Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.O[CH2:12][CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:25])([O:21][CH:22]([CH3:24])[CH3:23])[O:17][CH:18]([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][CH2:13]/[CH:14]=[CH:15]/[P:16]([O:21][CH:22]([CH3:23])[CH3:24])([O:17][CH:18]([CH3:19])[CH3:20])=[O:25]
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)ncnc21)OC(C)C
Temperature: 0 °C
Yield: 37.2 %

Procedure:
To a mixture of 6-chloropurine (414 mg, 2.67 mmol), diisopropyl (E)-4-hydroxybut-1-enylphosphonate (630 mg, 2.67 mmol) and triphenyl phosphine (1.05 g, 4.00 mmol) in dry tetrahydrofuran (30 ml) stirred at 0° C. was added diethyl azodicarboxylate (0.70 g, 4.02 mmol). The mixture was allowed to warm to room temperature and stirred for 27.5 hr. The solvent was removed and the residue Was purified by column chromatography on silica gel eluting with dichloro-methane-methanol (24:1, 13:1) to give (E)-6-chloro-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine as a white solid (0.37 g, 37%), m.p. 105° C.; λmax (EtOH) 266 (9,260)nm; υmax (KBr) 3435, 2980, 1590, 1560, 1330, 1230 and 1210 cm-1 ; δH (CDCl3) 1.25 (12H, dd, J 6 Hz and 21 Hz, CH(CH3)2), 2.88 (2H, m, CH2), 4.45 (2H, t, J 7 Hz, CH2N), 4.55 (2H, m, CH(CH3)2), 5.68 (1H, dd, J 17 Hz and 20 Hz PCH=CH), 6.70 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH), 8.10 (1H, s, H-2/H-8), 8.77 (1H, s, H-2/H-8); FABMS (thioglycerol) 373 (MH+) (Found: C, 48.40; H, 6.03; N, 14.81%. C15H22ClN4O3P requires C, 48.33; H, 5.95; N, 15.03%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Li+].CC([N-]C(C)C)C.[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[C:29]([CH3:33])([CH3:32])[CH:30]=O.O>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:33]\[C:29]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[F:20])([CH3:30])[CH3:32]
Reactant: COc1cccc(C(C)(C)C=O)c1F
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: COC(=O)/C=C\C(C)(C)c1cccc(OC)c1F
Reaction time: 0.75 h
Yield: 83 %

Procedure:
20.26 g (111.26 mmol) of phosphonoacetic acid trimethyl ester is introduced into 68 ml of tetrahydrofuran. At 0° C., 61 ml of a 2 M solution of LDA in THF/heptane/ethylbenzene is added in drops. After 45 minutes of stirring, 21.83 g (111.26 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanal, dissolved in 68 ml of tetrahydrofuran, is added in drops at 0° C. After stirring overnight, the reaction mixture is mixed with water while being cooled in an ice bath, and it is extracted three times with methyl tert-butyl ether. The combined organic extracts are treated as usual, and the residue that is obtained is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 23.30 g (75.8%) of the desired compound is isolated.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:20]4[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=4)[N:11]([CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:32][N:31]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(C1CCOCC1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(C2CCOCC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-1-isopropyl-4-oxo-5-(tetrahydro-pyran-4-yl)-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AU) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 0.98 min (HPLC 3); ESI-MS: tR=0.92 min, [M+H]+ 488 (LC-MS 1); TLC: Rf=0.20 (EtOAc).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([N+:26]([O-])=O)=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1[N+](=O)[O-])c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)-3-nitropyridine-2,6-diamine (Example 26; 0.40 g, 1.05 mmol) and zinc dust (0.342 g, 5.23 mmol) in MeOH-THF (1:1, 16 ml) was slowly added a saturated aqueous ammonium chloride solution (2.5 ml). The mixture was stirred at 25° C. for 1 hr, then treated with saturated ammonium acetate solution (4 ml). The resulting mixture was stirred for another 30 min. The Zn dust was removed by filtration and the cake was washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. Removal of the solvent gave the title compound at quantitative yield. 1H NMR (400 MHz) δ 11.5 (br, 1H), 7.98 (br, 1H), 7.43 (m, 2H), 7.07 (m, 2H), 6.67 (d, J=8 Hz, 1H), 6.09 (s, 1H), 5.63-5.70 (m, 2H), 5.19 (m, 1H), 4.04 (br, 2H), 1.77 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 0.85 (m, 2H), 0.59 (m, 2H). MS: Calcd.: 352. Found: [M+H]+ 353.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([NH:7][CH:8]1[CH2:12][O:11][C:10](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:6])[CH3:3].S(Cl)(Cl)=O>>[CH3:3][C:2]([CH3:18])([O:4][C:5]([NH:7][CH:8]1[CH2:12][O:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9]1)=[O:6])[CH3:1]
Reactant: COC(=O)C1(O)CC(NC(=O)OC(C)(C)C)CO1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CO1

