Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1)C1C=CC=CC=1.CO>[Pd].C(Cl)Cl>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1
Reactant: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1NC=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N)cc1NC=O
Reaction time: 20 h
Yield: 95.7 %

Procedure:
A 100 mL flask was charged with (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd—C (50 mg), and stirred under H2 (1 atm) for 20 h. CH2Cl2 (5 mL) was added to quench the catalyst, and the mixture then filtered through Celite, and concentrated to afford N-(5-amino-2-tert-butyl-phenyl)-formamide as an off-white solid (366 mg, 96%). Rotameric by 1H and 13C NMR (DMSO-d6). 1H NMR (400 MHz, DMSO-d6, rotameric) δ □9.24□ (d, J=10.4 Hz, 1H), 9.15 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.06 (d, J=10.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.46 (dd, J=2.5, 8.5 Hz, 1H), 6.39 (dd, J=2.5, 8.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 1.27 (s, 9H); 13C NMR (100 MHz, DMSO-d6, rotameric) δ 164.0, 160.4, 147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15, 115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 m/z (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]2[C:13](O[C:16](=[O:17])[C:6]=2[CH:5]=1)=[O:14]>CC(O)=O>[O:17]=[C:16]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:4][CH:5]=2)[C:13](=[O:14])[NH:3][NH:2]1
Reactant: NN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 120 °C
Yield: 84.9 %

Procedure:
Hydrazine hydrate (26 g, 0.52 mol) was added in one portion to a stirred mixture of 1,2,4-benzenetricarboxylic anhydride (100 g, 0.52 mol), in HOAc (1.0 L) at RT. The mixture was heated to 120° C. for 2 h and then allowed to cool to RT. The solid was filtered, washed with water (250 ml) and dried in the under vacuum at 50° C. for 20 hours to give the title compound (91 g, 85% yield).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[C:13]([NH2:18])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(O)C>[CH3:14][C:13]([NH:18][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH3:17]
Reactant: CCC(C)(C)N
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CCC(C)(C)NC[C@H](O)c1ccc2nnnn2c1
Yield: 96.1 %

Procedure:
A solution of 250 mg (1.54 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 663 mg (7.61 mmol) of tert amylamine in 0.6 ml of absolute ethanol in a pressure tube was heated at 100° C. (bath temperature) for two hours. The reaction mixture was concentrated under reduced pressure to yield 369 mg of crude product which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16]C1C=CC(N)=CC=1>>[F:16][C:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Yield: 57 %

Procedure:
Following the procedure described above for the compound 161 (scheme 45), but replacing aniline for 4-fluoroaniline, title compound 181 was obtained in 57% yield. MS (m/z): 224.0 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C.[C:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38](O)[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[Cl:43][C:44]1[N:49]=[CH:48][N:47]=[C:46]2[NH:50][N:51]=[CH:52][C:45]=12>O1CCCC1>[C:32]([O:31][C:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([N:50]2[C:46]3=[N:47][CH:48]=[N:49][C:44]([Cl:43])=[C:45]3[CH:52]=[N:51]2)[CH2:37]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Cl)ncnc32)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 11.1 %

