Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].II.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>ClCl.ClCCl.C(O)(=O)C.O1CCCC1.C(#N)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:10](=[O:12])[C@H:5]([CH2:6][CH2:7][S:8][CH3:9])[NH:4][C:1](=[O:3])[CH3:2])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: ClCl
Agent: II
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(C)=O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
A solution of 4.78 g (0.025 mol) of N-acetyl-L-methionine in CH2 Cl2 : acetonitrile (120 ml) was cooled to 0° C. To this solution was added 5.36 g (0.025 mol) of dicyclohexylcarbodiimide (DCC) followed by the rapid addition of 3.90 g (0.021 mol) of N-t-butoxycarbonylpiperazine in 6 ml of dichloromethane. The progress of the reaction was followed on silica gel TLC plates developed with 4:1 acetonitrile: tetrahydrofuran and visualized with either iodine or ninhydrin spray. The reaction was complete within 2 h. A few drops of glacial acetic acid were added to the reaction mixture and the solvent was removed on a rotary evaporator. The residue was taken up in ether and filtered. The clear filtrate was washed with dilute acid followed by dilute base. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give 8.2 g of 1-(t-butoxycarbonyl)-4-(N-acetyl-L-methionyl)piperazine, a colorless oil which required no further purification: IR (film) 3304, 3058, 2973, 2931, 2868, 1701, 1645, 1539, 1420, 1237, 1173 cm-1 ; NMR (CDCl3) δ 1.47 (s, 9 H), 1.80 (m, 2 H), 2.02 (s, 3 H), 2.10 (s, 3 H), 2.46 (m, 2 H), 3.53 (m, 8 H), 5.10 (M, 1 H), 6.35 (b, 0.5 H), 6.43 (b, 0.5 H).
Reaction SMILES: [OH:1][CH:2](CC#N)[CH2:3][C:4]#[N:5].CC[O:11][C:12]([CH3:14])=[O:13].Cl>N#N>[OH:1][C@H:2]([CH2:3][C:4]#[N:5])[CH2:14][C:12]([OH:11])=[O:13]
Reactant: CCOC(C)=O
Reactant: N#CCC(O)CC#N
Agent: Cl
Agent: N#N
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 22 h

Procedure:
3-hydroxyglutaronitrile (1 g, 9 mmol) was suspended in 37.5 mL of N2 (g) sparged, room temperature, 100 mM sodium phosphate buffer at pH 7. To this 240 mM solution of HGN was added 150 mg of cell lysate normalized for protein content. As assessed by PAGE, the nitrilase content was established to be 20% of the total protein. Therefore effectively, 30 mg of nitrilase is used in this reaction. The reaction was agitated at 100 rpm. Reaction progress was monitored by TLC (1:1 EtOAc:Hexanes, Rf=0.32, nitrile; Rf=0.0, acid) and GC. After 22 h, the reaction was filtered through a 10,000 MW cutoff filter and then concentrated in vacuo. The concentrated hydrolysis solution was acidified with 1M HCl and the product was continuously extracted with MTBE (30 mL). The acid product (R)-3-hydroxy-4-cyanobutyric acid was isolated as a yellow oil (1.15 g, 98% yield). 1H NMR (d6-DMSO, 500 MHz) δ 12.32 (s, 1H), 5.52 (s, 1H), 4.10 (m, 1H), 2.70 (dd, 1H, J=16.8, 4.1 Hz), 2.61 (dd, 1H, J=16.9, 6.3 Hz), 2.44 (dd, 1H, J=15.4, 5.3 Hz), 2.37 (dd, 1H, J=15.6, 7.8 Hz). 13C NMR (DMSO, 298K, 125 MHz) δ 171.9, 118.7, 63.4, 41.2, 25.2 MS calc'd for [C5H7NO3]: 129.0. found: 130.0 [M+H+], (ESI+). ee=95% [HPLC]. Based on the isolated yield a productivity of 40 g g−1 d−1 is calculated.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)cc1
Product: COc1ccc(Cc2nc3c(nnn3C(C)CCCc3ccccc3)c(=O)[nH]2)cc1

