Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2/[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[N:6][C:7](=[O:10])[S:8]/2)[CH2:18][CH2:17]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCCO)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)amino]-1,3-thiazol-2(5H)-one (1.20 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.54 g) in 2-propanol (20 mL) was added piperidinium acetate (1.09 g) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.12 g)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C@@H:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:11]2[C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[O:18])=[N:6][CH:7]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC(O)=O.CC(O)=O.[Pd]>[CH:31]1([C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C@@H:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:11]3[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[N:26]3[N:30]=[CH:29][CH:28]=[N:27]3)=[O:18])=[N:6][CH:7]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Br)cn2)c1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C3CC3)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(((5-bromopyridin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.052 g, 0.089 mmol), cyclopropylboronic acid (0.011 g, 1 mmol), Pd(Oac)2 (0.004 g, 0.018 mmol), tricyclohexylphosphine (0.01 g, 0.036 mmol) and K3PO4 (0.057 g, 0.267 mmol) in toluene (5 mL) and H2O (0.5 mL) was degassed, sealed and heated overnight at 100° C. in a microwave reactor. The reaction was filtered through a pad of diatomaceous earth, washing with EtOAc. The solvent was removed in vacuo and the crude was purified by reverse-phase preparative-HPLC to obtain the title compound. ESI-MS (m/z): 431 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@H]1CO

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C1COCC1.CCOC(C)=O>[CH:15]1([NH:18][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[CH2:17][CH2:16]1
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-N-methyl-3-nitrobenzamide (830 mg, 3.20 mmol), cyclopropanamine (666 μL, 9.61 mmol) in THF (10 mL) under N2 was heated at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using DCM-EtOAc (1:1) as eluent to give 2-(cyclopropylamino)-N-methyl-3-nitrobenzamide: 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.47 (m, 2H), 7.95 (dd, J=8, 4 Hz, 1H), 7.64 (dd, J=8, 4 Hz, 1H), 6.77 (dd, J=8, 4 Hz, 1H), 2.76 (d, J=8 Hz, 3H), 2.68-2.62 (m, 1H), 0.67-0.60 (m, 2H), 0.44-0.40 (m, 2H); LC-MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>CCCCO>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (327 mg, 1.63 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (140 mg) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. Then the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% gradient CH3CN/water gradient; 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3ylcarbamate (105 mg, 47% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[CH3:42][S:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=2)=[CH:33][CH:34]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: CS(=O)(=O)Oc1ccc(COC(=O)c2ccc(CC(SCCc3ccc(F)cc3)C(=O)OCC(Cl)(Cl)Cl)cc2)cc1
Yield: 53.1 %

Procedure:
The title compound was prepared from 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid (65 mg, 0.135 mmol) and methane-sulfonic acid 4-hydroxymethyl-phenyl ester (27.4 mg, 0.136 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was purified by flash chromatography using n-heptane/EtOAc 7:3 as the eluent to afford the final product as an oil (47.6 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.97 (d, 2H), 7.47-7.49 (d, 2H), 7.24-7.29 (m, 4H), 7.07-7.08 (m, 2H), 6.91-6.95 (m, 2H), 5.33 (s, 2H), 4.62-4.75 (dd, 2H), 3.55 (t, 1H), 3.25 (t, 1H), 3.13 (s, 3H), 2.79-3.04 (m, 6H). Mass Spectrum: M−H+ 663.04.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][C:45]=1[O:53][CH3:54]>>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](/[N:31]=[C:14]2/[N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]3)[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/2)=[O:50])=[CH:46][C:45]=1[O:53][CH3:54]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: COc1cc(C(=O)O)ccc1F
Product: COc1cc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)ccc1F

