Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(C)C.C(O)(C(F)(F)F)=[O:27]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(=[O:27])[CH3:5]
Reactant: O=C(O)C(F)(F)F
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Product: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A 20 mL vial with stir bar was charged with 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (850 mg, 2.44 mmol) and TFA (9.8 mL). The solution was heated to 65° C. After 3 h, the reaction was judged complete. The mixture was concentrated under reduced pressure; the resulting residue was taken up in CH2Cl2 and loaded onto a prepacked 25g silica gel cartridge. The product was purified by chromatography on a prepacked 80g silica gel column eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. The product containing fractions were combined and concentrated to provide 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (616 mg, 86%): 400 MHz 1H NMR (CDCl3) δ 8.00-7.94 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J=6.1 Hz, 2H), 2.69-2.64 (m, 2H), 2.63 (s, 3H), 2.21-2.09 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][N:13]([CH3:19])[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:7]1[C:8]2[C:3](=[C:2]([N:16]3[CH2:17][CH2:18][C@H:14]([N:13]([CH3:19])[CH3:12])[CH2:15]3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][N:6]=1
Reactant: Brc1cccc2cnccc12
Reactant: CN(C)[C@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)[C@H]1CCN(c2cccc3c2CCN=C3)C1
Temperature: 85 °C
Yield: 82.3 %

Procedure:
To 5-bromoisoquinoline (0.60 g, 2.88 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (0.428 g, 3.75 mmol), Pd2(dba)3 (0.053 g, 0.058 mmol), BINAP (0.072 g, 0.115 mmol), and sodium tert-butoxide (0.39 g, 4.04 mmol) was added degassed toluene (10 mL) and the mixture was heated to 85° C. overnight. The reaction mixture was dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. This intermediate was reduced and then, oxidized as described in Example 1 to afford 206A (577 mg, 82%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-pentanoic acid (0.30 g, 0.53 mmol) prepared in Example 128 was mixed with N-hydroxysuccinimide (64 mg, 0.56 mmol), N,N-dimethylformamide (5 ml) and WSC (113 mg, 0.59 mmol), followed by stirring overnight at room temperature. To the resulting mixture, tetrahydrofuran (5 ml) and sodium borohydride (61 mg, 1.6 mmol) were added and stirred at room temperature for 4 hours. The reaction mixture was poured into 10% citric acid, extracted with ethyl acetate, washed with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/10) to give the titled compound (0.17 g, yield: 59%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].[Cl-].[NH4+]>O1CCCC1>[C:16]([CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([OH:18])=[O:17]
Reactant: COC(=O)CN1CCN(c2ccc(C#N)cc2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(CC(=O)O)CC2)cc1
Reaction time: 3 h

Procedure:
To 3 g of 1-(4-cyanophenyl)-4-(methoxycarbonylmethyl)-piperazine in 46 ml of tetrahydrofuran 58 ml of a 1 molar aqueous lithium hydroxide solution are added, at ambient temperature and with stirring, and the reaction solution is left to stand for 3 hours at ambient temperature. Then 3.2 g of ammonium chloride are added and the tetrahydrofuran is distilled off under reduced pressure. The precipitate is suction filtered, washed with water and dried. Yield: 2.2 g (77% of theory), Melting point: over 300° C. Rf value: 0.18 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: CC(=CC)C.B.[O:7]1CCCC1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C:22](=[CH2:24])[CH2:21][CH:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+].OO>O1CCCC1.O>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH2:24][OH:7])[CH2:21][CH:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C1CCOC1
Reactant: C=C1CC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: B
Agent: CC=C(C)C
Agent: OO
Solvent: O
