Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])[C@@H:17]([CH3:29])[CH2:16]3)=[C:11]3[CH:30]=[N:31][CH:32]=[CH:33][C:10]=23)=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:36]([N:38]=C=O)=[O:37]>C(Cl)(Cl)Cl>[C:36](=[O:37])([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:22])[C@@H:17]([CH3:29])[CH2:16]3)=[C:11]3[CH:30]=[N:31][CH:32]=[CH:33][C:10]=23)=[CH:5][CH:4]=1)[NH2:38]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C[C@H]1CN(c2nnc(-c3ccc(CO)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(c2nnc(-c3ccc(COC(N)=O)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(4-(1-(4-(hydroxymethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 9 (100 mg, 224 μmol) in chloroform (2 mL) was added 2,2,2-trichloroacetyl isocyanate (39 μl, 314 μmol). The reaction was stirred at RT for 1 h and deposited on 3 g of Alumina (Brockmann II). After 1 h, the product was eluted from the alumina with 10% MeOH in dichloromethane. The crude reaction product was concentrated and purified by column chromatography to afford (S)-(4-(4-(3-methyl-4-(piperidine-1-carbonyl)piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)phenyl)methyl carbamate 10. MS 489.2 (calc'd) 490.1 (M+H, found).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:17]([O-])=O)=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C:5]2=[O:16].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>[Pd]>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH2:17][C:3]1[C:2]([NH2:1])=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:16])[NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: Nc1ccc2c(c1[N+](=O)[O-])c(=O)[nH]c1ccccc12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1N)c(=O)[nH]c1ccccc12
Reaction time: 0.83 h
Yield: 71 %

Procedure:
A mixture of 8-amino-7-nitro-5H-phenanthridin-6-one (412 mg, 1.62 mmol), Pd/C (10 wt %, 234 mg) in TFA was hydrogenated at 50 psi for 50 min. The catalyst was filtered through a plug of diatomaceous earth and rinsed with ethanol. The solvent was evaporated to obtain 7,8-diamino-5H-phenanthridin-6-one trifluoroacetate salt (520 mg, 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].CN(C)[CH2:16][CH2:17]N(C)C.C([Li])(CC)C.C(Br)C.Cl>C1CCCCC1.CCC(C)C.O.O1CCCC1>[CH2:16]([C:9]1[C:4]([C:3]([N:2]([CH3:1])[CH3:13])=[O:12])=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:17]
Reactant: CN(C)CCN(C)C
Reactant: COc1ccccc1C(=O)N(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCC(C)C
Solvent: O
Product: CCc1cccc(OC)c1C(=O)N(C)C
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
39.5 g of N,N-dimethyl-2-methoxy-benzamide and 28.5 ml of tetramethylethylenediamine are introduced into 190 ml of absolute tetrahydrofuran and the mixture is lithiated at -70° C. with 150 ml of a 1.4-molar sec-butyllithium solution in cyclohexane/isopentane. After subsequently stirring at -70° C. for 45 minutes, 25.6 ml of ethyl bromide are added dropwise within 25 minutes and the reaction mixture is then allowed to warm slowly to room temperature. Water is then added and the mixture is adjusted to pH 2 with hydrochloric acid and extracted twice with diethyl ether. The residue is purified on silica gel using ethyl acetate/n-hexane (4:6) to yield 6-ethyl-N,N-dimethyl-2-methoxy-benzamide in the form of a colourless oil, 1H-NMR (CDCl3): 3.82 ppm (m), 3.40 ppm (m) and 3.12 ppm (2q, N(CH2CH3)2), 2.56 ppm (m, CH2CH3).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C[Si](C)(C)I
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1nsc(N)n1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-[(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (486 mg) was suspended in methylene chloride (9 ml), followed by an addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (980 μl). The resulting mixture was stirred at room temperature for 1 hour. After ice-cooling, iodotrimethylsilane (410 μl) was added and the resulting mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:15])C.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[OH:15][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1cc[n+]([O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCOc1ccnc(CO)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-methyl-4-propoxypyridine-1-oxide (8.6 g), acetic anhydride (8.6 ml) and concentrated sulfuric acid (two drops) was heated at 100° C. for five minutes, to which were added ice-water and an excess amount of sodium carbonate. The mixture was subjected to extraction with chloroform. The extract was dried with sodium sulfate, and the solvent was evaporated off. The residue was chromatographed on a column of silica-gel (200 g), which was eluted with carbon tetrachloride-acetone (5:3). The eluate was subjected to evaporation to remove the solvent. The residue (7.3 g) was dissolved in a solution of potassium hydroxide (2.8 g) in a mixture of water (3 ml) and methanol (60 ml). The resultant solution was stirred at room temperature for 15 minutes, to which were added ice-water and an excess amount of sodium carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried with sodium sulfate, then the solvent was evaporated off. The residue was chromatographed on a column of silica-gel (150 g), which was eluted with 5% methanol-chloroform to yield 2-hydroxymethyl-4-propoxypyridine (4.4 g) as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 52.3 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (25 mg, 0.078 mmol) obtained in Example 1, (3), and 2,4-dichlorobenzoyl chloride (25 mg, 0.118 mmol), the title compound (20 mg, yield 52%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][OH:2].Cl.C([O-])([O-])=O.[K+].[K+].[O:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[C:19]#[N:20]>O.CCO>[OH:2][NH:1][C:19]([C:11]1[O:10][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=1)=[NH:20]
Reactant: NO
Reactant: N#Cc1cc2cnccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cc2cnccc2o1
Temperature: 70 °C

