Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([O:9][C:10]([N:12]1[C@H:16]([CH3:17])[C@H:15]([CH2:18][OH:19])[C@H:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:13]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC>CS(C)=O>[CH2:2]([O:9][C:10]([N:12]1[C@H:16]([CH3:17])[C@H:15]([CH:18]=[O:19])[C@H:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:13]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1[C@H](CO)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 141.5 %

Procedure:
To a stirred and water-cooled solution of (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine (2.60 g, 5.90 mmol) and Et3N (5.70 ml, d0.726, 40.9 mmol) in DMSO (dried over molecular sieves 4, 36 ml) was added sulfer trioxide pyridine complex (SO3Py, Wako, 5.42 g, 34.1 mmol) portionwise. Just after the addition the water bath was removed, and the stirring was continued at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of ice and water (80 ml). The mixture was extracted with CH2Cl2 (30 ml×5). The combined CH2Cl2 extracts were washed with 10% citric acid aq. solution (30 ml×4) until the aqueous washing reached the acidity of citric acid (pH ca.3), H2O (30 ml×1), sat. NaHCO3 aq. solution (40 ml×1), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (3.66 g, quant.) as a pale yellow viscous oil; while the yield was overestimated owing to contamination with the solvent employed, this crude product solidified on standing in a refrigerator: IRmax (film): 3400(m, shoulder), 3350(m), 2720(w), 1710(vs), 1690(vs, shoulder), 1605(w), 1585(w), 1520(s), 1500(s), 1165(s), 770(m), 730(s), 700(s) cm-1 ; 1H-NMR δ: 9.65(d, J=3.7 Hz, 1H), 7.40-7.10(m, 9H), 7.05(br.s, 1H), 5.27(d, J=8.5 Hz, 1H), 5.06(br.s, 2H), 4.78-4.57(m, 1H), 4.24(dq, J=9.5, 6.1 Hz, 1H), 4.05(br.d, J=9.2 Hz, 1H), 2.77-2.50(m, 1H), 1.61(d, J=6.1 Hz, 1H), 1.37(s, 9H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH2:33][C:34]([OH:36])=[O:35])[CH2:38][C:39]([OH:41])=[O:40])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)CC(CC(=O)OC)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CC(=O)N2CCc3cc(C(CC(=O)O)CC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A stirred suspension of dimethyl 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-pentanedioate [270 mg, Reference Example 4(c)] in ethanol (10 ml) was treated with a solution of sodium hydroxide (190 mg) in water (2 ml) and the mixture stirred at reflux for 3 hours. After cooling to room temperature the mixture was treated with water (10 ml) and then carefully acidified to pH1 by the addition of hydrochloric acid (3M) with ice cooling. the resultant precipitate was collected by filtration, then dried and then recrystallised from ethyl acetate to give the title compound (60 mg) as a white crystalline solid. LC-MS: RT=2.44 minutes (100% total area by ELS); MS (ES+) 568 (MNa+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(N[C@H](C)[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N[C@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.9 %

Procedure:
Intermediate 80E (36 mg, 0.073 mmol) was dissolved in DCM (900 μL) and TFA (100 μL) was added. The mixture was stirred at rt for 10 h. The reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution (3×5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give the title compound 80F (27 mg): MS (ES) m/z 394.5 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(C)C(S(O)(=O)=O)=CC=C[CH:15]=1>C(O)C>[CH2:10]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[CH3:15]
Reactant: NCCCCCC(=O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CCOC(=O)CCCCCN
Yield: 204.7 %

Procedure:
A mixture of ε-aminocaproic acid (70.0 g, 533.8 mmol), toluenesulfonic acid (111.7 g, 1.1 eq.) and ethanol (1.6 L) was heated to reflux for 20 hours. Thereafter, TLC (CH2Cl2/EtOH/TEA, 85:10:5) revealed complete conversion. The reaction mixture was concentrated until solids started to precipitate. The precipitation was driven to completion by adding diethyl ether (1.5 L). The white solid was filtered, washed with diethyl ether, and dried in vacuo affording 174.0 g (98.3%) of a white powder. 1H NMR: (200 MHz, CDCl3): δ 7.47 (d, 2H, J=8.2 Hz), 7.10 (d, 2H, J=8.2 Hz), 4.02 (q, J=7.0 Hz), 2.79-2.65 (m, 2H), 2.28 (s, 3H), 2.25 (t, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz), 1.49 (dt, 4H, J=7.6, 7.0 Hz), 1.29-1.22 (m, 2H). 13C NMR: 173.4, 145.6, 138.8, 128.9, 126.1, 60.4, 39.4, 33.9, 27.3, 25.9, 24.6, 21.5, 14.8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Br[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[CH:33]=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:7]=[C:8]([C:31]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=2[CH:33]=[O:34])[C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-benzyloxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:31])([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:30])[C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:30])=[CH:13][CH:12]=1)([CH3:10])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(CC(=O)c2c[nH]c3ccccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)c1ccc(CC(=O)c2c[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.3 %

