Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[N:11]=1.C1COCC1.CC([BH-](C(C)C(C)C)C(C)C(C)C)C(C)C.[Li+]>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]([OH:29])[CH3:30])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CCC2CO2)c2nc(Nc3ccccc3)ncc12
Agent: CC(C)C(C)[BH-](C(C)C(C)C)C(C)C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1Nc1nn(CCC(C)O)c2nc(Nc3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
A solution of 9 mg (0.02 mmol) of N3-(2,6-dimethylphenyl)-1-(2-(oxiran-2-yl)ethyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 42 (Example 9, Step A) in 2.5 mL of CH2Cl2 was cooled to 0° C. and treated with 120 μl (1.0 M, 0.12 mmol) of a THF solution of LS-Selectride. The resulting tan solution was stirred at 0° C. for 1.25 h. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (8 mL) and stirred vigorously at room temperature overnight. The mixture was extracted with CH2Cl2 (10 mL), and the organic layer was dried over Na2SO4 and filtered. The filtrate was purified by chromatography on silica gel (eleuens CH2Cl2:MeOH, 98:2) to give the title compound 46. 1H-NMR (CD3OD) δ 1.16 (d, J=6.3 Hz, 3H), 1.80-1.99 (m, 2H), 2.26 (s, 6H), 3.64-3.72 (m, 1H), 4.13-4.23 (m, 2H), 7.00 (t, J=7.4 Hz, 1H), 7.10-7.17 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.75 (d, J=7.7 Hz, 2H), 8.08 (s, 1H). Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5]C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:32]1([C:38]2[N:39]=[C:40]3[N:45]=[C:44]([NH:46][C:47]([C:49]4[N:53]=[N:52][NH:51][C:50]=4[C:54]([OH:56])=O)=[O:48])[CH:43]=[CH:42][N:41]3[CH:57]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCC1>CN(C=O)C.O.CC#N>[C:32]1([C:38]2[N:39]=[C:40]3[N:45]=[C:44]([NH:46][C:47]([C:49]4[N:53]=[N:52][NH:51][C:50]=4[C:54]([N:4]4[CH2:5][CH2:9][CH2:7]4)=[O:56])=[O:48])[CH:43]=[CH:42][N:41]3[CH:57]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)O
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Diisopropylethylamine (89 mg, 0.69 mmol) and TBTU (88 mg, 0.27 mmol) were added to a solution of 5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-3H-[1,2,3]triazole-4-carboxylic acid (80 mg, 0.23 mmol) in DMF (1 ml), and the dark brown solution was stirred for 30 min at RT. Azetidine (39 mg, 0.68 mmol) was added, and the mixture was stirred at RT overnight. The title compound (25 mg, 28%) was obtained from the reaction mixture by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN). MS (m/e)=389.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[CH:16]1([C:19]2[N:20]([NH2:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)[CH2:18][CH2:17]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH:16]1([C:19]2[N:20]([NH:29][C:8]([C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[N:5][CH:6]=3)=[O:10])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)[CH2:18][CH2:17]1
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Reactant: Nn1c(C2CC2)cc2cc(F)ccc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nccs2)ncc1C(=O)Nn1c(C2CC2)cc2cc(F)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
A solution of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (188 mg, 0.85 mmol) and 2-cyclopropyl-5-fluoro-indol-1-ylamine (135 mg, 0.71 mmol) in DMF (3 mL) is stirred at 40° C. for 1 h. The mixture is treated with DMTMM (235 mg, 0.71 mmol) and stirred at 40° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (2-cyclopropyl-5-fluoro-indol-1-yl)-amide (60 mg). MS: 394 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.15 (d, 1H), 8.08 (d, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 6.97 (m, 1H), 6.18 (s, 1H), 2.77 (s, 3H), 1.95 (m, 1H), 1.01 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:53]1([C:59]2[CH:69]=[CH:68][C:62]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[CH:61][CH:60]=2)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.Br[C:71]1[CH:72]=[C:73]([CH3:88])[C:74]([O:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][O:86][CH3:87])=[C:75]([CH3:77])[CH:76]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:87][O:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][O:78][C:74]1[C:73]([CH3:88])=[CH:72][C:71]([N:56]2[CH2:55][CH2:54][N:53]([C:59]3[CH:60]=[CH:61][C:62]([C:63]([O:65][CH2:66][CH3:67])=[O:64])=[CH:68][CH:69]=3)[CH2:58][CH2:57]2)=[CH:76][C:75]=1[CH3:77]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COCCCCCCCOc1c(C)cc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCN(c3cc(C)c(OCCCCCCCOC)c(C)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a mixture of cesium carbonate (1.39 g), palladium(II) acetate (34.1 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (142 mg) in toluene (3.1 ml) was successively added ethyl 4-(piperazin-1-yl)benzoate (0.85 g) and a solution of 5-bromo-2-(7-methoxyheptyloxy)-1,3-dimethylbenzene (1.00 g) in toluene (3 ml) in a stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes and refluxed for a further 20 hours. After cooling, the reaction mixture was concentrated in vacuo and to the residue was added water and methylene chloride. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting successively with the following solvent: (1) n-hexane, (2) n-hexane;ethyl acetate=9:1, (3) n-hexane:ethyl acetate=5:1. The fractions containing the object compound were concentrated in vacuo to give ethyl 4-[4-[4-(7-methoxyheptyloxy)-3,5-dimethylphenyl]piperazin-1-yl]benzoate (0.53 g) as a pale yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].Br[C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18]>C(Cl)Cl>[CH3:20][CH:16]1[CH2:21][C:13]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH:14]=2)[C:17]1=[O:18]
Reactant: CC(C)Cc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Reaction time: 2 h

Procedure:
17.3 g (125 mmol) of AlCl3 were added to a solution of 6.71 g (50 mmol) of isobutylbenzene in 30 ml of analytical grade methylene chloride, while cooling with ice. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were then added rapidly, and stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. The mixture was heated under reflux for a further 15 hours and then worked up analogously to Example A. The crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1). The yield was 8.42 g (83%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([NH2:29])[CH3:28]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][NH:29][CH2:27][CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CCN
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CNCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and ethylamine, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.06 (m, 4 H), 3.18 (m, 4 H), 2.32 (q, J=7.4 Hz, 2 H), 2.15 (t, J=5.2 Hz, 2 H), 1.13 (m, 18 H), 0.839 (t, J=7.4 Hz, 3 H), 0.698 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50° C. Rf=0.1 (20% ether/CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:27][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CCCCCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol), cyclooctylamine (0.762 g, 6 mmol) and ethanol (15 mL) were stirred at reflux under nitrogen for 20 hours. 1N NaOH (2 mL) was added and solvent was evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as white powder after crystallization from acetonitrile-methanol (0.623 g, 87%); m.p. 171°-173° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Temperature: 75 °C
Yield: 65.2 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (14.3 g, 0.091 mol) and 2-chloro-5-fluoro-pyridine (10 g, 0.076 mol) in toluene (100 mol) was added NaOtBu (8.77 g, 0.091 mol), BINAP (1.42 g, 2.28 mmol) and tris(dibenilideneacetone)dipalladium(0) (1.39 g, 1.52 mmol). The reaction mixture was heated at 75° C. for 2 hours, cooled down to RT, and diluted with AcOEt (100 mL) and H2O (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 12.5 g (65%) of 5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 253.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:26])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(N(CC)CC)C.[OH-].[Na+].Cl>ClC(Cl)C.O1CCOCC1>[CH3:26][N:5]1[C:6]2[C:7]([CH:8]=[CH:9][C:10]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=2[C:11]=34)=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:3]=[CH:4]1
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: CCS(=O)(=O)NC1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of Example 82d (0.09 g, 0.262 mmol) in dichloroethane (2 mL) and 1,4-dioxane (4 mL) was treated with ethanesulfonyl chloride (0.075 mL, 0.786 mmol) and triethylamine (0.183 mL, 1.31 mmol). The mixture was stirred at ambient temperature overnight and then concentrated. The mixture was redissolved in 1,4-dioxane (4 mL), treated with sodium hydroxide solution (4 M aqueous) (0.655 ml, 2.62 mmol) and heated at 50° C. for 1.75 hours. The mixture was then cooled to ambient temperature and neutralized with hydrochloric acid solution (2 M aqueous). The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×60 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-60%) to provide 0.0477 g (33%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.56 (s, 1H), 7.98 (dd, J=5.19, 1.22 Hz, 1H), 7.64 (d, J=2.44 Hz, 1H), 7.58 (s, 1H), 7.41 (m, 1H), 7.27 (d, J=8.54 Hz, 1H), 7.13 (dd, J=8.54, 2.44 Hz, 1H), 6.90 (s, 1H), 6.60 (dd, J=6.56, 5.65 Hz, 1H), 6.42 (d, J=8.85 Hz, 1H), 5.53 (s, 1H), 4.08 (s, 3H), 3.97 (s, 1H), 3.19 (q, J=7.32 Hz, 2H), 1.29 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 436.2 (M+H)+.