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.05 g (11.4 mmol) of methyl 4-methoxyphenylacetate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[NH:27][C:26]([CH:28]6[CH:33]7[CH2:34][CH:30]([CH2:31][CH2:32]7)[N:29]6[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:25][CH:24]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)O1.Br[C:44]1[NH:48][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:46][CH:45]=1.C([O-])(O)=O.[Na+]>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.COCCOC>[CH3:62][O:61][C:60]([NH:59][C@@H:55]([CH:56]([CH3:58])[CH3:57])[C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@H:49]1[C:47]1[NH:48][C:44]([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([C:23]5[NH:27][C:26]([C@@H:28]6[C@@H:33]7[CH2:34][C@@H:30]([CH2:31][CH2:32]7)[N:29]6[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[N:25][CH:24]=5)=[CH:15][C:14]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:45][N:46]=1)=[O:64])=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc([C@@H]5[C@H]6CC[C@H](C6)N5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: 120 °C
Yield: 88.2 %

Procedure:
To 1R,3S,4S)-tert-butyl 3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (97 mg, 0.17 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (67 mg, 0.18 mmol), Pd(PPh3)4 (10 mg, 0.009 mmol). DME (1.7 mL) was added and followed by 0.7 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide (1R,3S,4S)-tert-butyl 3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (110 mg, 88%). MS (ESI) m/z 734 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][N:5]([CH3:35])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[C:19]([CH3:32])=[CH:18][N:17]=2)=[C:8]([O:33][CH3:34])[CH:7]=1.[NH4+].[Cl-].C(Cl)Cl.CO>C(O)C.O.[Fe]>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:35])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[C:19]([CH3:32])=[CH:18][N:17]=2)=[C:8]([O:33][CH3:34])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[5-methyl-4-(1-methy-lindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (Intermediate 82, 202 mg, 0.41 mmol), iron (138 mg, 2.48 mmol) and NH4Cl (15.45 mg, 0.29 mmol) in ethanol (16 mL) and water (5.33 mL) was heated at reflux for 3 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) was then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed further with CH2Cl2 and CH3OH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% methanolic ammonia in CH2Cl2 gave the title compound (147 mg, 78%) as a yellow dry film; m/z: ES+ MH+ 460.36.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(F)(F)F)=[CH:18][C:17]=2[CH2:29][C:30](OC)=[O:31])(=[O:15])=[O:14])=[CH:10][C:5]2[B:6]([OH:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[OH-].[NH3:35]>CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:11]2[C:2]([F:1])=[CH:3][C:4]3[CH2:8][O:7][B:6]([OH:9])[C:5]=3[CH:10]=2)=[C:17]([CH2:29][C:30]([NH2:35])=[O:31])[CH:18]=1
Reactant: N
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Agent: [OH-]
Solvent: CO
Product: NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1cc2c(cc1F)COB2O
Temperature: 100 °C

Procedure:
To the solution of methyl 2-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (480 mg, 1 mmol) in methanol (5 ml), added ammonia hydroxide (2 ml), heated at 100° C. in a sealed tube overnight. The result mixture was concentrated, then dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as yellow solid. MS calcd for (C15H15BN3O5FS): 379.17. MS found (ESI negative): (M−H)−=378.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 9.20 (bs, 1H), 7.53 (d, J=8 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.13 (d, J=10.4 Hz, 1H), 7.04 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.29 (dd, J=8.8 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>CS(C)=O.C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=4)=[O:41])=[CH:28][CH:27]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)c1
Temperature: 85 °C
Yield: 100 %

