Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=CC=1.CCOCC.C1(N)CCCC1>C(O)(=O)C>[CH:8]1([NH:1][C:2](=[O:3])[NH2:4])[CH2:9][CH2:10][CH2:5][CH2:11]1
Reactant: NC(N)=O
Reactant: Cc1ccccc1
Agent: NC1CCCC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)NC1CCCC1

Procedure:
A mixture of 10.3 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-urea (m.p. 171° - 173°C), 300 ml of toluene, 30 ml of glycolmonomethyl ether, 1.65 g of glacial acetic acid and 2.4 g of cyclopentyl-amine was refluxed for 5 hours. Subsequently, the mixture was concentrated in vacuo and the residue was treated with alcohol. N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea obtained as a raw product was separated by suction-filtration and recrystallized from methanol. Melting point 184° - 185°C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O>>[BrH:15].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:16]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3ccccn3)cs2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 2-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(2-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 80%. Pale yellow prisms. Melting point: 243 to 244° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[N:29][OH:30])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(Sc2cccc(C=O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(Sc2cccc(C=NO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzaldehyde (0.225 g, 0.57 mmol) was dissolved in pyridine (10 mL) and then hydroxylamine hydrochloride (0.235 g, 3.42 mmol). The reaction stirred at room temperature for 45 minutes and was submitted to an aqueous workup to provide the title compound, which was taken to the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C1CCc2sccc21
Reactant: COc1ccccc1C(=O)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 59 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 2-Methoxy-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Methoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol) as yellow solid in 59% yield.
Reaction SMILES: [CH2:1]([N:5]([C:34]([NH:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([N:5]([C:34]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:35])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCN(C(=O)NCC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl {[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate (which was obtained in Example 379) by NaOH hydrolysis as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.1 Hz, 3 H), 1.15–1.60 (m, 6 H), 1.85–2.00 (m, 2 H), 2.65–2.95 (m, 5 H), 2.92 (s, 3 H), 3.42 (d, J=4.0 Hz, 2 H), 3.45–3.55 (m, 2 H), 3.65–3.80 (m,2 H), 4.65–4.75 (m, 1 H), 5.16 (t, J=4.0 Hz, 1 H), 6.83 (d, J=8.3 Hz, 1 H), 6.95–7.15 (m, 5 H), 7.20 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 576.3 (M−H)−; HRMS Calcd. for C27H38N5O7S (M−H)−: 576.2497. Found: 576.2502.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:28]([NH:35][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:6][N:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)nc2)c2cccnc21
Yield: 58.4 %

Procedure:
Into a round bottom flask was added 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 6 (160.0 mg, 0.40 mmol, prepared as described in Example 2), benzylamine (32, 0.1 mL, 0.90 mmol), palladium acetate (17.0 mg, 0.076 mmol), toluene (10.0 mL), potassium tert-butoxide (80.0 mg, 0.71 mmol) and 2-(di-t-butylphosphino)biphenyl (31.4 mg, 0.11 mmol) under an atmosphere of nitrogen. The reaction was stirred under reflux for 3 hours. TLC and MS indicated no starting material. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1:20) to give compound 10 (110 mg, yield=58.5%) as a white solid. MS (ESI) [M+H+]+=471.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 92 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (110 mg, 92%) which was obtained as a colourless oil. MS: m/e=412.2 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1>C1COCC1.CCCCCC>[C:16]12([C:14](=[O:15])/[CH:13]=[CH:32]/[C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(/C=C/c1cccnc1)C12CC3CC(CC(C3)C1)C2
Yield: 69.9 %

