Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC(C1[N:6](CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)[N:7]=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51](OC)=[O:52])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.O.NN>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([NH:6][NH2:7])=[O:52])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: NN
Solvent: O
Product: NNC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and hydrazine hydrate. m/e+ 370 for C17H14F2N7O (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:5][CH:4]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>CN(C=O)C>[N:2]1[NH:28][N:29]=[N:30][C:1]=1[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])[N:12]=[C:11]3[NH:25][N:26]=[CH:27][C:10]=23)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2c(C#N)c(-c3ccc(O)cc3F)nc3[nH]ncc23)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(O)cc2F)nc2[nH]ncc2c1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 130 °C
Yield: 28.7 %

Procedure:
To a solution of 100 mg (0.28 mmol) of 4-(4-cyanophenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in 5 ml of anhydrous DMF are added 84 mg (1.12 mmol) of sodium azide and 305 μL (366 mg, 1.12 mmol) of tributyltin chloride. The mixture is heated to 130° C. under nitrogen for 8 h. Then 19 mg (0.28 mmol) of sodium azide and 77 μL (92 mg, 0.28 mmol) of tributyltin chloride are added, and the mixture is again heated to 130° C. for 48 h. After return to room temperature, the mixture is poured onto a water/ice mixture and acidified with a 6N HCl solution. The aqueous phase is extracted once with dichloromethane and twice with chloroform. The organic phase is washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 15 to 25%) to give 0.032 g (29%) of 4-(4-(2H-tetrazole-5-yl)phenyl)-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of beige crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]1[C:15]1[CH:27]=[CH:26][C:18]2[NH:19][C:20](=O)[O:21][C:22]([CH3:24])([CH3:23])[C:17]=2[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:15]2[CH:27]=[CH:26][C:18]3[NH:19][C:20](=[S:37])[O:21][C:22]([CH3:24])([CH3:23])[C:17]=3[CH:16]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.3 g, 35 mmol, 1 eq) in toluene (130 mL) was added Lawesson's reagent (1.58 g, 3.9 mmol, 1.1 eq) and the reaction mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was dissolved in acetone/dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the product (0.51 g, 38%) as yellow crystals. 1H NMR (DMSO-d6) 1.35 (s, 9 H), 1.64 (s, 6 H), 6.47 (d, 1 H, J=3.6 Hz), 7.07 (d, 1H, J=8.1 Hz), 7.32 (d, 1 H, J=3.6 Hz), 7.37 (dd, 1 H. J=1.8, 8.1 Hz), 7.43 (d, 1 H, J=1.8 Hz), 12.28 (s, 1 H); MS (ESI) [M−H]−=382; Anal. Calcd. For C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C, 62.53; H, 5.6; N, 10.87.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:16])=[C:6]([Cl:15])[CH:7]=[C:8]([CH:12](Cl)[CH3:13])[C:9]=1[O:10][CH3:11].[CH3:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH2:27])[NH:20][N:19]=1>CN(C)C=O.C(Cl)Cl>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH:12]([N:20]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:27])=[C:26]3[C:18]([CH3:17])=[N:19]2)[CH3:13])[CH:7]=[C:6]([Cl:15])[C:5]=1[CH3:16]
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (36 mg, 0.91 mmol) was added to a mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol) in N,N-dimethylformamide (8 mL) and the reaction was stirred at 30° C. overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2 (103 mg, 50%). LCMS calculated for C16H18BrClN5O (M+H)+: m/z=410.0; Found: 410. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 5% ethanol in hexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide two enantiomers.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=C[CH:9]=1.[B:15]([OH:18])(O)[OH:16]>O>[B:15]([O:18][CH:12]([CH2:13][CH:8]([CH3:9])[CH3:14])[CH3:11])([O:16][CH:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5])[O:6][CH:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5]
Reactant: CC(C)CC(C)O
Reactant: Cc1ccccc1
Reactant: OB(O)O
Solvent: O
Product: CC(C)CC(C)OB(OC(C)CC(C)C)OC(C)CC(C)C