Product: CC(C)(C)OC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-2-butene (2M in tetrahydrofuran, 30 ml, 60 mmol) in anhydrous tetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 30 ml, 30 mmol) dropwise over 10 minutes and allowed to stir for 2 hours. The reaction mixture was cooled to −20° C. and a solution of 4-methylene-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (2.84 g, 10 mmol) (CAS reg 163 190-46-3) in tetrahydrofuran (20 ml) was added dropwise and stirred to room temperature over 18 hours. Water (40 ml) was added cautiously followed by sodium hydroxide (0.5M, 20 ml) then hydrogen peroxide (27.5% w/w in water, 10 ml) and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure and the aqueous extracted with ethyl acetate (2×60 ml). The combined extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 40% ethyl acetate/heptane to give the title compound as a mixture of diastereomers (˜5:1 2S,4S:2S,4R) as a colourless oil (1.25 g, 41%)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([NH:21]C(=O)OC(C)(C)C)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:6]=[CH:5][N:4]=1.[ClH:30].C(OCC)C>ClCCl.O1CCOCC1>[ClH:30].[NH2:21][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:18]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:2]([CH3:1])[CH3:29])[N:8]=2)[CH:10]=1
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(N)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl (3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)carbamate (140) (261 mg, 0.66 mmol) in dichloromethane (5 ml) was added 4 M hydrochloric acid in dioxane (2 ml). The mixture was stirred at room temperature for 24 hours. Diethylether (100 ml) was added and the solid filtered off and dried under vacuum to give 4-(4-amino-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (141) as a yellow solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH3:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CCCCCC>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH2:26][CH3:27])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
2,6-Difluoro-3-nitropyridine (Recl. Trav. Chim., 95, 127-156 (1976) and Tetrahedron Lett., 28, 111-114 (1987), 2.4 g, 15.0 mmol) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 3.3 g, 15 mmol) are dissolved in 37.5 mmol of acetonitrile at 0°. Then solid potassium carbonate (2.49 g, 18 mmol) is added and the reaction is slowly warmed to 20°-25°. After the reaction is complete by TLC (ethyl acetate/hexane, (25/75)), it is poured into water and extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and concentrated under reduced pressure. Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, mp=99°-100°; NMR (300 MHz, CDCl3) 8.00, 7.13-7.04, 6.02, 3.43, 3.31, 3.28, 2.77, 1.85, 1.71, 1.63 and 0.86δ; CMR (75 MHz, CDCl3) 163.5, 160.2, 151.2, 140.9, 130.4, 128.9, 128.0, 126.9, 96.9, 62.6, 59.6, 52.9, 38.7, 29.3 and 14.0δ.
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[NH:23][CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[N:23]([C:40](=[O:41])[CH2:39][C:36]5[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=5)[CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CC3COCCN3c3nc(-c4cccc5c4ccn5[Si](C)(C)C(C)(C)C)ncc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
2-(1-(tert-Butyldimethylsilyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x12, 42 mg, 0.100 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. 2-(4-Methoxyphenyl)acetyl chloride (0.018 mL, 0.120 mmol) was added, followed by triethylamine (0.028 mL, 0.199 mmol) to give a yellow solution. The reaction mixture was stirred for 2 hours at 0° C. The solvent was subsequently removed in vacuo and the resulting concentrate was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (42 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 0.64 (s, 6H), 0.89 (s, 9H), 3.02-3.22 (m, 4H), 3.42-3.61 (m, 2H), 3.66-3.78 (m, 3H), 3.87-3.92 (m, 2H), 3.91-3.98 (m, 1H), 4.30-4.47 (m, 1H), 4.64-4.75 (m, 1H), 6.79-6.93 (m, 2H), 7.00-7.30 (m, 3H), 7.42-7.51 (m, 2H), 7.61-7.68 (m, 1H), 8.02-8.07 (m, 1H), 8.32-9.02 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C32H39N5O3Si, 570.28. found 570.6.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:10])[N:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:10][N:3]1[C:2]([CH:11]=[CH2:12])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=[N:4]1
