS(=O)C3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrogen peroxide in trifluoroacetic acid (1M, 0.32 ml) wa s added to a solution of 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano-[4,3-b]benzofuran (120 mg) in trifluoroacetic acid (2.5 ml) at 4° C. The mixture was stirred at ambient temperature for 30 minutes and to the mixture was added water. The separated solid was collected and dried. The obtained solid was suspended in hot ethanol and to the mixture was added water. The mixture was cooled and the separated solid was collected to give 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano[4, 3-b]-benzofuran 2-oxide (70 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[FH:25].N1C=CC=CC=1>>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]([F:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: F
Reactant: CCOc1nc(N)c2ncccc2c1Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOc1nc(F)c2ncccc2c1Br
Temperature: 0 °C
Yield: 85 %

Procedure:
To a 100 mL round bottom flask was added 5-bromo-6-ethoxy-1,7-naphthyridin-8-amine (500 mg, 1.86 mmol), followed by pyridine hydrogen fluoride (10 mL). The mixture was cooled to 0° C. and sodium nitrite (0.154 mg, 2.24 mmol) was added in portions. The mixture was slowly warmed to room temperature over a period of 3 h. The reaction was neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-6-ethoxy-8-fluoro-1,7-naphthyridine as a pale yellow solid (430 mg, 1.59 mmol, 85%). 1H NMR (400 MHz, CDCl3): δ ppm 8.87 (d, J=3.52 Hz, 1H), 8.42 (d, J=8.79 Hz, 1H), 7.65 (dd, J=8.13, 3.30 Hz, 1H), 4.55 (q, J=7.03 Hz, 2H), 1.49 (t, J=7.03 Hz, 3H). LC/MS m/z 273 [M+H].
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17].[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:17][CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1ccccn1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-2-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: 1H NMR (300 MHz, CDCl3) δ 8.52-8.50 (m, 1H), 7.65-7.60 (m, 1H), 7.26-7.23 (m, 1H), 7.18-7.14 (m, 1H), 7.11-7.06 (m, 1H), 4.66 (d, J=5.6 Hz, 2H), 4.10-4.05 (m, 2H), 3.58-3.53 (m, 2H), 3.09 (d, J=7.5 Hz, 2H), 2.61 (s, 3H), 1.94-1.85 (m, 1H), 0.91 (d, J=6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.6, 155.8, 155.6, 152.3, 148.8, 136.5, 122.2, 121.7, 117.7, 51.4, 44.5, 42.7, 41.9, 26.6, 19.8, 17.1; MS (ES+) m/z 373.8 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.O[C@H]1CCN[C@@H]1C(O)=O.COC(=O)[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)CCN1C(OC(C)(C)C)=O.C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@H:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=C(O)[C@H]1NCC[C@@H]1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following procedures described for the preparation of (2S,3R)—N-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)proline methyl ester (51A), (2S,3S)-3-hydroxyproline was converted to (2S,3S)—N-tert-butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)proline methyl ester. To this material (4.3 g, 12 mmol) in THF (75 mL) at −78° C. under nitrogen was added dropwise 1.0 M lithium triethylborohydride in THF (60 mL, 60 mmol). The reaction was allowed to warm to rt and was stirred for 4 h. The reaction was quenched by pouring over ice (150 g) and stirring for 30 min. The product was extracted into EtOAc and washed with saturated aqueous NaHCO3. The organics were dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 0-15% EtOAc in hexanes) provided the title compound (3.3 g). 61B. (2S,3S)—N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-formyl-pyrrolidine
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a stirring solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (1000 mg, 3.41 mmol) in THF (20 mL) at −78° C. was added DIBAL-H solution (1.0 M in hexanes, 7.50 ml, 2.20 equiv.) dropwise. The mixture was stirred for 15 min and then gradually warmed to room temperature and stirred for another 4 hour. LCMS indicated clean conversion of the starting material to the product. The reaction was quenched with sodium bicarbonate, and then concentrated to dryness. The resulting solids were stirred with DCM (100 ml) for 1 hour and then filtered. The solids were rinsed with EtOAc until the rinse was free of product. The combined filtrate were dried over sodium sulfate, concentrated to dryness to give the desired product (788 mg)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:22]4[C:23](=[O:27])[CH:24]=[CH:25][CH:26]=[N:21]4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: O=c1cccn[nH]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-n4ncccc4=O)cc3s2)C1