Procedure:
A solution of triphenylphosphine (1.41 g, 5.4 mmol) in tetrahydrofuran (50 mL) under argon was cooled to 0° C. Diisopropylcarbodiimide (1.06 mL, 5.4 mmol) was added dropwise, followed by 1-Boc-3-hydroxypiperidine (Alfa Aesar, Ward Hill, Mass., USA; 0.92 g, 4.6 mmol) and then 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 0.55 g, 3.6 mmol). The mixture was stirred at room 0° C. for 4 h and the volatiles were then evaporated. The crude product was purified by silica gel chromatography, eluting with 16-20% ethyl acetate/hexanes to give 3-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (135 mg, 11%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[C:23]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:43][CH2:42]2)=[CH:24][C:25]([Cl:40])=[C:26]([CH:39]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38])=[O:28].[Cl-].[Li+]>CN(C=O)C>[Cl:40][C:25]1[C:26]([C:27](=[O:28])[NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:39][C:22]([NH:21][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:23]([N:41]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:45][CH2:46]2)[CH:24]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid 1h (122.2 mg, 0.79 mmol) in DMF (5.0 mL) HATU (404.4 mg, 1.06 mmol) was added and stirred for 3 min. N,N-diisopropylethylamine (0.46 mL, 2.66 mmol) was added to this followed by 5-amino-2-chloro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 1g (250.0 mg, 0.53 mmol) in DMF (5.0 mL) and the reaction was stirred at 25° C. for 16 h. LCMS indicated the completion of reaction. Saturated solution of lithium chloride was added to this and the contents were extracted with ethyl acetate, organic layer was dried on anhydrous sodium sulfate, concentrated and the crude ii was purified on preparative HPLC using water/methanol (0.1% TFA) (42.0 mg, 13%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]([CH2:15]Cl)=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:15][C:13]([Cl:12])=[CH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1S
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)CSc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 2-tert-butyl-benzenethiol (5.0 g, 24.09 mmol) in acetone (25 mL) is reacted with 2,3-dichloro-propene (2.2 mL, 24.09 mmol) and K2CO3 (4.3 g, 31.32 mmol) at reflux overnight. It is cooled to rt and filtered and washed with EtOAc, and concentrated. The crude material is purified by chromatography gives the title compound (5.66 g, 23.58 mmol, 98%). 1H NMR (CDCl3): δ 1.52 (s, 9H), 3.77 (s, 2H), 5.27 (bs, 1H), 5.31 (bs, 1H), 7.11-7.20 (m, 2H), 7.36-7.43 (m, 1H) ppm. ES-MS (m/z): calcd for C13H17CIS M+: 240.8. found: 240.9.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:23])[CH:15]([NH2:22])[CH2:16][S:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]([NH:22][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][S:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N)CSC(C)(C)C
Agent: Cl
Product: CCOC(=O)C(CSC(C)(C)C)NC(=O)c1ccccc1
Yield: 60 %

