Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:19][C:13]1[CH:12]=[C:11]([CH:10]([C:9](=[O:23])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[O:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(OCC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-hydroxy-4-methoxy-phenyl)-acetamide (0.158 g) at rt in DMF (1.5 ml) were added K2CO3 (0.067 g) and ethyl bromoacetate (0.081 g). The reaction mixture was then stirred at rt under an argon atmosphere for 24 h. The mixture was diluted with EtOAc (10 ml), washed with water (10 ml+10 ml) and brine (10 ml), dried (MgSO4), filtered and concentrated (rotavapor). The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 45:55) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.160 g) as a colorless gum.
Reaction SMILES: [F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])C(O)=O.[Br:38]Br.FF>Cl>[F:1][C:2]([Br:38])([F:37])[C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: Cl
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 200 %

Procedure:
Perfluorododecanoic acid 404 g (0.565 mole), bromine 49.4 g (0.309 mole) and Freon 113 (400 ml) were treated with fluorine at 30°-37° C. The reaction mixture was poured into 2N hydrochloric acid (500 ml) and the freon solvent was directly distilled off from the mixture. The residue was cooled and the precipitated solids were collected through known filtration techniques. The precipitate was then distilled under vacuum, to give pure perfluoroundecyl bromide 401 g (95% yield). The bromide has a boiling point of 105° C./2 mm Hg and a melting point of 96°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Cl
Temperature: 25 °C

Procedure:
A 8.5 Kg portion of 2,6-dimethoxybenzoic acid was dissolved in 60 liters of toluene and the solution was stirred at ambient temperature while 6.8 liters of thionyl chloride was added dropwise over forty-five minutes. Following the addition, the reaction mixture next was cooled to room temperature and the solvent was removed by evaporation under reduced pressure, washed with 25 liters of Pet. ether cooled and filtered to provide a crude solid product. The product was stirred for one hour with 25 liters of fresh Pet. ether, and then cooled to 10° C. and filtered to provide 8.94 Kg of 2,6-dimethoxybenzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 18.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.19 mmol) obtained in Example 97, step 4 and cyclopropanesulfonamide (115 mg, 0.95 mmol), the title compound (21 mg, 19%) was obtained.
Reaction SMILES: CO[C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0 M solution of methylamine in MeOH (2.0 mL). This mixture is stirred for 30 min at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (190 mg, 95%), 1H NMR (300 MHz, DMSO) δ 8.38 (d, 1H), 7.63 (d, 1H), 7.46 (dd, 1H), 7.27 (d, 1H), 5.05 (dd, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H), 2.65 (d, 3H); MS for C14H15N3O4SMS m/z 322.5 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)(=[O:12])=[O:11].[SH:23][C:24]1[C:33]([C:34]([NH:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(Cl)Cl>CC(C)=O>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[CH2:37][NH:36][C:34]([C:33]1[C:24]([S:23][CH2:8][CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:35]
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 30 %

Procedure:
151 mg (1.1 mmol) K2CO3 and 300 mg (1.1 mmol) 1-(2-chloroethylsulfonyl)-3-(trifluoromethyl)benzene were added to a solution of 300 mg (1.0 mmol) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV02) in acetone (10 ml) at RT and the mixture was heated for 3 h at 70° C. Then it was filtered and the filtrate was concentrated to small volume under vacuum. The residue was taken up with EE and washed with water and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (DCM/EE 20:1) of the residue yielded 163 mg (0.3 mmol, 30%) N-(2-thienylmethyl)-2-[2-[3-(trifluoromethyl)-phenyl]sulfonylethylthio]-3-quinoline carboxamide. MS: m/z 537.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][OH:86]>O1CCCC1>[OH:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: NCCOCCO
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCC(=O)NCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-Aminoethoxy)ethanol (23.4 mg, 16.0 μL, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-methyl ester as an off-white solid (24 mg, 15% yield). LCMS (ES+) m/z calcd. for C37H41Cl2F2N4O7 [(M+H)+]: 761. found: 761.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CO.[OH-].[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.40 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (79 mg, 1.98 mmol, 4.99 equiv), and water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (40%) of 2-(benzo[d][1,3]dioxol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)(=[O:36])[CH3:34]
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCOC(C)=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-propanol (80 mg, 0.148 mmol) in 1 ml of methylene chloride was treated with acetic anhydrous (38 mg, 0.37 mmol) and triethyl amine (38 mg, 0.37 mmol) and stirred at room temperature for 15 hours. The mixture was quenched with water and a few drops of dilute HCl and extracted with ethyl acetate. The organic layer was neutralized with aqueous sodium bicarbonate and washed with brine, separated, dried and concentrated to give the title compound as an oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 57 mg of the title compound as a white glass form. 1H NMR (CDCl3): 2.0(s,3H, 2.03(m,2H), 2.45(s,3H), 2.60(s,3H), 3.74(t,2H), 4.10(t,2H), 5.1(s,2H), 7.2-7.4(m,5H), 7.50(s,2H) ppm.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Yield: 15.3 %