Procedure:
The process of claim 1, wherein in step (g) methyl 4-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxytetrahydrofuran-2-carboxylate is reacted with thionyl chloride to produce methyl 4-[[(1,1-dimethylethoxy)carbonyl]amino]-4,5-dihydro-2-furan-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:33]1([CH2:32][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=2[CH:10]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]2)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Product: COc1cccc(OCC2CC2)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available (bromomethyl)cyclopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.86 min.; [M+H]+: 449.76 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCC/C=C\c1cccc(Cl)c1
Yield: 95 %

Procedure:
To a stirred suspension of (Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione (8.4 g, 27 mmol) in ethanol (100 mL) at ambient temperature was added hydrazine monohydrate (65%, 2.6 mL, 54 mmol). The resulting mixture was stirred and heated to reflux, and a yellow solution formed upon attaining reflux. About 10 minutes after reflux began, a precipitate formed in the reaction mixture. After a total of 35 minutes at reflux, the precipitate nearly filled the flask, and the heat was removed. On reaching ambient temperature, the reaction mixture formed a solid mass. The mass was dissolved by adding of 2M sodium hydroxide (100 mL). The resulting solution was concentrated to remove most of the ethanol. The remaining cloudy mixture was extracted with ethyl acetate (100 mL). The aqueous layer turned into a gel and the organic layer was decanted away. The organic layer was washed with water (50 mL), then dried over sodium sulfate and concentrated to afford (Z)-4-(3-chlorophenyl)but-3-en-1-amine as a light brown oil (4.66 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]([NH:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.C(O)C>[C:41]([NH:44][C:45]1[CH:50]=[C:49]([C:13]2[N:12]=[C:11]3[N:17]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:26][CH2:25]5)=[CH:22][CH:23]=4)[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]3=[CH:15][CH:14]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c3n2)c1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (3.0 g) in toluene (100 mL) and ethanol (100 mL) was added saturated aqueous sodium bicarbonate (15 ml) and (3-acetamidophenyl) boronic acid (2.18 g). The reaction was degassed for 5 minutes and Pd(PPh3)4 (0.300 g) was added. The reaction was again degassed for 5 minutes with nitrogen and then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, dichloromethane (250 ml) and water (100 ml) were added to the reaction. The organics were separated, the aqueous washed with dichloromethane (1×100 ml) and the organics combined. The organics were washed with saturated sodium bicarbonate (1×100 ml) and brine (1×100 ml). The organics were dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-10% methanol in dichloromethane) gave the product as a brown solid with some co-eluting impurities. The fractions with the product were combined and concentrated to give a dark brown solid. The solid was triturated with ethyl acetate to give a tan solid (2.6 g, 70%). 400 M Hz 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.11 (bs, 1H), 7.99 (dd, J=5.2 Hz and 2.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72-7.63 (m, 3H), 7.55-7.51 (m, 2H), 7.46-7.42 (m, 6H), 7.39-7.34 (m, 1H), 7.14-7.06 (m, 1H), 7.02 (s, 2H), 6.32 (dd, J=7.6 Hz and 4.8 Hz 1H), 2.48-2.40 (m, 4H), 2.07-1.98 (m, 4H), 1.89-1.79 (m, 1H), 1.38-1.12 (m, 9H); LCMS: 590 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.CN([C:14]([O:18][N:19]1N=NC2C=CC=C[C:20]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.COCN>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]([O:18][CH3:14])[CH3:20])=[O:7])=[CH:4][N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: COCN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 6-chloronicotinic acid (2.0 g, 12.7 mmol) in DMF (20 mL) was added TBTU (6.11 g, 19.0 mmol), di-iso-propylethylamine (4.9 g, 38.1 mmol), and N-methoxymethylamine hydrochloride (1.48 g, 15.2 mmol). The reaction mixture was stirred at 25° C. overnight. The reaction solution was poured into brine (40 mL) and extracted with ethyl acetate (40 mL*2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 6-chloro-N-methoxy-N-methylnicotinamide (2.3 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=2.0 Hz, 1H), 7.95 (dd, J=2.4, 8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 3.49 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][NH:7]1)=[O:5])C.CC1(C)CCNC1C(O)=O.C(C1(C(OCC)=O)C(C)(C)CCN1)(OCC)=O>>[C:11]1([CH:10]2[CH2:9][CH2:8][NH:7][CH:6]2[C:4]([OH:5])=[O:3])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1c1ccccc1
Agent: CC1(C)CCNC1C(=O)O
Agent: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Product: O=C(O)C1NCCC1c1ccccc1