Procedure:
A solution of NH2OH.HCl (1.22 g, 17.5 mmol) and K2CO3 (1.21 g, 8.75 mmol) in H2O (3 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carbonitrile (1.26 g, 8.75 mmol) in EtOH (6 mL). The reaction was heated to 70° C. for 2 h, before being concentrated in vacuo. The remainder was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc (8×), then the combined organic extracts were washed with brine, back-extracting with EtOAc (4×). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=178.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].COC1C([S:20][C:21]#[N:22])=CC(C)=C(O)C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([S:20][C:21]#[N:22])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: COc1cc(O)c(C)cc1SC#N
Product: Cc1cc(SC#N)cc(C)c1O

Procedure:
Compound XXA was prepared from 2,6-dimethylphenol in a similar manner as described for compound 1B. 400 MHz 1H NMR (DMSO-d6) δ 8.96 (s, 1H), 7.22 (s, 2H), 2.13 (s, 6H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1.Cl>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15]
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1CCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(Cl)c1
Temperature: 170 °C

Procedure:
A dispersion was prepared by suspending 1 eq of NaOH (flakes) in 3-chlorophenol (1 eq). The obtained dispersion was heated to 170° C. up to complete solubilization of the base. 1.4 Eq. of γ-butyrolactone were then dropwise added maintaining the reaction mixture at 170° C. for 5 hours. The reaction mixture was then poured into ice and then acidified with HCl 6N. The reaction product was extracted with CHCl3, dehydrated over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (eluent oil ligroin/ethyl acetate 4:1 v/v) to obtain a yellow solid corresponding to 4-(3-chlorophenoxy)butyric acid. 27.96 mmoles of 4-(3-chlorophenoxy)butyric acid were added to 48 grams of polyphosphoric acid and the resulting mixture was maintained under stirring at 90° C. for 2 hours. At the end the reaction mixture was then poured on ice and extracted with CH2Cl2. The pooled organic phases were washed with a 10% Na2CO2 aqueous solution, dehydrated over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (oil ligroin/ethyl acetate 9/1 v/v). An orange oil corresponding to 8-chloro-1-oxo-2,3,4,5-tetrahydrobenzo-cycloheptan-5-one was obtained.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][N:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][N:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2nnnc2c2[nH]cnc21
Solvent: CC#N
Product: CCCCCn1c(=O)n2nnnc2c2[nH]c(Br)nc21
Temperature: 70 °C

Procedure:
The mixture of 6-pentyl-6,9-dihydro-5H-tetrazolo[5,1-i]purin-5-one (0.020 g, 0.081 mmol) and N-bromosuccinimide (10 mg, 8.0 mmol) in acetonitrile (2 mL) in a 5 mL-microwave reaction tube was heated at 70° C. in microwave oven for 12 min. After cooling down to room temperature, the reaction mixture was purified using preparative LCMS to yield the desired product as a white powder. LCMS calculated for C10H13BrN7O (M+H): 326.0, 328.0. found: 326.0, 328.0.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=2[CH3:19])[CH2:5][O:4]1.C(OC(=O)C)(=[O:24])C>>[F:1][CH2:2][C:3]1([CH2:20][F:21])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:24])[C:12]=2[CH3:19])[CH2:5][O:4]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)cc[n+]([O-])c1C
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CO
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
The 4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (1.63 g, 5.37 mmol) obtained in the step (7b) was mixed with acetic anhydride (8 ml). The mixture was stirred at 100° C. for 2 hours, cooled to room temperature, and then, concentrated under reduced pressure. To the residue, methanol (10 ml) and a 5N aqueous sodium hydroxide solution (5 ml) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was separated between a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (385 mg, yield 23.6%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]4[N:41]=[CH:40][CH:39]=[CH:38][C:32]=4[C:33]([O:35]CC)=[O:34])=[CH:26][C:25]=3[F:42])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]4[N:41]=[CH:40][CH:39]=[CH:38][C:32]=4[C:33]([OH:35])=[O:34])=[CH:26][C:25]=3[F:42])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccnc1Nc1ccc(Oc2ccnc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)sc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(Nc5ncccc5C(=O)O)cc4F)c3s2)CC1
Reaction time: 1 h