Procedure:
With General procedure D, starting from 21 (5.94 g, 42.26 mmol) and 12 (8.54 g, 35.36 mmol), 6.56 g (60%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 2H), 7.52 (m, 3H), 6.97 (br d, 1H), 5.06 (m, 1H), 4.28 (q, 2H), 3.16 (m, 2H), 1.32 (m, 12H). MS m/z 310 (M+1). HPLC: 98.35% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]([C:15](=[C:18](OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]#[N:17])#[N:14].[H-].[Na+]>CN(C)C=O>[C:13]([C:15]1[C:16](=[NH:17])[N:1]2[C:2]([CH:3]=[CH:4][CH:5]=[CH:6]2)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[N:14]
Reactant: COC(=C(C#N)C#N)c1ccccc1
Reactant: CCOC(=O)Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c(C#N)c(=N)n2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of 2.50 g of ethyl 2-pyridylacetate and 2.79 g of 2-cyano-3-methoxy-3-phenylacrylonitrile was dissolved in 15 ml of dry N,N-dimethylformamide. To the solution was added 0.61 g of 60% sodium hydride and the reaction mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into ice-water, and precipitated crystals were collected by filtration, washed with water and dried under vacuum to obtain 2.50 g of 3-cyano-1-ethoxycarbonyl-4-imino-2-phenyl-4H-quinolizine.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]([C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=3)[NH:9][C:10](=[O:24])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:12]=2[CH3:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH:8]2[N:9]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10](=[O:24])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)[C:12]([CH3:13])=[C:7]2[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:32][CH:31]=1)#[N:30]
Reactant: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 4-{5-(cyclobutylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 20) (29 mg, 0.066 mmol) and potassium carbonate (16.4 mg, 0.12 mmol) in dimethylformamide (1 ml) is treated with tert.-butyl bromoacetate (14.2 mg, 0.073 mmol), and then stirred at room temperature overnight (16 h). The reaction solution is quenched with water (3 ml) and extracted with diethyl ether (2×5 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
Reaction SMILES: [C:1]1([C:7](=[N:15][OH:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[Br:17][CH2:18][CH2:19][O:16][N:15]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCBr
Reactant: ON=C(Cc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: BrCCON=C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]([CH3:14])([CH2:8][CH2:9][C:10](Cl)([CH3:12])[CH3:11])[CH3:7].O.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>>[Br:16][C:17]1[C:18]([CH3:23])=[CH:19][C:20]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:6]([CH3:14])([CH3:7])[C:21]=2[CH:22]=1
Reactant: Cc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
30 ml of 2-bromotoluene and 14 g (0.11 mol) of AlCl3 were introduced into a three-necked flask, cooling was carried out to 0° C. and a solution of 50 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane in 100 ml of 2-bromotoluene was added dropwise, and the reaction mixture was permitted to heat to room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was separated by settling, washed with an aqueous sodium bicarbonate solution and evaporated. The product crystallized on stirring in methanol. After filtration, 56.9 g (75%) of 2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene, with a melting-point of 92°-93° C., were recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-])=O.O1CC[CH2:15][CH2:14]1>>[NH:1]1[C:4]2[C:12](=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][OH:8])[CH:15]=[CH:14]1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccccc1CCO
Product: OCCc1cccc2cc[nH]c12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Dissolve the brown oil in tetrahydrofuran (500 mL), add distilled water (100 mL), and cool the mixture to 15° C. Add 1M aqueous hydrochloric acid (100 mL), then stir at 15° C. for 2 hours. Add solid sodium hydrogen carbonate until the reaction mixture is basic, and saturate by adding solid sodium chloride. Separate, filter, and concentrate under reduced pressure to obtain 9.3 of a brown oil, which is a mixture of the title compound and 2-nitrophenethyl alcohol.
Reaction SMILES: [Li+].[BH4-].CO.[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11]>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCBr
Yield: 101.5 %

Procedure:
Under argon, a suspension of LiBH4 (14.8 g, 646 mmol) in methylene chloride (600 mL) was stirred as methanol (25.6 mL, 20.2 g, 629 mmol) was added dropwise, taking care to keep the temperature below 30° C. To this mixture, a solution of ethyl 5-bromo-2,2-dimethylpentanoate (100.0 g, 392 mmol; prepared according to Kuwahara et al. Chem. Pharm. Bull 1997, 48, 1447) in methylene chloride (200 mL) was added dropwise over 20 minutes, and the solution was heated under reflux for 21 h. After chilling in an ice-bath, the reaction was quenched by adding H2O dropwise (100 mL). After the effervescence stopped, 2 N HCl (125 mL) was added dropwise and the solution was stirred until the effervescence ceased. The procedure was repeated with another portion of 2 N HCI (125 mL). The layers were separated, and the aqueous layer was extracted with an additional methylene chloride (500 mL). The two organic portions were combined and washed with 2 N HCl 9300 mL), then sat. NaHCO3 (300 mL). After drying the organics over Na2SO4, the solution was evaporated to yield the product as a light yellow oil (77.6 g, 91% yield). 1H NMR (d6-DMSO), d (ppm): 4.42 (s, 1H); 3.45 (t, 2 H, J=6.6); 3.08 (s, 2H); 1.84-1.69 (m, 2H); 1.27 (t, 2 H, J=8.3); 0.78 (s, 6H). 13C NMR (d6-DMSO), d (ppm): 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=392.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7 and 3.5 Hz, 1H), 1.25 (td, J=8.0 and 4.7 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.27-2.33 (m, 1H), 2.67-2.72 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.8 and 6.2 Hz, 1H), 3.70 (s, 2H), 4.53 (s, 1H), 6.90 (s, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.4 Hz, 1H).
Reaction SMILES: CN1CCOCC1.[C:8]([NH:11][CH:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)(=[O:10])[CH3:9].C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([NH:34][C:13](=[O:15])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH2:16][CH:17]=[CH2:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C=CCC(NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CCC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 63.5 %