Procedure:
After dissolving 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (919 mg, 2.5 mmol) in dimethylsulfoxide (10 ml), phenyl N-(3-(methylsulfonyl)phenyl)carbamate (801 mg, 2.75 mmol) was added and the mixture was heated at 85° C. for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with IN aqueous sodium hydroxide (10 ml), water (20 ml×2) and saturated brine (10 ml) and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the residue was suspended in ethyl acetate (30 ml), after which hexane (30 ml) was added, sonication was performed and the precipitated crystals were filtered out and dried under reduced pressure to obtain the title compound (1.43 g, 2.5 mmol, quantitative) as light brown crystals.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:35][CH2:36][CH2:37][F:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:38][CH2:37][CH2:36][CH2:35][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:2][CH2:3]1
Reactant: FCCCBr
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(CCCF)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one (50 mg) and 1-Bromo-3-fluoro-propane (18 mg) in DMF (1 mL) was added cesium carbonate (54 mg) and the mixture was stirred overnight. The crude mixture was purified by preparative HPLC. The product with the molecular weight of 509.63 (C29H36FN3O4) was obtained in this way; MS (ESI): 510 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.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>[N+:22]([C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC[C@H]1COc1cncc(-c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL), were added sodium carbonate (2.0 M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 3-nitrophenylboronic acid (250 mg, 1.50 mmol). The reaction mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (187 mg, 60%). MS (CI/NH3) m/z 314 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.72-1.97 (m, 3H), 2.03-2.14 (m, 1H), 2.30-2.47 (m, 1H), 2.53 (s, 3H), 2.67-2.80 (m, 1H), 3.12-3.22 (m, 1H), 4.00-4.15 (m, 2H), 7.43-7.46 (m, 1H), 7.63-7.70 (m, 1H), 7.88-7.94 (m, 1H), 8.25-8.31 (m, 1H), 8.38-8.51 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:22]2[CH2:23][CH2:24][CH2:25][C@@H:20]([OH:19])[CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O[C@@H]1CCCNC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(CCN2CCC[C@@H](O)C2)CC1

Procedure:
It is prepared analogously to 9 starting from tert-butyl ester 8 (3.52 g, 14.41 mmol), (R)-3-hydroxy-piperidine hydrochloride (2.18 g, 15.85 mmol), DIEA (5.6 ml, 33.14 mmol) and cyanomethyl-trimethyl-phosphonium iodide (4.2 g, 17.29 mmol).
Reaction SMILES: [NH2:1][C:2]1[N+:3]([O-:18])=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:13])[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])O.[K+].CN(C)C=O.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:5]([O:13][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[N+:3]=1[O-:18]
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
There were mixed 1.00 g of 5-amino-6-ethoxycarbonyl-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide, 1.18 g of potassium hydrogencarbonate (powder), 20 ml of dry dimethylformamide and 932 μl of benzyl bromide. The mixture was stirred for 16 hours at room temperature to effect a reaction. After completion of the reaction, the reaction mixture was poured into 50 ml of ethyl acetate. The resulting mixture was washed with 30 ml of water three times. The aqueous layer was extracted with 30 ml of ethyl acetate twice. The extract was combined with the above ethyl acetate layer. The combined solution was washed with 30 ml of water twice, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was recrystallized from ethanol to obtain 1.06 g of 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide (Compound B-10) as pale yellow fine needle-like crystals having a melting point of 114.5°-115.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH3:28].C(N(CC)CC)C.C(OC(C)(C)C)=O>O.CC#N.CC#N.O.C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[C:30]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH:15]([CH3:16])[CH3:17])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: CCc1ccc(C(=O)O)cc1OCCCOC
Agent: CC(C)(C)OC=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc1OCCCOC

