Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=[N+]([O-])c1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Solvent: CCOC(C)=O
Product: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reaction time: 18 h

Procedure:
To a solution of 3-Chloro-2-quinoloxy-5-nitropyridine (2.51 g, 8.34 mmol) (obtained in step iii), in ethyl acetate (50 mL) was added stannous chloride dihydrate (7.52 g, 33.36 mmol) at room temperature. Stirring was continued further for 18 hours. Removed the solvent under vacuum and chloroform (50 mL) was added. To the stirred mixture was added 1N sodium hydroxide solution until a clear solution was obtained. Separated the organic layer and extracted with chloroform. The chloroform layer was washed with brine and water successively, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, gradient 30-50% ethyl acetate in pet ether) to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14]([C:15]=1[CH2:16][N:17](C(OC)=O)C)=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH2:17])=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(CN(C)C(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
salt with HCl (prepared according to Example 104.2.) was converted to 5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 437.5 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C2C(=CC=CC=2)CCC1>CCOCC.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCc3cc(C)ccc32)cc1OC
Agent: [Pd]
Solvent: CCOCC
Solvent: c1ccc2c(c1)CCCC2
Product: COc1ccc(-c2nccc3cc(C)ccc23)cc1OC
Reaction time: 3.75 h
Yield: 107.4 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-6-methyl-3, 4-dihydroisoquinoline (C2) (5.0 g, 0.018 mol), 10% Pd/C (400 mg) and tetralin (50 ml) was boiled under nitrogen for 3.75 h. The cooled reaction mixture was diluted with ether and filtered The filtrate was treated with HCl gas to give 5.4 g (98%) of the title compound as the hydrochloride. A sample was recrystallized from i-PrOH to give pure 1-(3,4-dimethoxyphenyl)-6-methylisoquinoline hydrochloride, mp 225° dec.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N+:8]1([O-:27])[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)[N+]1([O-])Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione (7.5 g, 32 mmol) and 3-chloroperbenzoic acid (77%, 14.3 g, 64 mmol) were dissolved in chloroform (250 ml), and the mixture was stirred at room temperature for 20 hrs. The solvent was evaporated, and the residue was washed with ethyl acetate to give the titled compound (8.0 g, 99%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:24])([CH3:17])[CH2:19]2)=[O:9])[CH:3]=1
Reactant: CC1(C)CCCNC1
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)CCCN(C(=O)c2csc(Br)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). 3,3-Dimethylpiperidine (2.4 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.475 g). 1H NMR δ (ppm)(CHCl3-d): 7.4 (s, 1H), 7.1 (s, 1H), 3.6-3.1 (m, 4H), 1.7 (m, 2H), 1.4 (m, 2H), 0.9 (s, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2NC=C3C(=O)N(C4C=C[C:44]([O:47]C)=CC=4)N=C3C=2C=1>>[CH3:44][O:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Reactant: COc1ccc(-n2nc3c4cc(N)ccc4[nH]cc-3c2=O)cc1
Product: COc1ccc(-n2nc3c4cc(N5CCNCC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 7a using 6c. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.50 (4H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 376.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.[C:31](O)(=[O:34])[CH2:32][OH:33]>>[OH:34][CH2:31][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:27])[F:28])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:5][CH2:6]1)=[O:33]
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Reactant: O=C(O)CO
Product: O=C(CO)N1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1

Procedure:
Following the procedure for 116, 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with glycolic acid to give 151 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.21 (s, 1H); 7.73 (d, J=2.16 Hz, 1H); 7.29 (dd, J=8.37, 2.17 Hz, 1H); 7.21 (d, J=8.32 Hz, 1H); 6.97 (s, 1H); 5.72 (q, J=8.78 Hz, 2H); 4.55-4.43 (m, 4H); 4.13-4.05 (m, 2H); 3.79 (d, J=13.44 Hz, 1H); 3.23-3.15 (m, 3H); 3.09 (t, J=12.91 Hz, 1H); 2.91-2.82 (m, 1H); 2.77-2.65 (m, 1H); 1.86 (d, J=12.87 Hz, 2H). LCMS: RT=9.76 min, M+H+=477
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49](OC(C)(C)C)=[O:50])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)C(O)=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C.CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49](=[O:50])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])=[O:4]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@H](NC(=O)OC)c3ccccc3)[nH]2)ccc1-4)C(C)C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
Tert-butyl (2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (84 mg, 0.11 mmol) was dissolved in DCM (2.5 mL), MeOH (0.5 mL) and HCl (4 M in dioxane, 0.5 mL) was added. The reaction mixture was stirred for 18 h and then concentrated under reduced pressure. The crude residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (23 mg, 0.11 mmol), COMU (53 mg, 0.11 mmol) and DMF (3 mL), then DIPEA (0.10 mL, 0.56 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (41 mg, 45%). LCMS-ESI+: calculated for C47H50N8O7: 838.38; observed [M+1]+: 839.39
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13].[C:15](=[O:17])=[O:16].O>CCCCCC.O1CCCC1.CO>[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:15]([OH:17])=[O:16]
Reactant: C#CCN(C)CCOC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)CC#CC(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (37.8 mL, 2.5 M in n-hexane) was slowly added to (2-methoxy-ethyl)-methyl-prop-2-ynyl-amine (12.0 g, 94.5 mmol) in 90 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 15 g of 4-[(2-methoxy-ethyl)-methyl-amino]-but-2-ynoic acid: mass spectrum (m/e): M−H 170.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:14])C.CCCCCC>>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[CH:12]=[O:14]
Reactant: CCOC(C)=O
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Product: O=Cc1cc(C(F)(F)F)ccc1O
Yield: 34 %