Reactant: C=C[B-](F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c([N+](=O)[O-])cnn1C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Nitrogen was bubbled through a solution of 3-chloro-2-methyl-4-nitro-pyrazole (16 g, 100 mmol), potassium vinyltrifluoroborate (18 g, 134 mmol) and cesium carbonate (3.7 M in water, 50 mL, 190 mmol) in DMF (100 mL). 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (900 mg, 1.10 mmol) was added and degassing continued for 30 min. The reaction mixture was heated at 110° C. for 18 hr. More 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (900 mg, 1.10 mmol) was added and heating continued for 24 hr. More 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (400 mg, 0.49 mmol) was added and heating continued for 4 hr. The reaction was cooled to room temperature and brine (200 mL) and EtOAc (500 mL) were added. The organic layer was washed with water (4×300 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-40% EtOAc/isohexane) gave 1-methyl-4-nitro-5-vinyl-1H-pyrazole as a colourless solid (9.1 g). Through a solution of this solid (9.1 g, 59 mmol) in DCM (400 mL) cooled to −78° C. was bubbled ozone. When the solution turned blue, ozone addition was stopped. Nitrogen was passed through the solution until the blue colour was discharged. The mixture was allowed to warm to room temperature and flushed with nitrogen for 15 min Anhydrous dimethyl sulfide (5 mL) was added and the mixture warmed to room temperature. After stirring for 12 hr, the solvents were removed under reduced pressure. DCM (150 mL) was added and the mixture was washed with water (50 mL). The aqueous layer was extracted with DCM (3×100 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over Na2SO4 and concentrated to give 2-methyl-4-nitro-pyrazole-3-carbaldehyde as a yellow-orange solid (6.6 g, 43% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.11 (s, 1H), 4.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37]>CN(C)C=O.C(OCC)(=O)C.ON1C2C=CC=CC=2N=N1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)Nc1ccccc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.97 g), (Peschke, Bernd; Ankersen, Michael; Hansen, Birgit Sehested; Hansen, Thomas Kruse; Johansen, Nils Langeland; Lau, Jesper; Madsen, Kjeld; Petersen, Hans; Thogersen, Henning; Watson, Brett. Eur. J. Med. Chem. (1999), 34(5), 363-380) in dimethylformamide (8.0 ml) was treated sequentially with EDC.HCl (0.76 g), 2-aminophenol (0.43 g) and 1-hydroxybenzotriazole (0.05 g). The mixture was stirred for 2 h, diluted with ethyl acetate and washed with water, dried (MgSO4) and solvent removed at reduced pressure to give the title compound (1.29 g) as a gum.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]#[N:14])=[O:10])=[CH:3][CH:2]=1.B.CSC.O.[ClH:20]>O1CCCC1>[ClH:20].[C:9]([NH:11][CH2:12][CH2:13][NH2:14])([O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:10]
Reactant: N#CCNC(=O)OCc1ccccc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Under an atmosphere of dry argon, 24.3 g (0.128 mol) of N-CBZ-aminoacetonitrile (1e) was dissolved in anhydrous tetrahydrofuran (32 ml). The solution was stirred and 64 ml of borane-methylsulfide complex (2M in tetrahydrofuran) was added via syringe. The mixture was heated to reflux and stirred overnight. The mixture was cooled with an ice bath as 5 ml of water was added slowly, with vigorous stirring. The stirring was continued for ca. 5 minutes, then 75 ml of 6M HCl was slowly added. The mixture was stirred for 1 hour, then the excess tetrahydrofuran and dimethyl sulfide was removed in vacuo. The aqueous residue was extracted with ether (2×50 ml). The ether extracts were then discarded. The pH of the aqueous residue was raised to 11 by adding concentrated NH4OH. The resulting aqueous solution was extracted with ethyl acetate (3×100 ml) and the ethyl acetate extracts were combined and washed with brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo. The resulting oil was dissolved in 30 ml of anhydrous methanol, treated with cold methanolic HCl and concentrated in vacuo to produce a solid. The solid was triturated with ether and collected by filtration to give 15.1 g (51% yield) of N-CBZ-ethylenediamine hydrochloride (1f) as a white powder. 1H NMR(D2O) δ 3.15(m, 2H), 3.46(m, 2H), 5.14(s, 2H), 7.46(bs, 5H); 13C NMR (D2O) δ 41.1, 42.6, 70.4, 131.0, 131.3, 131.7, 132.0, 139.4, 161.7.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=[O:23].[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:14][CH:13]=2)=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=[O:23]
Reactant: CC(C)N
Reactant: Cn1c(-c2ccc(OCC3CO3)cc2)cc2ncccc2c1=O