Procedure:
The product of Example 1E (30 mg, 0.085 mmole), 3(2H)-pyridazinone (CAS #504-30-3) (16 mg, 0.17 mmole), copper (11 mg, 0.17 mmole), and potassium carbonate (71 mg, 0.51 mmole) were mixed in degassed pyridine (1 ml) and the mixture was heated at reflux overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 23 mg (74% yield) of title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (m, 1H) 8.05 (m, 1H) 7.92 (dd, J=3.74, 1.87 Hz, 1H) 7.69 (dd, J=8.73, 2.18 Hz, 1H) 7.20-7.32 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.86-3.99 (m, 1H) 3.58-3.70 (m, 1H) 3.15-3.27 (m, 1H) 3.01-3.13 (m, 1H) 2.74-2.87 (m, 1H) 2.28-2.71 (m, 4H) 1.90-2.03 (m, 1H) 1.79-1.90 (m, 1H) 1.66-1.78 (m, 1H) 1.44-1.65 (m, 1H) 1.16 (s, 3H) MS: (M+H)+=367.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH3:17])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH3:21]>C1COCC1>[CH2:16]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:13][C:12]=2[CH:14]([OH:15])[CH2:20][CH3:21])[C:7]([CH3:19])([CH3:18])[CH2:8][CH2:9]1)[CH3:17]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure C, 6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde (Intermediate 7, 5.78 g, 26 mmol) and a solution of ethyl magnesium bromide (2M, 35 ml, 65 mmol) in THF were reacted to give the title compound as a yellow oil after purification by column chromatography using 5% ethyl acetate in hexane.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([CH:27]2[O:31][C:30](=[O:32])[NH:29][CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([CH:27]2[O:31][C:30](=[O:32])[NH:29][CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CNC(=O)O1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (16 mg, 0.084 mmol) and N,N-dimethylformamide (15 μL) was stirred at room temperature for 10 minutes. A solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one (16 mg, 0.056 mmol) (racemic mixture of two diastereomers from step 2) in methylene chloride (0.3 mL) was added and the reaction was stirred at room temperature overnight. Thionyl chloride (12 μL, 0.17 mmol) was added and stirred for 10 min. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a racemic mixture of two diastereomers, 17 mg, 100%. LCMS calculated for C13H16Cl2NO3 (M+H)+: m/z=304.0; found: 304.1.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)(O)[O-].[Na+].[C:14](ON1C(=O)CCC1=O)(=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O.C(COC)OC.CCCCCC.C(OCC)C.C(O)(=O)C>[C:14]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4])(=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)N[C@H](C(=O)O)[C@@H](C)O