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH:20]1([NH:25][C:4]([NH:18][CH3:19])=[N:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: NC1CCCC1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CNC(=Nc1ccccc1N1CCOCC1)NC1CCCC1
Temperature: 110 °C

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydriodide (7.86 g prepared as described in Example 210), cyclopentylamine (2.9 g), anhydrous sodium carbonate (6.36 g) and ethanol (100 ml) was heated in a stainless steel pressure vessel in an oil bath at 110° C. for 24 hours. The reaction mixture was cooled, filtered and the solvent was partially removed. The residue was poured into ice and the resulting mixture extracted with dichloromethane. The extract was dried, filtered and the solvent removed to give a residue which was treated with fumaric acid to give 1-cyclopentyl-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m.p. 220° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:21]3[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:24][CH:25]=3)=[N:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=3[C:9]([C:21]3[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:24][CH:25]=3)=[N:10]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3cc[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of methyl 4-(4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (75.0 mg) in acetonitrile (5 mL) were added sodium iodide (68.6 mg) and chloro(trimethyl)silane (0.232 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (49.7 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:11][CH:12]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH2:13][CH:12]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:11][C:10]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(OC(CCCO)c2ccc(C#N)cc2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Yield: 100 %

Procedure:
A solution of methanesulfonyl chloride (3.4 mL, 5.0 g, 44 mmol) in DCM (15 mL) was added slowly to a cooled (−5° C.) mixture of 4-[1-(3,4-dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (from step (ii) above; 11 g, 34 mmol) and triethylamine (7 mL, 5.2 g, 50.6 mmol) in DCM (50 mL), during which addition the temperature did not rise above 2° C. Stirring was continued at between 0 and 5° C. for a further 2 h before water was added. The resulting organic layer was separated, and washed with water, separated again and then dried to give the sub-title compound in 100% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:6]2)[CH3:2].C(O)C.O.[OH-].[Li+].Cl>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Yield: 94 %

Procedure:
To the product of step 2 was added 80 mL of ethanol, followed by addition of a solution of 3.5 g (83 mmol) of lithium hydroxide hydrate in 80 mL of water. The resulting solution was heated to reflux for three h. The mixture was concd, the residue treated with 50 mL of water and the resulting solution acidified to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was further purified by silica chromatography with 1% HOAc in EtOAc/hexane (2:8) to afford 5.6 g (94%) of a green-yellow solid: 1H NMR (CDCl3/400 MHz) 7.80(s, 1H), 7.01(s, 1H), 6.43(s, 1H), 5.62(q, J=6.8Hz, 1H), 2.56(q, J=7.6 Hz, 2H), 1.26(t, J=7.6 Hz, 3H). MS (ESI+) 289.1(M+1, 100). MS(ES−) 287.1(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C13H10F3O4): 287.0526, found 287.0504.
