Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].CC#N.CN(C=O)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:9]#[C:10][C:5]1[N:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(N)cn1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
A mixture of 3-amino-6-bromopyridine (Alfa Aesar, 1.0 g, 5.8 mmol), ethynyl trimethylsilane (1.7 mL, 17.3 mmol), CH3CN (3 mL), DMF (2 mL) and Et3N (2 mL) was treated with CuI (60 mg, 0.32 mmol) and (Ph3P)4Pd (114 mg, 0.10 mmol) and the mixture stirred at 45° C. for 1.5 h. More ethynyltrimethylsilane (1.7 mL, 17.3 mmol) was added to the reaction and the mixture was stirred for 2 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using 0-6% EtOAc/hexanes to give the title compound (0.75 g, 68%) as a brown solid. 1H NMR (DMSO-d6) δ 7.85 (s, 1H), 7.15 (d, 1H, J=8.1 Hz), 6.81 (d, 1H, J=8.1 Hz), 5.76 (s, 2H), 0.19 (s, 9H); MS(ESI+): m/z 191.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH2:18][CH3:19])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([CH3:11])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[C:20](O)(=O)[CH3:21]>>[CH3:10][C:9]1[N:8]([CH2:20][CH3:21])[C:7]2=[N:6][C:5]([CH3:11])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:17][CH2:18][CH3:19])=[C:2]2[N:1]=1
Reactant: CC(=O)O
Reactant: CCNc1nc(C)c(C(=O)OCC)c(OCC)c1N
Product: CCOC(=O)c1c(C)nc2c(nc(C)n2CC)c1OCC

Procedure:
Crude 5-amino-4-ethoxy-6-ethylamino-2-methylpyridine-3-carboxylic acid, ethyl ester is refluxed in acetic acid overnight. The solvent is distilled off and the residue, 2,5-dimethyl-7-ethoxy-3-ethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is recrystallized from petroleum ether, m.p. 62°-65° .
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:36][C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1ccccc1-3
Reactant: Cn1cc(C=O)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(Cc1cnn(C)c1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-benzodiazocine-11-carboxylate (prepared as described in Example 48, Step 3) in MeOH (0.06 M), 1-methyl-1H-pyrazole-4-carbaldehyde (3 eq) was added and the pH adjusted to pH 4 with acetic acid. The solution was stirred at RT for 30 mins before addition of NaBH3CN (1.5 eq). The reaction was stirred at RT for 16 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a viscous oil (quantitative); MS (ES+) m/z 483 (M+H)+
Reaction SMILES: FC1C=CC(C[O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]3)=[C:12]([F:26])[CH:11]=2)=CC=1.Br>C(O)(=O)C>[F:26][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][C:13]=1[N:16]1[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]1
Reactant: O=c1n(CCCF)nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of 5.60 g (0.0153 mole) of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in 60 mL of glacial acetic acid was added 5 mL of 49% hydrobromic acid. This mixture was heated at reflux for 90 minutes, after which it was cooled to room temperature. The reaction mixture was then poured over ice, and the resulting aqueous solution was extracted with diethyl ether. The combined extract was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving 4.35 g of 1-(2-fluoro-4-hydroxyphenyl)-1,4dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one as a residue.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@@H:18]1[CH2:24][CH2:23][C@@H:22]2[C@@H:20]([O:21]2)[CH2:19]1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Si:16]([O:17][C@H:18]1[CH2:19][C@H:20]([OH:21])[C@@H:22]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:23][CH2:24]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2O[C@H]2C1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Yield: 51.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using the 1-methylpyrazole (500 mg, 6.09 mmol), n-butyl lithium (2.69 M solution in hexane, 2.37 mL, 6.37 mmol), tert-butyl(dimethyl) [(1S*,3R*,6R*)-7-oxabicyclo[4.1.0]hept-3-yloxy]silane (J. Pharm. Pharmacol., 49, 835-842, 1997; 1.32 g, 5.78 mmol) and THF (30 mL), to yield the title compound (932 mg, 52%) as a colorless solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[CH:26]=[C:27]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:34]([C:27]2[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([Cl:24])[CH:26]=2)(=[O:36])=[O:35])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Diisopropylethylamine (1.74 ml, 9.98 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.25 g, 1.25 mmol) in DCM (5 ml) at room temperature. To this mixture was added 3-chloro-4-nitrobenzene sulfonyl chloride (0.32 g, 1.25 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: % EtOAc: % Heptane) to give the title compound (0.44 g, 84% yield) as a white solid. δH (500 MHz, DMSO) 7.97-8.12 (m, 3 H) 6.93 (d, J=7.72 Hz, 1 H) 3.64 (d, J=12.77 Hz, 2 H) 3.43 (d, J=3.94 Hz, 2 H) 2.88-3.00 (m, 2 H) 1.78 (d, J=10.40 Hz, 2 H) 1.25-1.46 (m, 11 H). Tr=2.22 min, m/z (ES+) (M+Na)+ 442.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:16][C@@H:15]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:14]([CH3:26])[O:13][C:11]1=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH2-]CCC(C)C)CC(C)C.OO.[OH-].[Na+]>C1COCC1.O>[C:1]([O:9][C@@H:10]1[CH2:16][C@@H:15]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:14]([CH3:26])[O:13][CH:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OC(=O)[C@H](OC(=O)c2ccccc2)C[C@H]1OC(=O)c1ccccc1