Procedure:
4-Methylmorpholine (0.55 g, 5.40 mmol) was added to a cooled (-10° to -15° C.) THF solution (60 mL) of 2-acetamido-4-pentenoic acid (0.81 g, 5.18 mmol), and then isobutylchloroformate (0.75 g. 5.70 mmol) was added leading to the precipitation of a white solid. After 2 min, a solution of benzylamine (0.61 g, 5.70 mmol) in THF (10 mL) was slowly added at -10° to -15° C. The reaction was allowed to warm (5 min) at room temperature and the insoluble salts were removed by filteration, and the filtrate was evaporated to dryness. The residue was triturated with EtOAc (10 mL), and the remaining white solid was filtered to give 0.81 g (64%) of the desired product: mp 118°-120° C. (recrystallized from ethyl acetate/cyclohexane); Rf 0.36 (4% MeOH/CHCl3); IR (KBr) 3200 (br), 3040, 2900, 1650 (br), 1540 (br), 1350, 750, 700 cm-1 ; 1H NMR (DMSO-d6) δ 1.83 (s, C(O)CH3), 2.22-2.49 (m, CH2CH=CH2), 4.26 (d, J=5.3 Hz, CH2Ph), 4.25-4.33 (m, CH), 4.99-5.09 (m, CH2CH=CH2), 5.65-5.77 (m, CH2CH=CH2), 7.21-7.29 (m, 5 PhH), 8.05 (d, J=7.6 Hz, NH), 8.46 (br s, NH); 13C NMR (DMSO-d6) 22.41 (C(O)CH3), 36.24 (CH2CH=CH2), 41.91 (CH2Ph), 52.20 (CH), 117.15 (CH2CH=CH2), 126.54 (C4'), 126.99 (2C2' or 2C3'), 128.04 (2C2' or 2C3'), 139.25 (C1'), 134.25 (CH2CH=CH2), 169.02 (C(O)CH3), 170.96 (C(O)NH) ppm; mass spectrum, m/e (relative intensity) 246 (M+, 4), 205 (4), 163 (15), 140 (8), 106 (33), 91 (77), 70 (100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=O)[NH:14][C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:11]([CH2:13][NH:14][CH2:15]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CNCC3C2)cc1
Yield: 60.7 %

Procedure:
To a suspension of 5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (3.88 g) in THF (80 mL) at −5° C. was added LiAlH4 (1.92 g) slowly. The reaction mixture was heated to reflux for 4 h, and then quenched with water, the mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 200:30:1 (v/v) DCM/MeOH/NH3H2O) to give the title compound as oil (2.07 g, 61.00%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].C(O)(=O)C.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1Cc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.13 mmole) prepared in analogy to experiment K1 in THF (1 ml) was added acetic acid (15 ul) followed by the addition of benzaldehyde (0.14 mmole) and stirring was continued at 22° C. for 1 h. Sodium triacetoxyborohydride (0.38 mmole) was added in one portion and stirring was continued at 22° C. for 3 h. The mixture was quenched with aqueous HCL and MeOH and the solution was purified by prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-benzenesulfonyl-1-benzyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colourless oil. MS: 384.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1

Procedure:
56.5 mg of solid white 3-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[N:9]=[CH:10]2.[CH3:19][NH:20][CH3:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[N:9]=[CH:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(CBr)cc12
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)ccc2cnc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-isoquinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in THF (50 mL) was added a 50% solution of dimethylamine in THF (20 mL). The reaction mixture was stirred for 30 min. at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 95:5) to afford the title compound as a yellow oil (445 mg, 1.52 mmol, 100%). MS (ES+): 293 (M(C15H1735ClN2O2)+H)+.