Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:7]1([C:18]#[N:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])C#N.Cl.C(O)(=[O:24])C>CO>[Cl:16][C:13]1[CH:14]=[C:15]2[C:7]3([CH2:4][C:3](=[O:2])[NH:19][C:18]3=[O:24])[C:8](=[O:17])[NH:9][C:10]2=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Solvent: CO
Product: O=C1CC2(C(=O)N1)C(=O)Nc1ccc(Cl)cc12
Reaction time: 8 h

Procedure:
A stirred solution of the crude (5-chloro-3-cyano-2-oxo-2,3-dihydro-1H-indol-3-yl)-cyanoacetic acid methyl ester, intermediate 5 (53.3 g, 0.18 mol) in methanol (450 ml) was cooled in an ice-water bath and saturated with hydrogen chloride gas, keeping the temperature below 20° C. The resultant solution was left to stand at ambient temperature overnight and then heated cautiously under reflux for 5 hours to give a yellow suspension. The solvent was removed in vacuo to give a semi-solid residue, which was mixed with glacial acetic acid (375 ml) and heated under reflux, with stirring, for 16 hours. After cooling in an ice-water bath, the crude 5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione was removed by filtration, washed with cold glacial acetic acid (100 ml) followed by water (100 ml) and then diethyl ether (100 ml) and dried in vacuo to give an off-white solid. A second crop was obtained by removing the solvent in vacuo from the combined acetic acid filtrates and repeating the purification procedure to give a total of 30.5 g (66%). Sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][Br:30])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(CCBr)cc1
Yield: 54.5 %

Procedure:
A stirred solution of 4-chlorophenethyl alcohol (131 g) and triphenylphosphine (241.3 g) in dry THF (500 mL) at 0° C. was treated portionwise over 30 min. with N-bromosuccinimide (163.75 g). The resulting black solution was stirred overnight at room temperature, whereupon the THF was evaporated and the residue stirred with ether. The solution was filtered to remove triphenylphosphine oxide and the filtrate evaporated and treated with hexane. The stirred mixture was filtered, evaporated, and the residue distilled under reduced pressure to give 100 g of 4-chlorophenethyl bromide as a colorless liquid, b.p. 85° C. (3 mm Hg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-Methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.11) (0.197 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as light yellow solid (0.24 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][NH:10][CH2:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:11][CH3:12])[C:26](=[O:28])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([O:17][CH2:15][CH3:16])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccc(C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.706 g, 2.20 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.54 g (58%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5 g, 0.018 mol), 4-chlorophenyl isothiocyanate (3.76 g, 0.022 mol) and toluene (20 ml) was heated under reflux for 3 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 6.69 g (82%), m.p. 179°-180 ° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:15])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH3:13])[O:7][C:6]=2[CH:14]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+].N1CCC[C@H]1C(O)=O>[Cu](I)I.CS(C)=O>[F:15][C:4]1[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH3:13])[O:7][C:6]=2[CH:14]=[C:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:3]=1
Reactant: CNCC1OCc2c(F)cc(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1
Yield: 9.1 %