Procedure:
Following the general procedure and FCC purification with 30% ethyl acetate-hexane, 4-trifluoromethyl phenol (10.0 g, 61.7 mmol) gave 2-hydroxy-5-trifluoromethyl-benzaldehyde 27 (3.9 g, 34%) as a pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH3:30])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH3:30])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNC(CN1CCCC1)c1ccc(Br)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (4.7 g, 17 mmol) was dissolved in 150 mL of methylene chloride and treated with N-(3,4-dichlorophenyl)-N-methylglycine (4.02 g, 16.6 mmol), EDC (3.5 g, 18 mmol), HOBt (2.47 g, 18.2 mmol), and triethylamine (2.55 mL, 18.3 mmol). The reaction mixture was stirred at room temperature for 18 h. Methylene chloride (50 mL) was added and the reaction mixture was washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 15 mL of DMSO and purified by preparative HPLC (Phenomenex 75×30 mm column, 15 injections, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 4.01 g (48%) of the title compound as a light yellow solid. MS (ES) m/e 500 [M+H]+.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH:16]=[O:17].[CH2:18]([O:20][C:21]([CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[CH3:19]>CO.C(O)C>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[C:16](=[O:17])[CH:19]=[CH:18][O:20][CH2:21][CH3:23]
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC=CC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Reaction time: 3 h

Procedure:
36 ml of a 15% strength solution of sodium methylate in methanol were added dropwise, at 20° C., to a suspension of 22.6 g of 3,7-dichloro-8-formylquinoline and 38.4 g of ethoxycarbonylmethyl-triphenyl-phosphonium chloide in 200 ml of ethanol. The mixture was stirred for 3 hours, after which the precipitate was filtered off under suction, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH:7]=[N:6]1.[CH3:24][O:25][CH:26]([O:35][CH3:36])[CH2:27][NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([N:28]([CH2:27][CH:26]([O:35][CH3:36])[O:25][CH3:24])[C:18](=[O:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:9]=3)[CH:11]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COCCn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCCC1)OC
Product: COCCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)cn1

Procedure:
The subtitled compound (267 mg) was prepared from 3-(3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 36 Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=456 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.81 and 7.80 (2×s, 1H), 7.40-7.37 (m, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.23 and 7.22 (2×t, J=7.7 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.30 (t, J=5.2 Hz, 2H), 4.04-3.95 and 3.69-3.60 (2×m, 1H), 3.77-3.63 (m, 6H), 3.34 (s, 3H), 3.32 (s, 3H), 3.31 (s, 3H), 3.34 and 3.25 (2×d, J=5.1 Hz, 2H), 2.87-2.81 (m, 2H), 2.67-2.60 (m, 2H), 1.93-0.99 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH2:28])[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: C=Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
The above (S)-tert-butyl 1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (23.7 mg, 0.038 mmol) was dissolved in Trifluoroacetic Acid (2 mL) and Methylene chloride (2 mL). To the solution was add Trifluoromethanesulfonic acid (50 uL, 0.6 mmol) and Triethylsilane (30 uL, 0.19 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 307 as an off-white solid (5.1 mg, 34%). 1H NMR (400 MHz, DMSO) δ 9.32 (d, J=1.9 Hz, 1H), 9.20 (s, 1H), 9.11 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.52 (dd, J=8.0, 4.7 Hz, 1H), 6.80 (dd, J=17.7, 11.0 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.3 Hz, 1H), 3.77 (d, J=9.7 Hz, 1H), 3.58 (d, J=12.1 Hz, 1H), 2.92-2.82 (m, 2H), 2.82-2.72 (m, 1H), 1.95 (d, J=12.7 Hz, 1H), 1.87-1.71 (m, 2H), 1.25 (dd, J=19.0, 10.7 Hz, 1H); ESI MS m/z=398.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>ClCCl>[I:11][C:10]1[C:3]2[C:2]([CH3:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ncnc2[nH]ccc12
Solvent: ClCCl
Product: Cc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
To 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (18, 0.634 g, 4.76 mmol) in 50 mL of dichloromethane, N-iodosuccinimide (1.3 g, 5.7 mmol) was added and the reaction stirred at room temperature for 45 minutes. The reaction was concentrated under vacuum, then ethyl acetate was added and washed with 1 N aqueous sodium thiosulfate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (19, 0.94 g). MS (ESI) [M+H+]+=260.26.
Reaction SMILES: C([O:3][P:4]([CH:7]([N:12]1[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]1)[P:8](=[O:11])([OH:10])[OH:9])(=[O:6])[OH:5])C>Cl>[CH3:18][C:15]1([CH3:19])[CH2:16][CH2:17][N:12]([CH:7]([P:8](=[O:9])([OH:11])[OH:10])[P:4](=[O:3])([OH:5])[OH:6])[CH2:13][CH2:14]1
Reactant: CCOP(=O)(O)C(N1CCC(C)(C)CC1)P(=O)(O)O
Agent: Cl
Product: CC1(C)CCN(C(P(=O)(O)O)P(=O)(O)O)CC1