Agent: CC(C)CC[BH2-]CCC(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1OC(O)[C@H](OC(=O)c2ccccc2)C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
The compound (IX) (5 g, 14.11 mmol) dissolved in dry THF (15 ml) is added to 0.5M Diisoamylborohydride (127 ml) prepared in the reaction (1). Then, it is stirred for 20 hours at a room temperature. After the reaction is finished, water (3 ml) is added and then stirred for 30 minutes. The reaction mixture is cooled to 0° C., and then 30% H2O2 (15 ml) is added and 3N NaOH is added to maintain the pH 7-8. The solvent THF is vacuum concentrated, and then it is dissolved in CH2Cl2 (100 ml) and washed by water (50 ml). An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated, and then the compound (II) (4.72 g, 93.8%, α:β=4.6:1) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2cccc(Br)n2)CC1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of 6-bromo-pyridine-2-carboxylic acid (100.00 mg, 0.50 mmol) in DCM (5.0 mL) was added 1-isopropylpiperazine (95.20 mg, 0.74 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 189.78 mg, 0.99 mmol), 1-hydroxybenzotriazole (HOBt; 133.78 mg, 0.99 mmol), and iPr2NEt (0.86 mL, 4.95 mmol). After 18 h at rt, the mixture was diluted with water and extracted with DCM. Purification by FCC provided the desired product (83.0 mg, 54%). MS (ESI): mass calcd. for C13H18BrN3O, 311.06; m/z found, 312.2 [M+H]+. 1H NMR (CDCl3): 7.69-7.59 (m, 2H), 7.56-7.52 (m, 1H), 3.84-3.76 (m, 2H), 2.79-2.68 (m, 1H), 2.62 (t, J=5.1 Hz, 2H), 2.53 (t, J=5.1 Hz, 2H), 1.06 (d, J=6.5 Hz, 6H). Assay 1 (Human H3): Ki=1400 nM.
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:32](C2C=CC3C=CSC=3C=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:43][S:44]([C:47]1[CH:55]=[CH:54][C:50](C(O)=O)=[CH:49][CH:48]=1)(=[O:46])=[O:45]>>[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:32](=[O:33])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([CH3:43])(=[O:46])=[O:45])=[CH:48][CH:49]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(S(C)(=O)=O)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 22 %

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-(methylsulfonyl)benzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(methylsulfonyl)benzamide (22.0% yield). MS m/z=611.4 [M+H], calc 610.77 for C31H42N6O5S.
Reaction SMILES: C(OC([N:7]1[C@@H:12]([CH3:13])[CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][C:20]3[C@H:26]([CH3:27])[C@H:25]4[N:22]([C:23](=[O:31])[C@@H:24]4[C@H:28]([OH:30])[CH3:29])[C:21]=3[C:32]([O:34]CC=C)=[O:33])[S:17][CH:18]=2)[CH2:9][CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:30][C@@H:28]([C@H:24]1[C:23](=[O:31])[N:22]2[C@@H:25]1[C@@H:26]([CH3:27])[C:20]([S:19][C:16]1[S:17][CH:18]=[C:14]([C:10]3[CH2:9][CH2:8][NH:7][C@@H:12]([CH3:13])[CH:11]=3)[N:15]=1)=[C:21]2[C:32]([OH:34])=[O:33])[CH3:29]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CCN1
Yield: 73.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (270 mg, 0.49 mmol) in dichloromethane (10 ml) were added acetic acid (73 μl) and tributyltin hydride (1.23 ml, 4.6 mmol) and added at room temperature bis(triphenylphosphine)palladium chloride(II) (36 mg, 0.051 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (log) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 3–5% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(6S)-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (151.5 mg) as a white amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]=3[NH:8][C:9]=2[CH:14]=1
Reactant: Nc1cccnc1Nc1cc(Cl)ccc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)Nc1ncccc1N=C2c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 6.6 g (0.02 mole) of [2-[(3-amino-2-pyridyl)amino]-4-chlorophenyl]-(phenyl)methanone (Intermediate 2) in 200 ml of toluene was heated at reflux over night under nitrogen atmosphere. The reaction mixture was filtered hot and the filtrate heated back to reflux temperature. The precipitate formed in cooling to room temperature was separated by filtration and recrystallized from benzene and dried 4 hr at 97°-98° C./0.1 mm Hg and over night at room temperature/0.1 mm Hg to give 3.7 g; m.p. 250.5° to 252° C. Elemental analysis for carbon was high and the product was redried at 139° C. (xylenes in drying pistol) for 8 hr. Although the carbon analysis remained high, the proton nuclear magnetic resonance spectrum and mass spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:3](=[O:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)CCc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 102 °C