Procedure:
3-Phenyl-D,L-proline was prepared from diethyl-3-phenylpyrrolidine-2,2-dicarboxylate (2.82 g, 9.70 mmol) essentially according to the procedure described in U.S. Pat. No. 4,060,603 for the preparation of 3,3-dimethyl-D,L-proline from 2,2-dicarboethoxy-3,3-dimethylpyrrolidine. The product was isolated as a brown oil. LCMS RT=0.62 min. LCMS (M+H)=191.9. 1H NMR (CD3OD, 400 MHz): δ 7.36-7.28 (m, 5H), 4.60 (d, J=9.2 Hz, 1H), 3.97 (apparent q, J=8.4 Hz, 1H), 3.77-3.71 (m, 1H), 3.48-3.41 (m, 1H), 2.58-2.50 (m, 1H), 2.43-2.33 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:13]1[CH:14]=[C:10]([C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[NH:25][N:24]=2)[NH:11][CH:12]=1
Reactant: NN
Reactant: O=C(c1cc(-c2c(Cl)cccc2Cl)c[nH]1)c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: Clc1cccc(Cl)c1-c1c[nH]c(-c2n[nH]c3ncccc23)c1

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-[4-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone (150 mg) from above and hydrazine hydrate (0.5 mL) in ethanol (7 mL) was heated at 90–100° C. for overnight. The reaction was concentrated, the residue was washed with water, dried and triturated with ethyl acetate-hexane mixture to give 71 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cnc(Cl)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper(I) iodide (25 mg) and bis-(triphenylphosphine)-palladium(II)-chloride (30 mg) are added to 6-chloro-4-iodo-pyridin-3-ol (200 mg) in N,N-dimethylformamide (3 mL) under Ar atmosphere at room temperature. Triethylamine (110 μL) is added and the resulting mixture is stirred at room temperature for 1 h. 4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester (175 mg) dissolved in N,N-dimethylformamide (2 mL) is added dropwise and the mixture is stirred at 55° C. for 3 h. The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30) to give the title compound. LC (method 2): tR=1.40 min; Mass spectrum (ESI+): m/z=337/339 (Cl) [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CO.ClCCl>C(#N)C>[N:26]1([CH2:6][CH2:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)=[CH:12][CH:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3ccc(C#CCCOS(C)(=O)=O)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: Cc1ccn2cc(-c3ccc(C#CCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
The product of Step C (1.00 g) in acetonitrile (15 mL) was treated with piperidine (0.269 g) and potassium carbonate (1.17 g) and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to give crude product. Silica gel chromatography (methanol/dichloromethane) afforded the title compound (1.0 g). MS (ESI) m/z 344.1 (M+H+). 1H NMR (DMSO) δ 8.23 (d, J=6.95 Hz, 1H), 8.15 (s, 1H), 7.73 (d, J=8.37 Hz, 2H), 7.25 (d, J=8.34 Hz, 2H), 7.17 (s, 1H), 6.58 (dd, J=6.9, 1.45 Hz, 1H), 2.33 (m, 6H), 2.23 (b, 2H), 2.18 (s, 3H). 1.33 (pent, 4H), 1.21 (pent, 2H). HRMS: MH+ calcd for C23H26N3, 344.2127. found, 344.2134. Analysis: Calc'd for C23H25N3; C, 80.43; H, 7.34; N, 12.23. Found: C, 80.27; H, 7.15; N, 11.81.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[N+:4]([C:7]1[C:12]2[C:13](=[O:18])[NH:14][S:15](=[O:17])(=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)([O-:6])=[O:5]>O>[OH:3][CH2:2][CH2:1][N:14]1[C:13](=[O:18])[C:12]2[C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[S:15]1(=[O:17])=[O:16]
Reactant: C1CO1
Reactant: O=C1NS(=O)(=O)c2cccc([N+](=O)[O-])c21
Solvent: O
Product: O=C1c2c([N+](=O)[O-])cccc2S(=O)(=O)N1CCO
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To approximately 2 ml of ethylene oxide cooled in an ice bath was added a suspension of 4-nitro-2H-1,2-benzisothiazol-3-one 1,1-dioxide (2.0 g, 8.76 mmol) in H2O (140 ml). After stirring in the ice bath for 1 hour, the mixture was allowed to stir at 20-25° for 18 hours. Water was removed under reduced pressure and the residue flash chromatographed over silica gel. Elution with 2% isopropanol-98% CH2Cl2 gave product which was recrystallized from EtOAc-hexane to give the 2-hydroxethyl derivative (0.39 g, 16%), m.p. 140-1°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:19])[NH:13][NH:14][C:15]=2[CH:16]([CH3:18])[CH3:17])=[C:6]([CH3:20])[CH:5]=1.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:19])[NH:13][NH:14][C:15]=2[CH:16]([CH3:17])[CH3:18])=[C:6]([CH3:20])[CH:5]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(CCN)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCNC(=O)OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (0.3 g) in tetrahydrofuran (5 mL) was added N-(benzyloxycarbonyloxy)succinimide (0.33 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:28]3[N:19]([CH2:20][C@@H:21]4[C@H:26]([C:27]=3[CH:29]=1)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:18][CH2:17][CH2:16]2>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:28]3[N:19]([CH2:20][C@@H:21]4[C@H:26]([C:27]=3[CH:29]=1)[CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:18][CH2:17][CH2:16]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN3CCCc4cc(Br)cc(c43)[C@@H]2C1
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2CN4CCC3)c(Cl)c1