Procedure:
A round-bottomed flask was charged with ethyl 2-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)nicotinate (0.100 g, 0.169 mmol) and THF (1 mL). NaOH (3.0 mL, 1N) was added and the mixture stirred for 1 hour. The mixture was then acidified to pH 6 with HCl aq. (1N) and extracted with EtOAc. The organics were dried (MgSO4), filtered and concentrated to get product as a yellow solid. LRMS (esi+) 565 m/z (M+1) detected.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:22][C:21]=2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:18])=[CH:15][CH:14]=1.NN>CCO>[NH2:3][CH2:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:22][C:21]=2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN)cc1

Procedure:
Tert-butyl [2-({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzoyl}amino)-4-(2-thienyl)phenyl]carbamate (4.4 g, 7.95 mmol) and hydrazine (0.495 mL, 15.90 mmol) were stirred in refluxing EtOH (35 mL) for 5 hours. Room temperature was attained and the white precipitate removed by filtration and washed with EtOH. The filtrate was concentrated in vacuo and purified by MPLC (1-12.5% [MeOH+1% NH4OH]-DCM) to give tert-butyl [2-{[4-(aminomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH3:28]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium 4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml. of concentrated aqueous ammonia. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitated 4-acetylbenzenesulfonamide removed by filtration and crystallized from aqueous ethanol/acetone; m.p. 177°-179° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:11][C:10](=O)[C:9]([C:13]#[N:14])=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:9]([C:13]#[N:14])=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccco2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A suspension of 6-(2-furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridinecarbonitrile (21.0 g, 79.8 mmol) in phosphorus oxychloride (90 g) was stirred in a nitrogen atmosphere at 110° C. After 4 hours, additional phosphorus oxychloride (50 g) was added thereto, followed by heating under stirring for further 5 hours. After cooling as it was, the reaction solution was concentrated. After ice was added to the residue, it was neutralized with saturated sodium bicarbonate. After extracting with ethyl acetate (2 1)-tetrahydrofuran (1 1), the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. After adding diethyl ether to the residue, the resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (13.6 g, 61%) as a dark yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:22])[CH:6]=[C:7]([CH2:20][CH3:21])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:2].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:20]([C:7]1[CH:6]=[C:5]([O:22][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:21]
Reactant: CCc1cc(O)cc(CC)c1OCCCCOCC=C(Cl)Cl
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
A reaction vessel was charged with 0.35 g of 3,5-diethyl-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)phenol, 0.16 g of 1,1,3-trichloro-1-propene, 0.15 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.33 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)benzene (yield, 72%), nD24.4 1.5311.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1.C(NC(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccc(F)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluting several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[Si:18]([O:25][C@@H:26]([CH3:29])[CH2:27][OH:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[O:30]1[CH2:32][C@H:31]1[C:33]([O:35][CH3:36])=[O:34].O1CC1>CCOC(C)=O>[Si:18]([O:25][C@@H:26]([CH3:29])[CH2:27][O:28][CH2:32][C@H:31]([OH:30])[C:33]([O:35][CH3:36])=[O:34])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: C1CO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
Magnesium trifluoromethanesulfonate (1.779 g, 5.52 mmol) was added in one portion to (S)-2-(tert-butyldimethylsilyloxy)propan-1-ol (Intermediate AS4) (4.2 g, 22.06 mmol) and (S)-methyl oxirane-2-carboxylate (2.252 g, 22.06 mmol) in EtOAc (25 mL). The resulting suspension was stirred at 80° C. for 24 hours. A further 1.5 g of the oxirane was added and the reaction stirred for 4 days. The reaction mixture was diluted with EtOAc, filtered through celite and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane to afford the product (2.70 g, 41.8%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, d), 0.82 (9H, s), 1.06 (3H, d), 3.04 (1H, d), 3.25-3.39 (2H, m), 3.65-3.78 (5H, m), 3.83-3.92 (1H, m), 4.19-4.27 (1H, m)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Brc1ccccc1Oc1ncccn1
Temperature: 120 °C

Procedure:
To a 48 mL pressure tube containing a stirbar were added 2-chloropyrimidine (1.69 g, 14.7 mmol), 2-bromophenol (1.63 mL, 14.0 mmol), Cs2CO3 (5.49 g, 16.8 mmol) and DMSO (30 mL). The vial was sealed and heated at 120° Celsius for 15 hours. The reaction was then diluted with 100 mL of ethyl acetate and extracted with brine (2×50 mL). The organic layer was isolated, dried and concentrated to dryness to provide the crude product which was subsequently purified FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.56 (s, 1H), 7.72-7.60 (dd, J=8.0, 1.6, 1H), 7.45-7.34 (m, 1H), 7.32-7.23 (m, 1H), 7.23-7.11 (m, 1H), 7.10-7.01 (t, J=4.8, 1H).