Procedure:
21.6 g (131 mmol) 3-(3-pyridyl)-propionic acid methyl ester, 35.1 g (109 mmol) 4-(1-diphenylmethyl-piperidin-4-yl)-butylamine and 9.8 g (54.5 mmol) 30% sodium methylate solution in methanol are heated to boiling in 480 ml toluene for five hours. Subsequently, 30 ml of solvent is distilled off, sodium methylate precipitates thereby, and the temperature of the suspension increases under heavy foaming to 102° C. The mixture is cooled to 70-80° C. and extracted twice with 45 ml and 30 ml water. The organic phase is azeotropically dried in a moisture separator and cooled to ca. 0° C. The resulting precipitate is filtered and crystallized from 190 ml toluene. Colorless crystals with an MP of 139° C.; yield 46.3 g (93%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:3]=1.[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[NH:30][N:29]=[N:28][N:19]=3)=[CH:16][CH:17]=2)[CH3:11])=[O:8])=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-chloro-3-(3-chlorobenzyl)-N-[1-(4-cyanophenyl)ethyl]thiophene-2-carboxamide from Example 2, Step 1 (192 mg, 0.462 mmol) and azidotributyltin (0.380 mL, 1.39 mmol) in toluene (1 mL) was heated to reflux under N2 for 3 h and cooled to r.t. The crude was purified directly by flash chromatography (2-10% iPrOH/hexanes) to give the desired product as a white solid. MS (−ESI): m/z 456 (M−1)−.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][CH:5]2[CH2:4][N:3](C(OC(C)(C)C)=O)[CH2:2]1.Cl>ClCCl>[CH2:1]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NCCC2C1
Agent: Cl
Solvent: ClCCl
Product: c1ccc2c(c1)NCCC1CNCCN21

Procedure:
To a solution of Example 17A (50 mg, 0.165 mmol) in dichloromethane (5 mL) was added HCl (4 M in dioxane, 824 μL, 3.30 mmol). After reaction completion as indicated by LC/MS analysis, the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.48 (t, J=7.48 Hz, 1H), 7.36 (d, J=7.02 Hz, 1H), 7.19-7.29 (m, 2H), 3.47-3.57 (m, 1H), 3.35-3.44 (m, 2H), 3.10-3.35 (m, 6H), 1.76 (s, 2H); MS (ESI) m/z 204.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:33]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 42 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid (30 mg, 42%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[C:24]3[C:23](=[N:25][OH:26])[CH2:22][CH2:21][CH2:20][C:19]=3[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]=2[CH3:33])=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[C:1]([O:26][N:25]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[N:18]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:33])=[C:16]([S:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[C:24]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NOC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (4.33 mL, 45.8 mmol) was added to a slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (15 g, 38.2 mmol) in xylene (33.75 mL) and acetic acid (3.75 mL) and the mixture stirred at r.t. for around 20 mins. A sample of the title compound was isolated by filtration and dried at 40° C. m/z 435/437 (MH+); 1H NMR: 7.27-7.23 (2H, m), 7.00-6.96 (2H, m), 4.92 (2H, s), 4.19 (2H, q, J=7.1 Hz), 2.68-2.59 (4H, m), 2.19 (3H, s), 1.90 (3H, s), 1.89-1.81 (2H, m), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([O:24]C)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:34][NH2:35]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:34][NH2:35])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 215.5, 2.15 g, 4.99 mmol, 1.00 equiv) in methanol (20 mL), was added hydrazine hydrate (80%, 15 mL) batchwise. The reaction was stirred at 80° C. overnight. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:1) to furnish 1.13 g (53%) of the desired product as a pinkish solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10](N)=[N:11][C:12]=2[Cl:16])=[O:4].[CH3:20][S:21]SC.N(OC(C)(C)C)=O>C(#N)C>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10]([S:21][CH3:20])=[N:11][C:12]=2[Cl:16])=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc2c(Cl)nc(N)nc21
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CSc1nc(Cl)c2ncn(COC(=O)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a stirred solution of 2-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate 81 (0.566 g, 2 mmol) in acetonitrile (2 mL) was added methyl disulfide (0.94 g, 10 mmol), and tert-butyl nitrite (90%, 1.14 g, 10 mmol) and the resulting reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated in vacuo, and the resulting crude product was subjected to silica gel column chromatography (AcOEt/petroleum ether=1/10), which furnished 82 (0.364 g, 55%): 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 6.12 (s, 2H), 2.65 (s, 3H), 1.17 (s, 9H). MS (m/e) (positive-FAB) 315 (M+1)+.