Procedure:
A mixture comprising 10 g of 4,4-dimethylpiperidinomethylene bisphosphonic acid ethyl ester obtained in Example 59 and 80 ml of 12N hydrochloric acid, was treated in the same manner as in Example 2 to give 4.0 g of the above identified compound as a colorless crystalline powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.Cl[C:20]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]([NH2:27])[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH2:5][C:20]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]([NH2:27])[CH:21]=1)[CH3:9]
Reactant: C=CCCC(=O)OCC
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1cc(N)nc(N)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Ethyl 4-pentenoate (4.93 gm, 38.4 mmol) was treated with 9-BBN (92.2 mL, 46.1 mmol; 0.5M in THF) at room temperature for 16 hours. To this solution was added Pd(OAc)2 (863 mg, 3.84 mmol), 6-chloro-2,4-diaminopyrimidine (2-1, 5.0 g, 34.6 mmol), K2CO3 (7.95 g, 57.6 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (2.13 g, 3.84 mmol) and DMF (100 mL). The mixture was degassed with argon for 10 minutes then heated to 90° C. for 24 hours. The reaction mixture was cooled and stirred with ethanolamine (10 mL) for 1 hour. The volatiles were removed in vacuo and the black tarry residue was partitioned between water and EtOAc. After extraction with EtOAc (4×), the organic layers were washed with water (4×), then brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography (5% MeOH in CHCl3) afforded the title compound 2-2 as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH:16]=[O:17])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[CH3:19].C(=O)([O-])O.[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH:16]=[O:17])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[CH3:19])(=[O:27])[CH3:26]
Reactant: CCC(C)c1cc(C=O)c2nc(C)c(C)c(O)c2c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
800 Milligrams of the resultant 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was dissolved in 2.5 ml of 20% sulfuric acid and stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was neutralized with an aqueous saturated sodium hydrogencarbonate solution to produce precipitates, which were washed with water and n-hexane and then dried under reduced pressure to obtain 490 mg of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline. 440 Milligrams of 4-hydroxy-6-s-butyl-8-formyl-2,3-dimethylquinoline was suspended in a mixture of 3 ml of acetic anhydride and 0.5 ml of pyridine and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The resultant organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (10:1) to obtain 220 mg of 4-acetoxy-6-s-butyl-8-formyl-2,3-dimethylquinoline (yield 13%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH2:12][OH:13])=[C:10]([CH:14]2[CH2:16][CH2:15]2)[N:9]=[C:8]([CH3:17])[C:7]=1[O:18][C:19](=[O:21])[CH3:20])(O)=O>CO.O.[Pd]>[OH:13][CH2:12][C:11]1[C:6]([CH3:5])=[C:7]([O:18][C:19](=[O:21])[CH3:20])[C:8]([CH3:17])=[N:9][C:10]=1[CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)Oc1c(C)nc(C2CC2)c(CO)c1COC(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCc1nc(C)c(OC(C)=O)c(C)c1CO
Yield: 84.5 %

Procedure:
The acetic acid 4-carboxyoxymethyl-6-cyclopropyl-5-hydroxymethyl-2-methyl-pyridin-3-yl ester (175) (10.6 g, 35.9 mmol) in methyl alcohol:water (1:1, 100 mL) was hydrogenated in the presence of 10% palladium on carbon (3.8 g) at room temperature for overnight. The product was filtered through a celite pad and evaporated to give acetic acid 5-hydroxymethyl-2,4-dimethyl-6-propyl-pyridin-3-yl ester (176) (7.2 g, 89% yield).