Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-AMINOTHIAZOLE (1.80 g, 0.0179 mol) in Pyridine (6 mL, 0.08 mol) at 0° C. was added 2-Chloropyridine-5-sulfonyl chloride (1.55 g, 0.00717 mol) portion-wise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified on ISCO companion (silica gel, 10% to 100% ethyl acetate in hexanes) to give product as a brown solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:4]([C@@H:5]1[C:6](=[O:7])[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][C@@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C[C@H](c2ccc(C)cc2)[C@H](Cc2ccccc2)C(=O)O1
Yield: 74 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 74% yield as a single diastereomer (colorless oil). [α]D2 (c 1.02, CHCl3)=+310.3; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.16-7.07 (m, 4H), 6.93-6.91 (m, 2H), 6.65 (d, 1H, J=6.8 Hz), 4.30 (q, 1H, J=7.1 Hz), 3.58 (t, 1H, J=6.7 Hz), 3.29-3.23 (m, 2H), 2.41 (dd, 1H, J=15.8, 10.9 Hz), 2.35 (s, 3H), 1.33 (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 168.9, 160.7, 142.1, 138.3, 132.8, 130.0, 129.1, 128.8, 128.4, 126.9, 118.9, 62.1, 45.0, 40.3, 32.1, 21.3, 14.3; IR (thin film) ν 3062, 3027, 2982, 2925, 1776, 1732, 1316, 1267, 1106 cm−1; HRMS (ESI) calcd for C22H22O4 [M+Na]+ 373.1410, found 373.1409; 97% ee (4S,5S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (4S,5S)=21.7 min, tr (4R,5R)=13.4 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH:38]([F:40])[F:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH:38]([F:39])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1OC(F)F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example A5, 2.78 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[2-(difluoromethoxy)phenyl]ethoxy}thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:21][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1CCN(C(=O)c2ccccc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)N1CCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
NaBH4 (85 mg, 2.25 mmol) is added to a solution of 1-benzoyl-2,3-dihydro-1H-quinolin-4-one (from step C) in methanol (5 mL) at 0° C. The resulting mixture is stirred at room temperature. After 1 h, the reaction is quenched by 1 N HCl. The solvent is removed under vacuum. The residue is taken up in CH2Cl2 and washed by brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by flash chromatography to give the title compound (380 mg, 84.8% yield for the two steps).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>CCOCC>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCn1ccc2ccccc21
Solvent: CCOCC
Product: COCn1cc(C(=O)C(=O)Cl)c2ccccc21
Yield: 48.3 %

Procedure:
Using the procedure of Example 1, step B, the reaction of 0.23 g (1.43 mmol) of 1-methoxymethyl-1H-indole (9) from Step A above with 0.25 ml (2.86 mmol) of oxalyl chloride in 3.5 ml of ether produced 0.174 g (48.5%) of (1-methoxymethyl-1H-indol-3-yl)-oxo-acetyl chloride (10) as a yellow solid. This material was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[CH:38]1([C:41]2[N:46]=[C:45]([O:47][CH3:48])[C:44]([CH2:49][CH2:50][NH2:51])=[CH:43][CH:42]=2)[CH2:40][CH2:39]1.Cl.C(N=C=NCCCN(C)C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:51][CH2:50][CH2:49][C:44]3[C:45]([O:47][CH3:48])=[N:46][C:41]([CH:38]4[CH2:39][CH2:40]4)=[CH:42][CH:43]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1nc(C2CC2)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4OC)cc3)c(Cl)cc21
Reaction time: 5 h
Yield: 46.5 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (200 mg, 0.531 mmol) and 1-hydroxybenzotriazole monohydrate (89.4 mg, 0.584 mmol) was added 2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethanamine (117 mg, 0.610 mmol) (in dimethylformamide, 3 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg, 0.584 mmol) was added and the reaction was stirred for 5 hours. The reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (136 mg, 0.247 mmol, 46.5% yield). MS (apci+es, positive) m/z=552.2.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH3:22])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene (27 mg, 0.0419 mmol) in tetrahydrofuran (1 ml) was combined with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml, 0.25 mmol), and stirred at room temperature for 20 hours, then with heating under reflux for 2 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1 and 0.25 mm×1, dichloromethane:ethanol=20:1, developed twice) to give the title compound as a colorless oil (17.3 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylic acid (D38) (320 mg, 1.24 mmol) in acetone (10 ml), TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol) were added and the resulting mixture was stirred at RT for 18 hrs. TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol) were added and the reaction stirred for 24 hrs prior addition of further TEA (0.35 ml, 2.49 mmol) and benzyl bromide (0.23 ml, 1.86 mmol). The final mixture was then refluxed for 18 hrs. Solvents were evaporated off and the resulting residue was re-dissolved in EtOAc, washed with water (3×10 ml), dried over Na2SO4 and evaporated in vacuo to afford a residue that was purified by Biotage SNAP-Si column (25 g) eluting with a mixture DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D39) (260 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:42](OC)[N:43]([CH3:45])[CH3:44].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26](/[CH:33]=[CH:42]/[N:43]([CH3:45])[CH3:44])[N:25]=[C:24]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 130 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate (350 mg, 0.64 mmol) was dissolved in DMF (5 mL), dimethyl formamide dimethyl acetal (0.26 mL) was added and the mixture was heated to 130° C. for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.23 g). 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 7.94 (d, J=12.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 5.89 (d, J=12.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.80 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 3.32 (m, 6H), 2.41 (m, 4H), 1.38 (s, 9H), 1.32 (t, J=6.8 Hz, 3H); MS m/z 596.4 (M+1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[ClH:29]>>[ClH:29].[ClH:29].[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCOc1ccc(N2CCN(C(C)=O)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCOc1ccc(N2CCNCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 1-acetyl-4-(4-hexyloxyphenyl)piperazine (14 g) in 1N HCl was refluxed for 5 hours. The reaction mixture was adjusted to pH 8 with saturated Na2CO3 aq. and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added ethyl acetate and 4N HCl in ethyl acetate (23 ml) and stirred for 1 hour. The resulting precipitate was collected by filtration to give 1-(4-hexyloxyphenyl)piperazine dihydrochloride (8.669 g).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>O>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2nnc3n2-c2ccc(Br)cc2C(c2ccccn2)=NC3)CC1
Reaction time: 24 h