Procedure:
Approximately 306 grams of 4-methyl-2-pentanol, 100 grams of toluene, and 62 grams of boric acid were charged to a 2-liter glass reactor having an inert nitrogen atmosphere and equipped with heater, agitator, and Dean-Stark tube with condenser. The reactants were heated up to about 155° C. for a period of about 5 hours with agitation until water evolution during azeotropic distillation ceased. Approximately 52 grams of water was collected. The product was vacuum topped at about 155° C. to remove volatile solvent and filtered hot through diatomaceous earth to form a clear, water-white liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 201] followed by evaporation in vacuo.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=O)[NH:22]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=[S:43])[NH:22]2
Reactant: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=O)C2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=S)C2(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 1.189 g (2.71 mmol) of the 4-[3-(2-quinolinylmethoxy)benzyloxy]-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one obtained in Example 13, 1.076 g (2.71 mmol) of the Lawesson's reagent and 10 ml of toluene were added, followed by stirring at a bath temperature of 100° C. for 3 hours. After CHCl3 was added to dissolve the insoluble matter, the resulting solution was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from AcOEt, whereby 678 mg of the title compound were obtained as pale yellow powder (yield: 55.0%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C([Li])CCC.[BH:25]([OH:27])[OH:26].O[C:29]([C:32](O)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1>[CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][C:17]([B:25]3[O:27][C:32]([CH3:34])([CH3:33])[C:29]([CH3:31])([CH3:30])[O:26]3)=[CH:18][CH:19]=2)[CH2:4][O:5][CH2:6]1)[CH3:2]
Reactant: OBO
Reactant: CC(C)(O)C(C)(C)O
Reactant: CCC1(COCCCCCCc2cccs2)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(B3OC(C)(C)C(C)(C)O3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-ethyl-3-(6-thiophen-2-yl-hexyloxymethyl)oxetane (6.0 g, 21.28 mmol) in dry THF (70 ml) was added n-butyllithium (2.5 M in hexanes, 8.10 ml, 21.28 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of pinacol boronate (3.96 g, 21.28 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1), to afford the product as a yellow oil (6.28 g, 72%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.45 (d, J=3.4 Hz, 1H, Ar—H), 6.85 (d, J=3.4 Hz, 1H, Ar—H), 4.44 (d, J=5.8 Hz, 2H, OCH2), 4.36 (d, J=5.8 Hz, 2H, OCH2), 3.51 (s, 2H, OCH2), 3.45 (t, J=6.4 Hz, 2H, OCH2), 2.83 (t, J=7.6 Hz 2H, ArCH2), 1.32-1.77 (m, 22H, CH2 and CH3), 0.88 (t, J=7.4 Hz, 3H, CH3); δ (ppm) 153.5 (quat.), 145.6 (quat.), 137.3 (CH), 125.9 (CH), 83.9 (quat.), 78.6 (OCH2), 73.4 (OCH2), 71.5 (OCH2), 43.4 (quat.), 31.6 (CH2), 30.1 (CH2), 29.4 (CH2), 28.8 (CH2), 26.8 (CH2), 25.9 (CH2), 24.8 (CH3), 8.2 (CH3); MS (m/e): 408 (M+, 0.5%), 223 (27), 165 (30), 141 (35), 123 (100), 97 (52).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: N
Reactant: Clc1nccc2scc(Br)c12
Solvent: C1COCCO1
Product: Nc1nccc2scc(Br)c12
Temperature: 150 °C
Reaction time: 96 h

Procedure:
To the solution of 3-bromo-4-chloro-thieno[3,2-c]pyridine (3.2 g) in dioxane (30 ml) was added 28% ammonia solution (10 ml) in an autoclave and put into the oil bath. The reaction mixture was allowed to heat up to 150° C. and stir for 4 days at 150° C. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on a silica gel column to afford 3-bromo-thieno[3,2-c]pyridin-4-ylamine (1.7 g) 1H NMR (400 MHz, DMSO-d6) ppm 7.84 (d, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.27 (d, J=5.6 Hz, 1H), 6.51 (s, 2H). MS: m/z 229, 231 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11](OC(=O)C)[C:2]=12.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH:11]1[C:2]2=[N:1][CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC1CCCCc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCCCc2cccnc21
Temperature: 60 °C
Yield: 42 %

Procedure:
This ester was dissolved in DMF (420 mL), treated with sodium azide (33.40 g, 0.514 mol), and heated at 60° C. overnight. The mixture was cooled to room temperature and concentrated. The resultant slurry was poured into brine (500 mL) and extracted with ether (4×500 mL). The combined organic extracts were washed with brine (2×100 mL), dried (Na2SO4), and concentrated. The crude material was filtered (eluant CH2Cl2) through a short plug of silica gel to provide 23.18 g (42% from 2,3-cycloheptenopyridine) of 9-azido-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine as a red oil. 1H NMR (CDCl3) δ 1.53-1.66 (m, 1H), 1.73-2.14 (m, 5H), 2.63-2.72 (m, 1H), 2.99-3.09 (m, 1H), 4.93 (dd, 1H, J=7.8, 1.7 Hz), 7.13 (dd, 1H, J=7.9, 4.8 Hz), 7.44 (d, 1H, J=5.7 Hz), 8.39 (dd, 1H, J=4.8, 1.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH2:25][CH3:26]>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH2:24][CH2:25][CH3:26])=[CH:29][CH:30]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(-c4ccc(OCCC)cc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 194–197° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][O:60][C:61]1[N:66]=[CH:65][C:64]([CH2:67]O)=[CH:63][CH:62]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:67][C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(CO)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2ccc(OC)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (6-methoxypyridin-3-yl)methanol (0.58 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.09 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[C:12](=O)[CH2:13][CH2:14][CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1.[OH2:17].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:26]O>C(O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[C:12](=[N:26][OH:17])[CH2:13][CH2:14][CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=C1c2cc(Cl)ccc2CN2C(=O)CCC12
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2cc(Cl)ccc2CN2C(=NO)CCC12
Yield: 81.4 %