Reaction SMILES: [Si](OCCC1C2C(O)=C(F)C=CC=2N(C)C=1)(C(C)(C)C)(C)C.[N:23]([CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([F:45])[C:35]=2[O:37]CC2C=CC=CC=2)[N:30]([CH2:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH:29]=1)=[N+]=[N-]>[OH-].[OH-].[Pd+2].[Pd]>[NH2:23][CH2:26][CH2:27][C:28]1[C:36]2[C:35]([OH:37])=[C:34]([F:45])[CH:33]=[CH:32][C:31]=2[N:30]([CH2:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH:29]=1
Reactant: [N-]=[N+]=NCCc1cn(CC2CCCCO2)c2ccc(F)c(OCc3ccccc3)c12
Agent: [Pd+2]
Agent: [Pd]
Agent: Cn1cc(CCO[Si](C)(C)C(C)(C)C)c2c(O)c(F)ccc21
Product: NCCc1cn(CC2CCCCO2)c2ccc(F)c(O)c12
Yield: 45 %

Procedure:
Following the procedure (step 4, scheme 17) used to prepare compound 17-5, compound 19-2 was used as starting material, using Pd(OH)2/C (20%) as source of Pd to afford 19-3 (45% yield) as a white solid. The compound was then converted to the hydrochloride salt. 1H NMR (D2O, 300 MHz) δ (ppm) (HCl salt): 7.06 (s, 1H), 7.03 (dd, J=11.2, 9.1 Hz, 1H), 6.89 (dd, J=9.1, 3.6 Hz, 1H), 4.10 (dd, J=15.1, 4.1 Hz, 1H), 4.04 (dd, J=15.1, 7.7 Hz, 1H), 3.75-3.84 (m, 2H), 3.27-3.36 (m, 3H), 3.12-3.17 (m, 2H), 1.63-1.79 (m, 2H), 1.40-1.50 (m, 3H), 1.20-1.28 (m, 1H). LRMS: calc 292.2 found 293.1 [MH]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[N:12]([CH2:13][CH2:14][O:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=[CH:10][C:9]=1/[CH:35]=[CH:36]/[N+:37]([O-])=O.[F-].[Na+].O>O1CCCC1>[NH2:7][C:8]1[N:12]([CH2:13][CH2:14][O:15][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]=[CH:10][C:9]=1[CH2:35][CH2:36][NH2:37]
Reactant: Nc1c(/C=C/[N+](=O)[O-])cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Yield: 88.1 %

Procedure:
To a suspension of lithium aluminum hydride (3.22 g) in tetrahydrofuran (100 ml) was added 5-amino-4-[(E)-2-nitroethenyl]-1-(2-triphenylmethyloxyethyl)-1H-pyrazole (4.4 g) under ice-cooling. The mixture was refluxed for 5 hours. After cooling on an ice bath, sodium fluoride (14.3 g) and water (6.12 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 5-amino-4-(2-aminoethyl)-1-(2-triphenylmethyloxyethyl)-1H-pyrazole (3.63 g). This product was used in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH2:12][N:13]([CH3:17])[CH2:14][CH2:15][CH:16]=1)=O.O.[OH-].[Na+]>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][CH:16]=[C:11]([CH2:9][OH:8])[CH2:12]1
Reactant: COC(=O)C1=CCCN(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC=C(CO)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
6.5 g of LiAlH4 (3.2 equiv.) was suspended in 100 mL dry THF and cooled with an ice bath. To this was added dropwise a solution of 8.27 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester (free base) in 50 mL dry THF. The mixture was stirred for 3 hours at room temperature. The mixture was cooled with an ice bath and 6.5 mL H2O, 13 mL 2 M NaOH and 6.5 mL H2O were added dropwise. The residue was filtered, washed with ether and the filtrate was concentrated in vacuo to yield 6.7 g of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 2.18-2.26 (m, 2H), 2.36 (s, 3H), 2.49 (t, J=6 Hz, 2H), 2.92-2.97 (m, 2H), 4.00 (br s, 2H), 5.68 (br s, 1H).