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 22 mmol), 4-ethyl-3-(3-methoxy-propoxy)-benzoic acid (5.76 g, 24.2 mmol), BOPCI (6.16 g, 24.2 mmol) and triethylamine (12.3 g, 88 mmol). TLC, Rf (CH2Cl2/MeOH 95:5)=0.32. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 8.81 min. MS (LC-MS): [M+H-BOC]+507.3
Reaction SMILES: Br[CH:2]([CH2:13][C:14]([Cl:17])([Cl:16])Cl)[C:3]([CH3:12])([CH3:11])[CH:4]([C:9]#[N:10])[C:5]([O:7]C)=[O:6].[OH-].[K+]>CO>[C:9]([C:4]1([C:5]([OH:7])=[O:6])[C:3]([CH3:11])([CH3:12])[CH:2]1[CH:13]=[C:14]([Cl:16])[Cl:17])#[N:10]
Reactant: COC(=O)C(C#N)C(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1(C#N)C(=O)O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Methyl 4-bromo-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoate (64.0 g, 0.166 m) was added over a period of 25 minutes to a suspension of potassium hydroxide (120.0 g, 1,8 m) in methanol (2100 ml) at 20° C. The mixture was then stirred for 1 hour at 35° C. and subsequently heated under reflux for 2.5 hours. The solvent was then removed under reduced pressure and the residue was dissolved in water (1500 ml). The aqueous phase was washed once with dichloromethane and acidified with concentrated hydrochloric acid to about pH 1. The mixture was then extracted three time with dichloromethane and the extracts were dried. The solvent was removed under reduced pressure to yield the required acid 1-cyano-2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid, as a white crystalline solid (m.p. 128°-132° C., yield 37.6 g, 97%). The NMR spectrum of the compound measured at 60 MHz in deuterochloroform solution showed the following absorptions relative to a tetramethylsilane standard. On the basis of the spectrum it was established that the product consisted of two geometric isomers, Z and E, in the ratio Z:E=56:44.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9]C=O)[CH:5]=[CH:6][CH:7]=1.[ClH:18]>>[ClH:18].[NH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=CNC(c1ccccc1)c1cccc(O)c1
Agent: Cl
Product: NC(c1ccccc1)c1cccc(O)c1
Yield: 97.9 %

Procedure:
Methanol (125 mL), was cooled to 0° C., and acetyl chloride (17.8 mL) added dropwise to give a 2M solution of methanolic hydrogen chloride. N-((3-hydroxyphenyl)-(phenyl)methyl)formamide was stirred at 40° C. for 1.5 hours with the 2M methanolic hydrogen chloride. The solvent was removed under reduced pressure and the residue re-dissolved in methanol and the solvent removed under reduced pressure. This process was repeated three times to give the title compound (29.09 g, 97.9%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH:16]=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][C:20]=1[O:23][CH3:24])[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1)=[CH:16]2
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(NC(C)=O)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 434(MH+).
Reaction SMILES: C(=O)([O-])OC[C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[C:5]=1[CH:13]=[O:14].[OH-:17].[Na+]>CO>[Br:12][C:6]1[C:5]([CH:13]=[O:14])=[C:4]([OH:17])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(Br)c(C=O)c1COC(=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)c(C=O)c1O
Temperature: 25 °C

Procedure:
A solution of 3-bromo-2-formyl-6-methoxyphenylmethyl carbonate (100 g, 0.34 mole), 500 mL 10% aqueous NaOH, and 2 L MeOH was stirred at reflux for 2 hours. After cooling to room temperature, the MeOH was removed (in-vacuo). The aqueous solution was cooled to 0° and acidified with concentrated HCl. The solid was filtered, washed with water, and dried (in-vacuo) to yield 107 g yellow solid which was recrystallized from 2-propanol to yield 62 g yellow solid; mp 95°-6°; M+ 230.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)CO.CCOC(C)=O>[CH2:18]([NH:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCCCN
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) in dry ethylene glycol (2.3 mL) was added 1-pentylamine (689 mg). The solution was stirred at reflux (120° C.) overnight. The reaction was cooled, taken up in EtOAc (30 mL) and washed with water (2×20 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a viscous brown oil (561 mg).