Procedure:
A stirred suspension of 12.65 g of 8-chloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione (prepared in substantially the same manner as the 7-chloro compound in Example 12, m.p. 130°-136° C.) in 95% ethanol (85 ml) was treated with a premixed solution prepared from sodium acetate trihydrate (14.56 g) in water (48 ml) and hydroxylamine hydrochloride (7.44 g) in water (48 ml). The stirred suspension was heated to reflux, during which a solution formed followed by separation of a crystalline precipitate. After 2 hours of refluxing, the mixture was cooled and the precipitate was collected and washed twice with 50% aqueous ethanol. Drying at 40° C. overnight in vacuo gave 10.95 g of a solid, m.p. 227.5°-230.5° C. Recrystallization of the solid from n-propanol (300 ml) afforded 8.56 g of crystals, m.p. 229°-235° C.
Reaction SMILES: [CH2:1]([I:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[I-:6].[CH2:1]([P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCI
Product: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]

Procedure:
Using the procedure of Step B of Example 1, n-pentyl iodide and triphenylphosphine were reacted to obtain n-pentyl-triphenylphosphonium iodide melting at 174° C.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]1([CH3:12])[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1>>[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CC=C
Reactant: Cc1ccccc1C
Product: C=CCCCc1ccccc1C

Procedure:
The synthesis of 2,6-NDC typically includes several steps. In a typical synthesis, orthoxylene and butadiene are reacted over an alkali metal or other catalyst to yield a 5-orthotolyl pentene (5-OTP) alkenylation product. The 5-OTP is then cyclized over an acid catalyst to yield 1,5 dimethyltetralin (1,5-DMT). The 1,5 DMT is dehydrogenated over a noble metal or other dehydrogenation catalyst to yield 1,5 dimethylnaphthalene (1,5-DMN), which is subsequently isomerized to produce 2,6-DMN.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: O=C1CCc2c(OC[C@@H](O)CNC3CCN(c4ccc(CC5SC(=O)NC5=O)cc4)CC3)ccc(O)c2N1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-5-(3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one) (which was obtained in Example 12) according to the procedure of Example 73 as a pale yellowish solid; mp>140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.55 (m, 2 H), 1.85–2.00 (m, 2 H), 2.40 (t, J=8.0 Hz, 2 H), 2.60–3.00 (m, 8 H), 3.25 (dd, J=15.9, 3.9 Hz, 1 H), 3.50–3.70 (m, 2 H), 3.80–4.00 (m, 3 H), 4.50 (dd, J=9.7, 3.9 Hz, 1 H), 6.34 (d, J=8.9 Hz, 1 H), 6.61 (d, J=8.9 Hz, 1 H), 6.85 (d, J=8.6 Hz, 2 H), 7.05 (d, J=8.6 Hz, 2 H), 8.76 (s, 1 H), 9.24 (brs, 1 H); MS (ES) m/z: 541.1 (MH+); HRMS Calcd. for C27H33N4N4O6S (MH+): 541.2121. Found: 541.2148.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2)CC1
Yield: 80.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and oxazolidin-2-one (104 mg)), the title compound (327 mg) was obtained.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][C:102]1[CH:110]=[CH:109][C:105]([C:106]([NH2:108])=[NH:107])=[CH:104][CH:103]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](=[O:71])[NH:100][CH2:101][C:102]4[CH:103]=[CH:104][C:105]([C:106]([NH2:108])=[NH:107])=[CH:109][CH:110]=4)[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: N=C(N)c1ccc(CN)cc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccc(C(=N)N)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-aminomethyl-benzamidine. MS (ES+) m/e 771.56 (MH+)
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of di-tert-butyl [{(3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidin-1-yl}methylylidene]biscarbamate 171 (0.34 g, 0.56 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 172 (0.28 g, 97%) as white solid.