Procedure:
(2-Methyl-2-{4-[2-oxo-2-(4-oxo-1,4-dihydro-quinolin-3-yl)-ethyl]-phenyl}-propyl)-carbamic acid tert-butyl ester (88) (0.50 g, 1.15 mmol), TFA (5 mL) and CH2Cl2 (5 mL) were combined and stirred at room temperature overnight. The reaction mixture was then neutralized with 1N NaOH. The precipitate was collected via filtration to yield the product 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one as a brown solid (651 mg, 91%). HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 336.5 m/z (MH+).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=[O:18])=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C2=CCCC2)c(OCC2CC2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
The mixture of 5-cyclopentenyl-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (0.95 g, 4 mmol), Pd/C (10% w/w, 0.2 g) in 30 mL of ethanol in a hydrogen atmosphere was stirred for 4 h at room temperature. The mixture was filtered and the filtrate was evaporated to dryness to obtain the product (0.76 g, 79%) as white solid. The product was directly used for the next step; MS (LC/MS): 262.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([O:31]C)=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([OH:31])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2NCCCCN(C)C)ccc2c1OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CN(C)CCCCNc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Yield: 45.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 161, 0.485 g) and lithium hydroxide monohydrate (0.505 g) in dioxane (9 mL) and water (3 mL) was irradiated in the microwave at 130° C. for 45 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was triturated with 20% methanol in DCM, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant solid was triturated with ethyl acetate and filtered off to give (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.215 g) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[C:23]3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[C:23]3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:20][CH:21]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(C(=O)OCC)cc2-c2nnn[nH]2)cc1
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1-trityl-1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (115 mg), conc. hydrochloric acid (0.25 ml) and methanol (20 ml) was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give 2-butyl-3-[4-[4-ethoxycarbonyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (53 mg) as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13](Cl)=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.C([O:21][C:22](=[NH:37])[CH2:23][C:24]1[C:32]2[C:27](=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH3:36])[CH:25]=1)(C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:14])[NH:37][C:22](=[O:21])[C:23]=3[C:24]3[C:32]4[C:27](=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:36])[CH:25]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=N)Cc1cn(C)c2c([N+](=O)[O-])cccc12
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc(F)cc21
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4c([N+](=O)[O-])cccc34)C(=O)NC2=O)c2ccc(F)cc21

Procedure:
3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-7-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (6-Fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-7-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([OH:25])[CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[CH3:7][C:5]1[N:6]=[C:2]([N:22]2[CH:23]=[CH:24][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][C:21]2=[O:25])[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Oc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2ccc(-c3ccccc3)cc2=O)nc1C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.50 g, 2.00 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 4-phenylpyridin-2-ol (0.31 g, 1.80 mmol), copper(I) iodide (0.053 g, 0.28 mmol), 8-hydroxyquinoline (0.041 g, 0.28 mmol), and potassium carbonate (0.39 g, 2.80 mmol). The mixture was degassed and the flask was filled with nitrogen. The reaction mixture was heated at 100° C. for 6 hours and then diluted with ethyl acetate (25 mL), washed with 14% aqueous ammonium hydroxide (2×7 mL) and brine (7 mL). The organic layer was dried over anhydrous sodium sulfate, filtered concentrated in vacuo to afford as a yellowish solid (0.45 g, 66%): 1H NMR (300 MHz, DMSO-d6) δ 8.83-8.75 (m, 1H), 7.88-7.81 (m, 2H), 7.60-7.50 (m, 3H), 7.14-7.03 (m, 2H), 4.26 (q, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.28 (t, J=7.0 Hz, 3H); MS (ES+) m/z 341.6 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17](C4C=NNC=4C#N)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(=O)N(C1C=CC(N2CCOCC2)=CC=1)C1C2N(C=CN=2)C([Sn](CCCC)(CCCC)CCCC)=CN=1)(C)(C)C.Br[C:73]1[O:81][CH:76]2[CH2:77][NH:78][C:79](=[O:80])[CH:75]2[CH:74]=1>CN(C=O)C.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>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17]([C:73]4[O:81][C:76]5[CH2:77][NH:78][C:79](=[O:80])[C:75]=5[CH:74]=4)=[CH:18][N:19]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1NCC2OC(Br)=CC12
Reactant: N#Cc1[nH]ncc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Solvent: CN(C)C=O
Product: O=C1NCc2oc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4nccn34)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
In the same way as described for Compound 212, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (255 mg, 0.373 mmol), 2-bromo-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one (50 mg, 0.249 mmol) and Pd(PPh3)4 (29 mg, 0.0249 mmol) in DMF (3 mL). The reaction mixture is concentrated in vacuo and the residue dissolved in 1:1 DCM:TFA (drop of H2O) and stirred at room temperature for 3 hours. The mixture is partitioned between ethyl acetate and sat. NaHCO3 and the aqueous layer is extracted with ethyl acetate (3×). The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with DCM followed by a 97:3 mixture DCM:NH3 (7M in MeOH). The fractions containing the desired compound are concentrated in vacuo to give a solid which is triturated with diethyl ether to afford the title compound (66.3 mg, 64%). Conversion of the compound into the mesylate salt using 1M MsOH (0.16 mL) affords the title product as a solid (69.3 mg, 87%). LCMS: Rt 2.52 min (99%), m/z (APCI) 417 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.36 (3H, s, MsOH), 3.25 (4H, m), 3.84 (4H, m), 4.52 (2H, s), 7.18 (2H, br s), 7.40 (1H, s), 7.83 (1H, s), 7.90 (3H, m), 8.21 (1H, br s), 8.44 (1H, s), 10.25 (1H, br s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 1 A suspension of 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide (prepared according to Step 2 of Example 33-1, 168 mg, 0.528 mmol) and TEA (0.184 mL, 1.320 mmol) in THF (18 mL) was treated with acetic anhydride (0.080 mL, 0.845 mmol). The mixture was stirred at rt for 2 h, then was partitioned between EtOAc and 1 M hydrochloric acid. The organic phase was washed with NaHCO3 (aq) and brine, dried and concentrated to provide 7-(acetamidomethyl)-4-bromo-9H-carbazole-1-carboxamide as an off-white solid. Mass spectrum m/z 359.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5](=[CH2:29])[CH2:6][C@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH3:29])[CH2:6][CH:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid ethyl ester (2-a, R1=Boc, R2=H, R3=CO2Et) is added to ethanol (5 ml) at ambient temperature. Triethylamine (170 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-b, R1=Boc, R2=H, R3=CO2Et). Spectroscopic data as in Example 63. Ratio of diastereomers 70:30 (1-a, R1=Boc, R2=H, R3=CO2Et:1-b, R1=Boc, R2=H, R3=CO2Et) as determined by hplc (hplc method as in Example 65)
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:13].C(N(C(C)C)CC)(C)C.[Br:23][CH2:24][CH2:25]Br>CC#N>[Br:23][CH2:24][CH2:25][O:1][N:2]1[C:11](=[O:12])[CH2:10][C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3]1=[O:13]
Reactant: O=C1CC2(CCCC2)CC(=O)N1O
Reactant: BrCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2(CCCC2)CC(=O)N1OCCBr
Reaction time: 7 h