Procedure:
Using 2,4-dichlorophenylboronic acid and following the procedures described in EXAMPLE 20, (±)-cis tert-butyl 2-bromo-5,6,8,8a,9,10,12,12a-octahydro-4H,11H-quino[1,8-bc]-2,6-naphthyridine-11-carboxylate from EXAMPLE 127, Part F was converted into the title compound of EXAMPLE 128. 1H NMR (CDCl3) δ: 7.44 (d, 1H, J=1.6 Hz), 7.27-7.18 (m, 2H), 6.94 (B, 1H), 6.81 (s, 1H), 3.96 (dd, 1H, J=11.5, 3.1 Hz), 3.51-3.43 (m, 1H), 3.30-3.20 (m, 2H), 3.13 (d, 2H, J=7.3 Hz), 2.98-2.85 (m, 2H), 2.84-2.73 (m, 2H), 2.08-1.88 (m, 4H), 1.71-1.60 (m, 1H), 0.90-0.80 (m, 1H). LRMS (ES)+: 373.3 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.[CH2:6](Cl)[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[C:17](=[O:19])=[O:18].Cl>CC(OC)(C)C.C(Cl)C(C1C=CC=CC=1)(C)C.O1CCCC1>[CH3:8][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:6][C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: CC(C)(CCl)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)c1ccccc1
Reaction time: 1.7 h

Procedure:
Magnesium (36.9 g, 1.52 mol, 50-150 mesh), neophylchloride (2.0 g, 0.01 mol) and tetrahydrofuran (40 ml) were placed in a flask under an atmosphere of argon. A Grignard reaction was then started with 1,2-dibromoethane (0.2 ml) and tert.-butyl methyl ether (MTBE, 50 ml) was subsequently added while maintaining reflux. Neophylchloride (258 g, 1.53 mol) dissolved in MTBE (400 ml) was then added at 48° C. over a period of 5.5 h. After 1.7 h stirring at the same temperature, the reaction mixture was diluted with MTBE (500 ml). Dried CO2 was then introduced above the surface at a temperature of 35° C. (ice cooling) for 18 min and directly into the solution for 5 min. The mixture was then acidified with HCl 16% and the organic phase was extracted with NaOH 32% (160 ml). The alkaline solution was first washed with MTBE and then again acidified with HCl 16%. Extraction with MTBE and evaporation of the solvent gave 3-Methyl-3-phenyl-butanoic acid (247.2 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH2:35][C:36]1[CH:41]=[C:40](Br)[CH:39]=[CH:38][N:37]=1>>[NH2:35][C:36]1[CH:41]=[C:40]([C:17]2[CH:18]=[CH:19][C:14]([C@@H:12]([N:8]3[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:10][C:9]3=[O:11])[CH3:13])=[CH:15][CH:16]=2)[CH:39]=[CH:38][N:37]=1
Reactant: Nc1cc(Br)ccn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(N)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-amino-4-bromopyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.951, m/z=432; 1H NMR (CDCl3) 1.26-1.40 (m, 1H), 1.48 (d, 3H), 1.59-1.63 (m, 1H), 1.83-1.95 (m, 2H), 2.09-2.20 (m, 1H), 2.21-2.37 (m, 2H), 2.86 (m, 1H), 3.50 (m, 2H), 4.54-4.75 (s, 2H), 5.62 (m, 1H), 6.56 (s, 1H), 6.71 (d, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 8.00 (m, 1H).