Procedure:
A mixture of L-threonine (5 mmol, 0.595 g), sodium bicarbonate (5 mmol, 0.420 g) and succinimidyl nervonate (5 mmol, 2.320 g, prepared according to Example 1A) in water (2 mL) and dimethoxyethane (5 mL) were refluxed for 2 hours until no ester remained according to TLC (hexane-diethyl ether-acetic acid, 80:18:2). Acidification to pH 2 with concentrated hydrochloric acid and chilling gave the title product, which was washed with water, dried and crystallised from chloroform. It was finally washed with hexane to remove small amounts of non-polar contaminants.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:29])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of deoxycholic acid (25.0 g) and anhydrous potassium carbonate (8.8 g) in anhydrous dimethylformamide (65 ml) is added methyl iodide (4.8 ml) and the mixture stirred at room temperature for about 4 hours. The mixture is diluted with ethyl acetate and washed four times with water and once with saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography in 80% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14](I)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>O.[Cu]>[F:10][C:11]1[CH:19]=[C:15]([C:14]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)ccc1Sc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 150 g of potassium hydroxide in 850 ml of water is treated with 47.5 ml of thiophenol at 55° C under a nitrogen atmosphere. The mixture is stirred for 15 minutes and subsequently treated with 1.9 g of copper powder and 207 g of 5-fluoro-2-iodo-benzoic acid. The mixture is heated under reflux for 7 hours, filtered while hot, cooled and acidified with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and dried. There is obtained 3-fluoro-6-(phenylthio)-benzoic acid which melts at 146°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 84.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.251 mmol) obtained in step 2 and cyclopropanesulfonamide (0.155 g, 0.125 mmol), the title compound (0.066 g, 42%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C:14]1[C:15]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[N:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][C:15]2[C:14]([NH:13][S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])=[CH:19][CH:18]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[N:16]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 75.9 %

Procedure:
3,5-difluorobenzene sulfonyl chloride (0.5 g, 2.35 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.77 g, 2.35 mmol) using the reagents and reaction conditions described in Example 1(c) to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 6.82 (1H, d), 6.95 (1H, d), 7.11 (2H, d), 7.24 (3H, m), 7.34 (2H, d), 7.80 (7H, m).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19]>>[C:23]([NH:22][CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(CNC(=O)c1ccccc1)C(=O)O
Product: O=C(NCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-benzoylamino-propionic acid to provide the title compound in good yield.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][NH:10][S:11](=[O:12])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][NH:10][S:11](=[O:12])[C:6]=2[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)S(=O)NC=C2
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)S(=O)NC=C2

Procedure:
0.01 mol of 7-acetylbenzothiazinone, described in Am. Chem. Rome, is dissolved in 100 cm3 of methylene chloride. 0.011 mol of bromine is added dropwise and with stirring via a dropping funnel, and stirring is maintained for 13 hours. The mixture is filtered and evaporated to dryness and the residue is recrystallized.
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][CH:6]1[CH:15]2[C:10]([CH:11]=[CH:12][CH:13]([CH3:26])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([OH:25])[O:19]2)=[CH:9][CH:8]([CH3:27])[CH2:7]1)=[O:4].[C:30](=O)(O)[O-].[Na+]>CO.C(Cl)(=O)C>[CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:26])[C:14]=2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([O:25][CH3:30])[O:19]2)[CH:9]=[C:8]([CH3:27])[CH:7]=1)=[O:4]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(O)O3)C21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCC(C)C(=O)Oc1cc(C)cc2ccc(C)c(CCC3CC(O)CC(OC)O3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 393.1 %

Procedure:
Acetyl chloride (200 μL, 2.8 mmol) was added to a stirred solution of hemiacetals II (19.0 g, 46.7 mmol) in methanol (100 ml). The solution was stirred for 15 min at ambient temperature. Sodium bicarbonate (1.0 g) was added and the mixture was stirred for another 15 min. The mixture was filtered through a pad of Celite (5.5×1 cm) and washed with toluene. Evaporation of solvent of the filtrate gave crude acetals III (19.4 g, yield 98%) as a colorless syrup (HPLC purity >95%). This was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Br)[CH3:18])=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:27]#[N:28])#[N:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].[I-].[Na+]>>[C:1]([C:3]1[C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH3:18])=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:27]#[N:28])#[N:2]
Reactant: CCNCC
Reactant: CC(Br)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccc(Br)cc1)=NC2
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)C(C)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccc(Br)cc1)=NC2

Procedure:
In the manner given in Example 1, 7,8-dicyano-1-(α-bromoethyl)-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 7,8-dicyano-1-[α-(diethylamino)ethyl]-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.