Product: CC(C)NCC(O)COc1ccc(-c2cc3ncccc3c(=O)n2C)cc1
Yield: 92 %

Procedure:
6-Methyl-7-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1,6-naphthyridin-5(6H)-one was prepared analogous to Example 1b from 6-methyl-7-[4-(2,3-epoxypropoxy)-phenyl]-1,6-naphthyridin-5(6H)-one and isopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](Cl)=[N:10][C:4]=2[CH:3]=1.[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:30]3[CH2:31][CH2:32][N:27]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCN1CCNCC1
Reactant: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCCN1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CC1

Procedure:
The mixture of 8, 11-dichlorodibenz[b,f][1,4]oxazepine (0.32 g, 1.19 mmol), 1-nonylpiperazine (0.38 g, 1.79 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.72 mL, 0.73 g, 4.77 mmol) in acetonitrile (15 mL) was heated at reflux for 6 h. After the mixture was concentrated, water (20 mL) and ethyl acetate (20 mL) were added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried over magnesium sulfate and filtered. The filtrate was then concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The title compound was obtained as a white solid (0.15 g, 28%), m.p. 64°-66° C., MS 440 (M+ +1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[CH2:12][N:13]2[C:17](=[O:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[S:14]2(=[O:24])=[O:23])[CH:6]=1>CN(C=O)C>[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH2:12][NH:13][S:14]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]([O:2][CH3:1])=[O:18])(=[O:24])=[O:23])=[O:25])[CH:6]=1
Reactant: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1S(=O)(=O)NCC(=O)Nc1cc(C)on1
Yield: 74.4 %

Procedure:
To 60 ml DMF is added 13.5 grams (0.25 mole) of sodium methoxide. To this slurry at 15° C. is added a solution of 20 grams (0.062 mole) of 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide dissolved in 70 ml DMF. The reaction mixture is stirred at 25°-30° C. for a half hour whereupon it is acidified and extracted with chloroform. These extracts are washed with sodium bicarbonate and water, dried (Na2SO4) and concentrated to an oil which is triturated with petroleum ether to give 16.3 grams (75%) of methyl 2-{[({[(5-methyl-3-isoxazolyl)amino]carbonyl}methyl)amino]sulfonyl}benzoate, mp 153°-156° C.
Reaction SMILES: C[C:2]1[C:3]([I:15])=[C:4]([O:13][CH3:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:14][O:13][C:4]1[C:5]([I:12])=[C:6]([C:10]([I:11])=[CH:2][C:3]=1[I:15])[C:7]([Cl:19])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(I)c(C)c(I)c(C(=O)O)c1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(I)cc(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL round-bottom flask equipped with a condenser, methyl 3-methoxy-2,4,6-triiodobenzoic acid (0.250 g) was suspended in 3 mL anhydrous methylene chloride. Oxalyl chloride (0.58 mL) and one drop of DMF was added. The reaction mixture was stirred for 4 h at RT. The solvent and excess oxalyl chloride were removed by rotary evaporation. The desired acyl chloride was dried under vacuum to give a pale yellow solid which was used in the next step without any further purification. Yield 0.272 g (crude ˜100%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([OH:16])=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1ccc2ccc(Cl)cc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)O)n1ccc2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of (S)-2-(7-chloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid, tert-butyl ester (322 mg) in dichloromethane (14 ml) was cooled to 0° C. Trifluoroacetic acid (3.5 ml) was added and the resulting mixture allowed to warm to room temperature and stirred for 2 hours. The mixture was then concentrated under reduced pressure and the residue re-dissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the sub-title product as a white solid (236 mg, 89%). m.p. 159.6-160.1° C.; [α]24D −47.0° (c=1.01, CHCl3); IR (solid) 1731.4, 1639.3, 1577.8, 1209.1, 1168.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.82 (3H, t), 2.00-2.25 (2H, m), 5.20 (1H, m), 6.70 (1H, d), 7.49 (1H, d), 7.70-7.81 (2H, m), 8.18 (1H, s) ppm; 13C NMR (100 MHz, d6-DMSO) δ 10.8, 22.7, 60.8, 104.9, 126.5, 126.6, 128.8, 131.6, 132.5, 133.1, 135.8, 160.5, 171.7; MS ES (+) 266.27 (M+H).