Procedure:
Preparation according to Example 17 with a small alteration, no base used. 1-(7-bromo-5-fluoro-4H-1,3-benzodioxin-2-yl)-N-methylmethanamine (0.33 g, 1.2 mmol), sodium methanesulfinate (0.18 g, 1.49 mmol, 85%), copperiodide (23 mg, 0.12 mmol), L-proline (69 mg, 0.60 mmol) and DMSO (6.0 ml) was heated at 140° C. for 45 min. Purification by flash column chromatography (EtOAc/MeOH 4:1) afforded the title compound (30 mg, 10%). The amine was converted into the hydrochloric acid salt and crystallized from MeOH/EtOH/DEE. The crystals were washed thoroughly with DEE. M.p. 234° C. 1H-NMR (400 MHz, MeOH): δ 7.28 (2H, m), δ 5.26 (1H, t, J 4.8 Hz), δ 5.05 (2H, dd, J1 20.4 Hz, J2 16.0 Hz), δ 3.13 (3H, s), δ 2.95 (2H, m), δ 2.47 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1ccccc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (7.21 mg, 0.0202 mmol, 10.1%). ESI-MS m/z calc. 356.1. found 357.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]([C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)(=O)[NH2:24])C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[NH2:24][N:16]1[CH:15]=[CH:14][N:13]=[C:12]1[C:10]([NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11]
Reactant: O=C(Nc1ccccc1)c1ncc[nH]1
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nn1ccnc1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
0.430 g (10.75 mmol) of sodium hydride (60% dispersion in mineral oil) was added to a 0° C. cooled solution of N-phenyl-1H-imidazole-2-carboxamide (1.55 g, 8.27 mmol) in DMF (50 mL). The mixture was stirred at 0° C. for 30 minutes and 2.70 g (11.57 mmol) of DPPONH2 (P,P-diphenylphosphinic amide, available from Sigma Aldrich®, cat. no. 5994-87-6) were added portionwise. A thick suspension formed and additional 100 mL of DMF were added. The mixture was stirred at room temperature for 3 hours and then it was poured into 150 mL of a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (20% to 40% AcOEt/Hexanes) to yield 1.27 g (76% yield) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:8]/[S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].[CH2:15]1COCC1.C[Mg]Br.CCOCC>[NH4+].[Cl-]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:8][S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH3:15]
Reactant: C1CCOC1
Reactant: Cn1ccnc1/C=N/S(=O)C(C)(C)C
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(NS(=O)C(C)(C)C)c1nccn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In a 250 mL round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-(1-methyl-1H-imidazol-2-yl)-meth-(E)-ylideneamide (670 mg, 3.14 mmol) was combined with THF to give a colorless solution. Methylmagnesium bromide in ether (3.0 M, 5.24 ml, 15.7 mmol) was added at 0° C. The reaction was stirred at 0° C. for 2 h. The reaction mixture was diluted with sat aq. NH4Cl. The aqueous layer was back-extracted with dichloromethane (2×100 mL). The aqueous layer was back-extracted with EtOAc (1×125 mL). The crude reaction mixture was concentrated in vacuo to provide 700 mg (92%) of 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide as a single diastereomer. 1H NMR (300 MHz, DMSO-d6): δ 6.98 (bs, 1H), 6.82 (bs, 1H), 4.61 (q, 1H, J=6 Hz), 4.10 (bs, 1H), 1.61 (d, 1H, J=6 Hz), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]#[N:15])=[C:11]([Cl:16])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[CH3:25])=[C:19]([Cl:26])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2nc(Cl)c(CC#N)n2Cc2ccccc2)cc1Cl
Yield: 63.7 %

Procedure:
2 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylaminophenyl)imidazole and 1 g of N-chlorosuccinimide were stirred in 30 ml of dioxane at 50° C. for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 100 ml of chloroform, followed by washing twice with water and evaporating to dryness under reduced pressure. The residue was recrystallized twice from 20 ml of methanol, thus yielding 1.4 g of 1-benzyl-4-chloro-5-cyanomethyl-2-(4-dimethylamino-3-chlorophenyl)imidazole as slightly yellow, needle-formed crystals, m.p. 142°-143° C.
Reaction SMILES: OC[C:3]1([OH:14])[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1>C1COCC1.O>[O:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[O:8][CH2:9][C:3](=[O:14])[CH2:4]1
Reactant: OCC1(O)COc2ccccc2OC1
Solvent: O
Solvent: C1CCOC1
Product: O=C1COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
A solution of Example 280B (5.29 g, 27 mmol) in THF (50 mL) was treated with a suspension of NaIO4 (6.33 g, 30 mmol) in water (10 ml) and THF (50 mL), then stirred at rt for 1.5 h. Diluted with water, extracted twice with ether. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was suspended in ether, filtered and the filtrate was concentrated to give 2.75 g (55%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][CH2:23][CH2:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[O:21])=[N:5][N:4]=[N:3]1
Reactant: O=C(CCCCl)c1ccccn1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 2-pyridyl ketone (2.8 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrated is concentrate under reduced pressure. The residue is purified by silica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1)) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (yield 50%) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][C:3](=[O:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99084.2 %