Procedure:
To a stirred solution of diisopropylamine (1.54 ml, 11 mmol) in THF (40 ml) at 0° C. was added butyllithium (1.6M; 6.25 ml, 10.0 mmol) in hexane, followed after 5 minutes by 1-adamantyl methyl ketone (1.96 g, 11.0 mmol). After stirring for 30 minutes at 0° C. the resulting solution of the lithium enolate of 1-adamantyl methyl ketone was then added to a stirred solution of 3-pyridinecarboxaldehyde (0.94 ml, 10.0 mmol) in THF (12 ml) at room temperature. After 3 hours the mixture was partitioned between diethyl ether and water, and the ether layers were concentrated. Chromatography, on elution with petrol-ether-triethylamine, 100:50:1 afforded the product as a solid (1.87 g, 70%), which crystallised from hexane, m.p. 98°-101° C.; IR νmax 1679 cm-1 ; 1H-NMR (CDCl3) δ1.65-1.84 (12H, m, adamantyl CH2), 2.10 (3H, s, adamantyl CH), 7.27 (1H, d, J 15.8 Hz, COCHCH), 7.38 (1H, m, Py 5-H), 7.68 (1H, d, J 15.8 Hz, COCHCH), 7.93 (1H, m, Py 4-H), 8.55 (1H, m, Py 6-H), 8.81 (1H, m, Py 2-H); MS m/z 267 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 0.064 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.020 g, 60% yield) as the dihydrochloride salt. MS ESI (+) m/z 521 detected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:7]1)[CH3:2].Cl[CH2:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].[I-]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:12](=[O:13])[N:11]([CH2:26][C:27]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2NC1=O
Reactant: O=C(CCl)C1CCCC1
Agent: [I-]
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O

Procedure:
reacting the (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester with 2-chloro-1-cyclopentyl-ethanone; in the presence of an organic or inorganic base; in an organic solvent; in the presence of a source of iodide; to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([O:27]CC)=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37].[OH-].[Na+]>O1CCCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([CH3:38])[CH3:37]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(O)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(O)cc12
Temperature: 70 °C

Procedure:
To a solution of EXAMPLE 149B (22 mg) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 10% NaOH 0.3 ml. The reaction was heated at 70° C. for 24 hours, cooled, acidified with diluted aqueousHCl and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.83 (s, 1H), 8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45-7.55 (m, 5H), 7.34-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7.17 (td, J=7.36, 1.23 Hz, 1H), 7.04 (dd, J=7.52, 1.38 Hz, 1H), 6.85 (d, J=7.36 Hz, 1H), 6.75 (dd, J=8.90, 2.45 Hz, 1H), 6.37 (d, J=2.15 Hz, 1H), 4.84 (t, J=7.52 Hz, 2H), 4.15 (t, J=5.68 Hz, 2H), 2.63-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J=6.75 Hz, 3H), 0.96 (d, J=7.06 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[Br-].[Li+].[H-].[Na+].Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>CN(C)C=O.O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][CH2:19][N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: COc1cnc2ccc(=O)[nH]c2n1
Reactant: BrCCC1OCCO1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc2ccc(=O)n(CCC3OCCO3)c2n1
Temperature: 25 °C

Procedure:
3-Methoxypyrido[2,3-b]pyrazin-6(5H)-one (400 mg, 2.26 mmol) was dissolved in N,N-dimethylformamide (12 ml). Lithium bromide (206 mg, 2.37 mmol) and sodium hydride (55%, 104 mg, 2.37 mmol) were added to the solution under cooling on ice and stirred for one and a half hours while the temperature of the reaction solution was raised to room temperature. The reaction solution was cooled on ice again, 2-(2-bromoethyl)-1,3-dioxolane (0.345 mmol, 2.94 mmol) was added thereto and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate and washed with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 731 mg (quantitative) of the title compound in the form of a yellow oily product.
Reaction SMILES: [Br:1][C:2]([Br:16])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N+:13]([O-])=O>CO.[Pt]>[Br:1][C:2]([Br:16])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[NH2:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(C=C(Br)Br)c1
Agent: [Pt]
Solvent: CO
Product: CCOc1ccc(N)c(C=C(Br)Br)c1
Yield: 84.7 %