Procedure:
To a solution of 8-hydroxy-8-azaspiro[4.5]decan-7,9-dione (30 g) in 600 ml of dry CH3CN were added diisopropylethylamine (57 ml) and 1,2-dibromoethane (42.4 ml). The mixture was heated to 70° with stirring. After 7 hours, heating was discontinued and the mixture was stirred at room temperature for 48 hours.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15](O)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH3:15])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(=O)O
Solvent: O
Product: Cc1nnc2cnc3ccc(Br)cc3n12
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.84 mmol) and AcOH (5 mL) was refluxed overnight. After cooling to r.t., the mixture was treated with water (10 mL); the solid was collected on a filter and dried by vacuum to give 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as gray solid (200 mg, yield: 91.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([Li])CCC.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:46])=[C:35](OS(C(F)(F)F)(=O)=O)[CH:36]=3)[C:31](=[O:47])[C:30]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:29]2)[CH2:27][CH2:26]1>O1CCCC1.CCCCCC.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:46])=[C:35]([C:2]4[CH:3]=[C:4]([CH:12]5[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]5)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=4[O:8][CH3:9])[CH:36]=3)[C:31](=[O:47])[C:30]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:29]2)[CH2:26][CH2:27]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2c1=O
Reactant: COc1cc(C2OCC(C)(C)CO2)cc(Br)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C4OCC(C)(C)CO4)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 1.17 g of 2-(3-bromo-4,5-dimethoxy-phenyl)-5,5-dimethyl-1,3-dioxan (Example 6a)) in 10 ml of tetrahydrofuran is treated dropwise at -100° over 20 minutes with 2.2 ml of a 1.6M n-butyllithium solution in n-hexane. The solution is stirred for a further hour at -100° and then treated dropwise at this temperature with 7 ml of a 0.5M zinc chloride solution in tetrahydrofuran within 20 minutes. The reaction mixture is warmed slowly to 0° and stirred at this temperature for a further 1hr. The solution is then slowly added dropwise through a Teflon tube to a boiling mixture of 1 g of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[(trifluoromethyl)sulphonyl]oxy]quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)) and 20 mg of tetrakis-triphenylphosphine-palladium in 10 ml of tetrahydrofuran. The mixture is stirred at reflux temperature for a further 2 hrs. it is cooled to room temperature, diluted with 50 ml of ethyl acetate and washed with 50 ml of a saturated aqueous ammonium chloride solution, 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with ethyl acetate. 850 mg (68%) of ethyl 1-cyclopropyl-7-[5-(5,5-dimethyl-1,3-dioxan-2-yl)-2,3-dimethoxy-phenyl]-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate are isolated as a colourless solid. M.p. 178°-180° after recrystallization from ethyl acetate/n-hexane.