Procedure:
Chloroacetone (32.3 g, 0.347 mol) was added to a mixture of 4-chlorothiophenol (50 g, 0.347 mmol) and sodium hydroxide (14 g, 0.347 mol) in water (400 ml) and the mixture was stirred at 25° C.. for 1 hour. The mixture was extracted with ethyl ether and the organic phase was washed with water, dried with magnesium sulfate and concentrated to give 69 g (99%) of 1-[(4-chlorophenyl)thio]-2-propanone.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])[CH3:4].Cl[C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:4]
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])c2cccnc12
Reactant: CCc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccccc1Sc1cc(NC(C)=O)c2ncccc2c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.09 g of 60% in oil) is added to 2-ethylthiophenol (0.26 g) in tetrahydrofuran (10 mL) and stirred for 15 minutes. N-(6-chloro-5-nitro-quinolin-8-yl)-acetamide (Gilman H., et al., Journal of American Chemical Society, 1946;66:1577) (0.5 g) is added and the mixture stirred at room temperature for 12 hours. The mixture is added to water (150 mL) and extracted with ethyl acetate (3×100 mL). The extracts are washed with saturated brine (150 mL), dried over magnesium sulfate, filtered, and evaporated to leave an oil. The oil is purified by chromatography on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([C:15](Cl)=[O:16])[S:11][N:10]=1.Cl>O1CCCC1>[C:1]([CH:3]([C:15]([C:12]1[S:11][N:10]=[C:9]([Cl:8])[C:13]=1[Cl:14])=[O:16])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(=O)c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of methyl cyanoacetate (1.98 g) in unhydrous tetrahydrofuran (20 ml) 60% sodium hydride (1.6 g) was added at a temperature below 10° C. To the reaction mixture a solution of 3,4-dichloro-5-isothiazolecarbonyl chloride (4.30 g) in unhydrous tetrahydrofuran (15 ml) was added dropwise at the same temperature. After finishing the addition, the reaction mixture was stirred at room temperature for 2 hours and 1N-aqueous hydrochloric acid (10 ml) was added. After extraction with ethyl acetate and drying the organic phase with unhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain methyl 2-cyano-3-(3,4-dichloro-5-isothiazolyl)-3-oxopropanoate (4.7 g) as pale yellow crystals. mp 119-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14](N1C2C=CC=CC=2CN2C(C)=CC=C2C1)=[O:15].[Cl:31]C1C=C(N2C=CC(C)=N2)C=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([Cl:31])=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(C)n4Cc4ccccc43)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step e) [2-Chloro-4-(3-methylpyrazol-1-yl)-phenyl]-(3-methyl-5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone: A mixture of 2-chloro-4-(3-methylpyrazol-1-yl)-benzoic acid (0.18 g) from step c) of Example 10, oxalyl chloride (0.18 g) and one drop of dimethylformamide in dichloromethane (10 ml), was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was redissolved in dichloromethane and reconcentrated in vacuo to yield 2-chloro-4-(3-methyl-pyrazol-1-yl)-benzoyl chloride. A slurry of the acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 h, and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to yield 0.115 g of product as colorless crystals, m.p. 178-180° C., MS m/z: 417.3 (M+H)+, 833.3 (2M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[NH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncc2[nH]ccc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncc2[nH]cc(Br)c2n1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g, 10 mmol) in DMF (10 mL) was added NBS (2.00 g, 11 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.75 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.60 (s, 1H); MS m/z 234.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].C([Mg]Br)C.Br[CH2:15][C:16]([CH3:27])=[CH:17][CH2:18][CH:19]=[C:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:15][C:16]([CH3:27])=[CH:17][CH2:18][CH:19]=[C:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCCCl
Reactant: CCCCCC(C)=CCC=C(C)CBr
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(C)=CCC=C(C)CC#CCCCCCCCl
Reaction time: 0.33 h

Procedure:
A solution of 12.0 g. of 1-chlorooct-7-yne in 20 ml. of tetrahydrofuran is added to a mixture of 27 ml. of 3N ethyl magnesium bromide in ether and 50 ml. of tetrahydrofuran. The mixture is stirred and heated under reflux for 30 min. under nitrogen, then 0.45 g. of powdered cuprous chloride is added and heating and stirring is continued for 20 min. A solution of 20.0 g. of 1-bromo-2,6-dimethyl-2,5-undecadiene in 15-ml. of tetrahydrofuran is added and the mixture is heated under reflux for 10 hrs., then allowed to stand for about 18 hrs., and poured into saturated aqueous ammonium chloride and ether. The mixture is filtered and the ether solution is separated, washed with water, dried over sodium sulfate, and evaporated to leave a residue comprising 1-chloro-10,14-dimethylnonadeca-10,13-dien-7-yne.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][CH:20]=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].C([O-])(=O)C.[Na+].[I:27]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]3[N:18]=[CH:19][C:20]([I:27])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: ClI
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 15.2 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.36 g, 16.6 mmol) and drop wise a solution of iodine monochloride (2.69 g, 16.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.96 g, 93%) as a yellow solid. MS (EI) 436.9 [(M)+]; mp 151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:7][CH:6]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A 1.7 g. portion of 1-(p-aminophenyl)-5-(p-fluorophenyl)-1H-1,2,4-triazole is gently refluxed in a mixture of 5.0 ml. of dimethylformamide dimethylacetal and 2.5 ml. of dimethylformamide. Heating is continued for 1.5 hours, then the mixture is evaporated under high vacuum (70° C.) to a brown oil. This oil is triturated with 50 ml. of ether. The solid is collected by filtration, dried and recrystallized from 25 ml. of hot cyclohexane, giving 1.1 g. of the desired product as a light tan solid, mp. 90°-93° C.