Procedure:
Using 2-trifluoromethylaniline (1.77 g, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 474 mg (15.3%) the title compound in the form of colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:25])([C:23]#[CH:24])[CH:21]=[CH2:22]>C(N(CC)CC)C.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH:23]=[CH2:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(O)C=C
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(C)(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Yield: 63.5 %

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 2.88 g (30 mmol) of 3-methyl-1-penten-4-yn-3-ol, 110 mg of bis(triphenylphosphine)-palladium(II) dichloride and 35 mg of copper(I) iodide were heated to boiling under reflux for 12 hours in 60 ml of triethylamine and 30 ml of dimethyl-formamide. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the residue from acetonitrile there was obtained 4.34 g (63%) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-4-penten-1-ynyl)-5-methyl-6H-imidazo[1,5-a][1,4-]benzodiazepin-6-one of melting point 185-187°.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:20][O:21][CH2:22][CH2:23][CH:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.CS(C)=O>C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: COCCC1CNCCN1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 115 °C
Yield: 66.4 %

Procedure:
Add 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (65.0 g, 215 mmol) and 2-(2-methoxy-ethyl)-piperazine (96.3 g, 668 mmol) to a solution of DMSO (650 mL) and toluene (1300 mL) with stirring under nitrogen. Heat at gentle reflux (115° C.) for 2 days, and then allow cooling to ambient temperature. Remove most of the organic portion under reduced pressure, and then partition the residue between ethyl acetate (450 mL) and aqueous saturated ammonium chloride solution (450 mL). Separate the layers, and then extract the aqueous layer with ethyl acetate (3×200 mL). Extract the combined organic layers with brine (3×200 mL). Concentrate the organic layer under reduced pressure. Purify the crude product by flash chromatography, eluting with 90:10/methylene chloride:MeOH to give 56 g (66%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.86 (bm, 2H), 3.39 (m, 2H), 3.23 (s, 3H), 2.88 (bd, 1H), 2.72 (bm, 3H), 2.44 (bt, 1H), 2.31 (s, 3H), 2.31 (bm, 1H), 1.53 (m, 2H). HRMS (ES) exact mass M+H calcd for C19H22F2N4OS 393.1561; found 393.1554.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].ClCCl>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:22]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
For example, 4-amino-benzoic acid methyl ester, is treated with a sulfonyl halide, in this case 4-methanesulfonyl benzenesulfonyl chloride, in a suitable solvent, such as a 1:1 mixture of dichloromethane and pyridine at ambient temperature for 2-24 hours to yield 4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid methyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1.CO>C1COCC1>[Cl:20][C@@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
A solution of triphenylphosphine (8.22 g.) in THF (80 ml.) is added dropwise to N-chlorosuccinimide (4.18 g.) with stirring and cooling so that the temperature remains below 30°. A solution of 3β-hydroxy-17β-methoxy-5α-androstane (Example 27, 4.8 g.) in THF (50 ml.) is slowly added to the N-chlorosuccinimide mixture. After 2 hours, methanol is added and the mixture is filtered to obtain the title compound (recrystallized from acetone): m.p. 151°-154°; NMR (CDCl3) 0.74, 0.78, 3.20, 3.33 and 4.47 δ; MS (m/e) 324, 309, 277 and 251.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:8][OH:9])[NH2:7].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C>O1CCOCC1.B(F)(F)F.C(OCC)C>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:9][N:8]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NC(=NO)c1cccs1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: C
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccs3)no2)cc1
Yield: 65.3 %

Procedure:
To a solution of 2-thiopheneamidoxime (10 g, 0.07 mole) and p-nitrobenzoyl chloride (13 g, 0.07 mole) in 400 ml of dry dioxane, 1 ml of BF3 -ethyl ether is added and the mixture is heated to reflux for 16 hours. Evaporation of the solvent in vacuo gives a dark solid. It is decolorized by treating with Darco (CHCl3). The solvent is concentrated in vacuo and the product is crystallized from ethanol to give 12.5 g (65%) of product, m.p. 169°-171°.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:20]O>>[NH:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:14][CH:15]=2)[N:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2c[nH]cn2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of 4-(1H-imidazol-4-yl)benzoic acid hydrochloride (20 mg, 0.089 mmol) at 0° C. in MeOH (5 mL) was added thionyl chloride (11.6 mg, 0.097 mmol) and the solution was allowed to warm to rt. After stirring overnight the solution was concentrated under reduced pressure to dryness and the crude residue was partitioned between EtOAc (25 mL) and sat'd NaHCO3 (5 mL). The organic layer was collected, dried (Na2SO4) and concentrated under reduced pressure to afford the desired product as a pale yellow solid (15 mg, 86% yield). 1H NMR: 3.92 (s, 3H), 7.41 (s, 1H), 7.67-7.77 (m, 3H), 8.03 (s, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27](O)=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[NH4+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([NH2:31])=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A solution of compound 21a (100 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), DIPEA (77 mg, 0.6 mmol) in DCM (5 mL) was stirred at it for 0.5 hr. Ammonium hydroxide (12 mg, 0.36 mmol) was added and the mixture was stirred at it for 2 hr. The reaction mixture was quenched with water and extracted with DCM. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the desired compound 23 (32 mg, 32% yield). LCMS (m/z): 412.2 (MH+).