Procedure:
A stirred mixture of 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (2.19 g.) and 1-methylpiperazine (10 ml.) is kept under nitrogen at 125°-130° C. for 15.5 hours and at 135°-145° C. for 24 hours. It is then cooled, mixed with cold water, treated with a little sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is treated successively with xylene and toluene with concentration after each addition and the resulting material is chromatographed on silica gel (150 g.) with mixtures of chloroform and methanol containing 5-10% methanol. The product thus obtained is crystallized from methanol-ethyl acetate to give 8-bromo-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 4 crops as follows: 0.799 g., melting point 250.5°-253.5° dec; 0.062 g., melting point 248.5-249.5° dec; 0.344 g., melting point 250°-252° dec., and 0.206 g., melting point 245.5°-247.5° dec. The analytical sample has a melting point of 252°-253° dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([C:27](O)=[O:28])[NH:25][CH:26]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([C:27]([NH:14][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])[NH:25][CH:26]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1-n1cncn1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1-n1cncn1

Procedure:
3-Methoxy-4-(1H-1,2,4-triazol-1-yl)benzenamine, prepared as described in Bioorg. Med. Chem. Lett. 2003, 13, 2059, was converted to the title compound (45 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (30 mg) following the procedure described in step C of Example 1. MS (ESI) 394 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][S:12][CH2:13][CH2:14][CH:15]=[O:16]>CO>[CH3:11][S:12][CH2:13][C:14](=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:15]=[O:16]
Reactant: CSCCC=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSCC(C=O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Into a 100 ml three necked reaction flask equipped with stirrer, thermometer and addition funnel is charged a solution of 0.5 grams of potassium hydroxide in 10 ml methanol. Benzaldehyde (10.0 grams) is added as the mixture is cooled to 5°-10° C. Methional (10.0 grams) is then added dropwise while maintaining the reaction temperature at 5°-10° C. The mixture is then allowed to warm to room temperature and stirred for a period of 1 hour. Most of the solvent is evaporated at reduced pressure and the mixture is partitioned between water and ether. The organic layer is washed several times with water and once with saturated brine. The solvent is evaporated leaving a yellow oil wich is distilled to give 6.1 grams product, boiling point 104°-111° C (0.4 mm Hg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)N2
Yield: 60 %

Procedure:
5-Nitro-2-oxindole (6.3 9) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.Cl.C(O[CH:23](OCC)[CH2:24][CH2:25][CH2:26][NH:27][CH3:28])C>O>[CH3:28][NH:27][CH2:26][CH2:25][C:24]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:23]=1
Reactant: CCOC(CCCNC)OCC
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Agent: Cl
Solvent: O
Product: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Temperature: 70 °C

Procedure:
The title compound was prepared by General Method 3. 1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine (250 mg) was suspended in water (2 mL) and 28% aqueous HCl (0.135 mL) was added. 4,4-diethoxy-N-methylbutan-1-amine (0.18 g) was added to the resulting solution and the reaction mixture was heated to 60-80° C. and an additional 28% HCl (0.135 mL) was added and the reaction mixture was heated for additional 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 7/3/1) to obtain the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-ethanone (4.9 g, 24 mmol), 4-trifluoromethyl phenyl boronic acid (4.6 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol), potassium phosphate (10 g, 49 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a clear oil (5.6 g, 87%). MS (ESI): mass calcd. for C15H11F3O, 264.0; m/z found, 265.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (t, J=1.6, 1H), 8.04-7.98 (m, 1H), 7.85-7.78 (m, 1H), 7.76-7.69 (m, 4H), 7.60 (t, J=7.7, 1H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]1[C@H:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: CI
Reactant: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H,11aH)-dione (9.9 g, 45.8 mmol) in DMF (150 ml) at 0° C. was added NaH (2.0 g, 50.4 mmol). The mixture was warmed to room temperature and stirred for 1 h before methyl iodide (8.56 ml, 137 mmol) was added dropwise. After stirring for an additional 1 h, the mixture was dumped into water (1 l) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.7 g, 54%), m.p. 118-120° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][N:27]([CH3:48])[CH2:28][CH2:29][N:30](CCN(C)C)[S:31]([C:34]1[S:35][C:36]([Cl:42])=[C:37]([N+:39]([O-])=O)[CH:38]=1)(=[O:33])=[O:32]>>[Cl:42][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[NH:30][CH2:29][CH2:28][N:27]([CH3:48])[CH3:26])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCN(CCN(C)C)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CN(C)CCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.14) according to general procedure II.