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-fluoro-3-methoxybenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxybenzamide (43.1% yield). MS m/z=581.4 [M+H], calc 580.69 for C31H41FN6O4.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]/[C:10]/1=[CH:34]\[C:35](OCC)=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>ClCCl.C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11]/[C:10]/1=[CH:34]\[CH2:35][OH:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\CO
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of (E)-4-(t-butyldimethylsilyloxy)-3-[(ethoxycarbonyl)methylidene]-1-(triphenylmethyl)piperidine (15.14 g) in dichloromethane (110 ml) was added dropwise a 1.01N solution of diisobutyl aluminium hydride in toluene (66.40 ml) at −70° C., and the resulting mixture was stirred at the same temperature for 3 hours. After stirring, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (13.22 g, yield: 95%) as a colourless amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO.O1CCCC1>[C:23]1([C:18]2[C:17]([NH:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:12][CH:11]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCCc1ccc(OCCNc2cccnc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCc1ccc(OCCNc2cccnc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
4-{4-[2-(2-phenylpyridinylamino)ethoxy]phenyl}butanoic acid methyl ester (149 mg) from the previous step was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and 2N sodium hydroxide aqueous solution (0.6 mL) was added, then stirred overnight at room temperature. The reaction solution was concentrated with 2N hydrochloric acid (0.6 mL), then the residue was purified by silica gel flash column chromatography (developing solvent: chloroform:methanol=19:1) to give the above-identified compound (115 mg, yield 80%) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNCCN1CCCC1
Solvent: ClCCl
Product: CN(CCN1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 6-chloropyridine-3-sulfonylchloride (636 mg, 3 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) in methylene chloride (10 mL) was added methyl-(2-pyrrolidin-1-ylethyl)amine (384 mg, 3 mmol; described in: J. Amer. Chem. Soc. 1955, 77, 3632-3634) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred over night at room temperature followed by the extraction with aqueous HCl (3%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.75 gram (80% yield) of the title compound: MS (ES) m/z 304 (M++1).
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[N:17][CH:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[CH:18][N:17]=[CH:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1cnccc21
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3cccnc3)C1)c1cnccc21
Yield: 17 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (136 mg, 0.31 mmol) with nicotinic acid (42 mg, 0.34 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxy-7-azabenzo-triazole (46 mg, 0.34 mmol), and N,N-diisopropylethyl amine (0.20 mL, 1.15 mmol), in N,N-dimethylformamide (4 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanol/dichloromethane to give 22 mg (17%) of the desired amide as a white solid. MS(EI): Exact Mass Calc'd for: C23H24N5O3 418.1879 m/z. Found: 418.1869 m/z.
Reaction SMILES: C(N(C)CCC(O)CCCC)C1C=CC=CC=1.[C:18]([O:22][C:23](=[O:37])[N:24]([CH2:26][CH2:27][C:28](=[O:36])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:37])[N:24]([CH2:26][CH2:27][CH:28]([OH:36])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(CCC(=O)CC1CCCCC1)C(=O)OC(C)(C)C
Agent: CCCCC(O)CCN(C)Cc1ccccc1
Product: CN(CCC(O)CC1CCCCC1)C(=O)OC(C)(C)C

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol, (4-cyclohexyl-3-oxo-butyl)-methyl-carbamic acid tert-butyl ester affords the title compound: 1H NMR (CDCl3) δ 3.90-3.80 (m, 1H), 3.62-3.52 (m, 1H), 2.88-2.96 (m, 1H), 2.83 (s, 3H), 1.80-1.60 (m, 6H), 1.56-1.32 (m, 3H), 1.47 (s, 9H), 1.31-1.08 (m, 4H), 0.98-0.77 (m, 2H).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][CH:36]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25ClN4O3 (m/e) 428, obsd 429 (M+H).
Reaction SMILES: C([C:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:16](=[O:20])[C:17]([OH:19])=[O:18])C.[OH-].[Na+].Cl>C(O)C>[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:16](=[O:20])[C:17]([OH:19])=[O:18]
Reactant: CCc1c(C(=O)C(=O)O)ccc2c1Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)c1ccc2c(c1)Cc1ccccc1-2
Yield: 79.8 %