Procedure:
To a suspension of 2-(2,2-dibromovinyl)-4-ethoxynitrobenzene (200 mg) in methanol (3 mL) was added 1% platinum on activated carbon (vanadium doped, 50% hydrous, 27.5 mg) at room temperature, and the mixture was stirred for six and a half hours under a hydrogen atmosphere. 1% Platinum on activated carbon (vanadium doped, 50% hydrous, 27.5 mg) was added, and the mixture was stirred for additional one hour under a hydrogen atmosphere. The reaction mixture was filtered through celite (registered trademark) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (155 mg).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][O:21][C:22](=[O:25])[NH:23][CH3:24])[CH:16]=[CH:15][C:14]=1[Cl:26])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C>C(Cl)Cl>[Cl:26][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][O:21][C:22](=[O:25])[NH:23][CH3:24])=[CH:18][C:13]=1[CH2:12][NH:8][CH:9]1[CH2:11][CH2:10]1
Reactant: CNC(=O)OCCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)OCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.2 %

Procedure:
HCl (4M in dioxane, 18 mL) was added to a sol. of [2-chloro-5-(2-methylcarbamoyloxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (1.76 g, 4.60 mmol) in CH2Cl2 (18 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and more CH2Cl2 was added. The mixture was washed with aq. 1M NaOH and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (1.46 g, quantitative yield) that was used further without purification. LC-MS: tR=0.64 min; ES+: 283.40.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
106.6 g of 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are refluxed with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then removed by distillation at atmospheric pressure and the residue is fractionated in a high vacuum. 104.7 g of 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride pass over at 110°-115° C./0.08-0.09 mbar. On standing, crystals of melting point 35°-37° C. form.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1ccc(CCl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(NC(C)=O)cc2)c(OC)c1
Temperature: 130 °C

Procedure:
p-Acetylaminophenol (15.1 g, 0.1 M) in dimethyl formamide (30 ml) containing potassium carbonate (1.36 g, 0.1 M) is treated with 2,4-dimethoxybenzyl chloride (1.86 g, 0.1 M). The mixture is then heated at 130° C. for 3 hours, then the solvent removed by evaporation under reduced pressure. The residue is treated with water, and the precipitate filtered off and recrystallized from ethanol to afford p-(2,4-dimethoxybenzyloxy)acetanilide.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl>ClCCl.C(OCC)C>[CH3:1][O:2][C:3]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:4][CH2:5][CH:6]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: COC1(Cc2ccccc2C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC1(Cc2ccccc2C)CCC(N2CCNCC2)CC1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of EXAMPLE 15D (0.51 g, 1.26 mmol) in dichloromethane (5 mL) at room temperature was treated with 2M HCl in diethyl ether (5 mL), stirred overnight, and concentrated to provide the desired product (0.38 g, 100%). MS (ESI) m/e 303 (M+H)+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:2]=1.Br[CH2:20][C:21]([O:23]C)=[O:22]>>[CH3:17][C:16]1[C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:3]2[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NS(=O)(=O)c2ncccc2C)c1
Reactant: COC(=O)CBr
Product: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid m-tolylamide with methyl bromoacetate
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:24])=[C:16]2[N:15]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[NH2:28][CH2:27][C:26]([NH:25][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:24])([CH3:37])[CH3:36]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(CN)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-tert-butyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methylpropylcarbamate (109 mg, 0.212 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (0.530 mL, 2.12 mmol) was added. The mixture was stirred at ambient temperature for 4 hours and was concentrated afford the title compound (105 mg). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H][H]>C(O)C.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: c1cnc2c(c1)CCN2
Yield: 59.6 %

Procedure:
A solution of 7-azaindole (20.0 g, 169 mmol) in ethanol (200 ml) was treated with wet Raney Nickel (4 g, 50% water) and stirred in a hydrogen atmosphere at 5 atmospheres pressure at 95° C. over 2 days. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under vacuum The residue was purified by column chromatography eluting with ethyl acetate followed by increasingly polar mixtures of methylene chloride and methanol (saturated with ammonia) to give 7-azaindoline (12.1 g, 79%).