Procedure:
A mixture of ethyl fluorene-2-glyoxylic acid (9.95 g) and sodium hydroxide (1.60 g) in 50% aqueous ethanol (100 ml) is refluxed for 0.5 hour, cooled and acidified to pH 2.0 with 10% HCl. The reaction mixture is extracted with ether, and the ether extracts dried (MgSO4) and evaporated. The residue is crystallized from benzene-hexane (Darco) to give the title compound (7.1 g. mp 135°-137°). The analytical sample is prepared by recrystallization from benzenehexane: mp 139°-140°.
Reaction SMILES: [C:1]1([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[H-].[Na+].C1(C)C=CC=CC=1>O>[Cl:22][CH2:21][CH2:20][CH2:19][O:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC(CCCc1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: ClCCCOC(CCCc1ccccc1)c1ccccc1

Procedure:
A mixture of 30 g of 1,4-diphenyl-1-butanol, 42 g of 1-bromo-3-chloropropane, 9.5 g of sodium hydride (65%) and 400 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(3-chloropropoxy)-1,4-diphenylbutane.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1>>[CH3:27][C:28]1[C:32]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CC(=O)O
Product: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. White solid. MS (ESI): 474.2 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([C:18]2[C:19]3[C:39]([CH3:40])=[N:38][N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:20]=3[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C4CCCCO4)=[CH:26][CH:25]=3)[CH:23]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:13][CH2:14]2)[N:11]([CH2:16][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:21]=[C:20]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:19]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Yield: 74 %

Procedure:
To a solution of 272 mg of) 4-{3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carbonyl}-4,7-diaza-spiro[2.5]-octane-7-carboxylic acid tert-butyl ester in 4 ml of dry THF 3.5 ml of borane-dimethyl-sulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 60 min. The reaction was quenched by the addition of 2.2 ml of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 170 mg (74%) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.NC1C=CC=CC=1.[OH:26][C:27]1[CH:28]=[C:29]([C:33](=[O:44])[CH:34]([CH3:43])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:30]=[CH:31][CH:32]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.COCCOC.CO.[Cu]I.CS(C)=O>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([O:26][C:27]4[CH:28]=[C:29]([C:33](=[O:44])[CH:34]([CH3:43])[CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:30]=[CH:31][CH:32]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CC(CCN1CCOCC1)C(=O)c1cccc(O)c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: COCCOC
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(C(=O)C(C)CCN4CCOCC4)c3)cc21
Temperature: 170 °C
Yield: 46 %

Procedure:
Under argon, to a suspension of 4-(6-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-amine (prepared by the method of Example 8, Steps 3-7, substituting ethylamine for aniline in Step 3) (80 mg, 0.26 mmol) in toluene (4 mL) and DME (4 mL), was added the product of Step 2 (88 mg, 0.31 mmol), CuI (50 mg, 0.26 mmol), 1,10-phenanthroline (94 mg, 0.52 mmol), and Cs2CO3 (170 mg, 0.52 mmol). This mixture was then heated to 170° C. by microwave for 15 min. To the reaction mixture was added DMSO (2.0 mL), diluted with EtOAC/MeOH, sonicated for 10 min, then filtered and concentrated. The residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (72.0 mg, 46%). 1H NMR (400 MHz, DMSO) δ ppm 9.71 (bs, 1H), 8.77 (d, 1H, 0.8 Hz), 7.84 (d, 1H, 8.0 Hz), 7.69 (t, 1H, 2 Hz), 7.59-7.64 (m, 2H), 7.45 (dd, 1H, 8 Hz, 0.8 Hz), 6.96 (s, 2H), 4.70 (q, 2H, 7.2 Hz), 3.98 (d, 2H, 12.4 Hz), 3.60-3.81 (m, 2H), 3.42-3.47 (m, 2H), 3.01-3.19 (m, 4H), 1.96-2.01 (m, 1H), 1.41 (t, 3H, 7.2 Hz), 1.38 (d, 3H, 10.4 Hz). MS (ES+) m/e 492 [M+H]+.