Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]#[C:12][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH3:1])=[N:3][CH:4]=1)#[CH:12]
Reactant: Cc1ncc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
A solution of 2-methyl-3-nitro-5-[(trimethylsilyl)ethynyl]pyridine (2.32 g, 9.90 mmol) in methanol (22 mL) was cooled to 0° C. and potassium carbonate (137 mg, 0.99 mmol) was added. The reaction mixture was allowed to warm and stir at rt for 10 min, during which time a yellow precipitate formed. The reaction mixture was then concentrated and diluted with ether (200 mL). The organic solution was washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated to give 5-ethynyl-2-methyl-3-nitropyridine (1.48 g, 92%) as a solid. LCMS (FA): Rt=1.64 min, m/z=163.0 (M+H).
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.OC1C=CC([I:25])=CC=1C(OC)=O>>[I:25][C:13]1[CH:2]=[CH:3][C:4]2[O:8][CH:7]=[C:6]([CH2:9][CH2:10][NH2:11])[C:5]=2[CH:12]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: COC(=O)c1cc(I)ccc1O
Product: NCCc1coc2ccc(I)cc12

Procedure:
Synthesized as described for 2-(6-iodo-1-benzofuran-3-yl)ethanamine using methyl 2-hydroxy-5-iodobenzoate. 1H-NMR (400 MHz, DMSO-d6): δ 2.91 (t, J=7.7 Hz, 2H), 3.11 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.8 Hz, 1H), 7.90 (s, 1H), 8.09 (bs, 2H), 8.11 (d, J=1.7 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C@@H:12]([CH2:14][OH:15])[C@@H:11]([NH:16][CH2:17][CH:18]=[CH2:19])[CH2:10][CH2:9]2.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C@@H:12]([CH2:14][OH:15])[C@@H:11]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2
Reactant: C=CCN[C@H]1CCc2cccc(OC)c2[C@H]1CO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN[C@H]1CCc2cccc(OC)c2[C@H]1CO
Reaction time: 18 h

Procedure:
The mixture of 0.99 g (4.0 mmol) of cis-(+-)-1,2,3,4-tetrahydro-8-methoxy-2-(2-propenylamino)-1-naphthalenemethanol hydrochloride, 0.5 g 10% Palladium on carbon, and 80 mL of 95% ethanol was shaken in a Parr shaker apparatus under 50 p.s.i. of hydrogen atmosphere. After 18 hours, the mixture was filtered through a Celite pad, concentrated in vacuo. The resulting oil was treated with excess HCl/MeOH and recrystallized from ethyl acetate/methanol to give pure title compound as a white solid: m.p. 233°-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:27]([C:31]1[CH:32]=[C:33]([NH:34][C:24](=[O:25])[CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=2)[CH:35]=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2cccc(CCC(=O)O)c2)ccn1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Oc2cccc(CCC(=O)Nc3cccc(C(C)(C)C)c3)c2)ccn1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of 3-[3-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)phenyl]propanoic acid (333 mg, 0.93 mmol) in DCM (10 mL), were added 3-tert-butylaniline (152 mg, 1.02 mmol), DMAP (125 mg, 1.02 mmol) and then EDCI (196 mg, 1.02 mmol). The reaction was stirred for 18 h., and then diluted with DCM and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white solid (389 mg, 86%). LCMS: (FA) ES+ 490.2 (M+1), ES− 488.2 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: ClCCCN1CCOCC1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Product: O=c1oc2c(c(OCCCN3CCOCC3)c1-c1ccccc1)CCCC2
Yield: 45.7 %

Procedure:
Obtained by causing the reaction, as indicated in Example 14, Stage B, of 14.5 g. (0.06 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin with 15.6 g. (0.078 mol) of 3-morpholino-1-chloropropane. 10.1 g. of a paste which cannot be crystallised are isolated. Yield 45.7% (theoretical yield 22.1 g.).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[CH:13][CH:14]=1)#[N:17]
Reactant: OC1CNCc2occc21
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(OC2CNCc3occc32)cc1

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzonitrile instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[Li+].CS(C)=O>O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1

Procedure:
2-Chloro-5-nitropyridine (9.5 grams), 2,2,2-trifluoroethanol (6.0 grams), and lithium hydroxide (4.0 grams) were mixed in 50 ml. of DMSO and stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product was separated by filtration. It was crystallized from ethyl acetate-hexanes, yield 5.0 grams, m.p., 35°-37° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46][CH2:45]4)=[CH:40][CH:39]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][O:29]CC6C=CC=CC=6)[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([C:8]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:45][CH2:46][CH2:47]4)=[CH:40][CH:39]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](COCc7ccccc7)C6)c5)nc43)cc2)CCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](CO)C6)c5)nc43)cc2)CCC1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 14.6 %

Procedure:
10% Pd/C (30 mg) was added to a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-(3-{(2S)-2-[(benzyloxy)methyl]morpholin-4-yl}phenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (36.0 mg, 0.0488 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 14 hours and 7.5 hours at 50° C. under hydrogen atmosphere. The catalyst was removed by filtration through a Celite pad and washed with MeOH. The combined filtrate and washings were concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired compound (4.6 mg, 14.6%) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH:35]=[CH2:34])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 18 h

Procedure:
To a mixture of 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]- benzoic acid (150 mg) (prepared as described in Example 4) and potassium carbonate (125 mg) in DMF (5 ml) was added allyl bromide (0.076 ml). The mixture was stirred for 18 hours, then potassium carbonate (125 mg) and allyl bromide (0.076 ml) were added and the mixture stirred for a further 18 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The combined organics solutions were washed with brine (25 ml) and sodium bicarbonate (25 ml), dried (magnesium sulphate) filtered and evaporated. There was thus obtained allyl 4-[3-(2-benzyloxy-5-(allyloxy)phenyl)propyl]benzoate (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].CO[C:21]1(OC)[CH2:25][CH2:24][CH2:23]O1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:21]=[CH:25][CH:24]=[CH:23]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: COC1(OC)CCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)cc21
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-n3cccc3)cc21

Procedure:
2.5 Grams of 6-fluoro-7-amino-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 15 ml of acetic acid, and 1.32 gram of dimethoxytetrahydrofuran is added; the mixture is heated gradually until the solid dissolves, and is then allowed to cool. The precipitate formed is filtered off and washed with ethanol. The product is recrystallized in acetonitrile, and 1.4 gram of needles is obtained, of melting point 251°-252° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24]([C:26]6[C:27]([NH:32]CC7C=CC(OC)=CC=7)=[N:28][CH:29]=[CH:30][CH:31]=6)=[O:25])[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:42]([NH2:44])=[O:43])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:32][C:27]1[C:26]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:16]3[CH2:15][CH2:14][C:13]4[C:12]([C:42]([NH2:44])=[O:43])=[N:11][N:10]([C:8]5[CH:7]=[CH:6][C:5]6[O:1][CH2:2][O:3][C:4]=6[CH:9]=5)[C:18]=4[C:17]=3[CH:19]=2)=[O:25])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc4c(c2)OCO4)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cccnc3N)cc1-2
Yield: 32.5 %

Procedure:
The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 mL CH2Cl2 and reacted with 5 mL TFA at room temperature for 36 h. The crude reaction mixture was diluted with CH2Cl2 and basified with a saturated aqueous solution of Na2CO3. The layers were separated and the organic layer was dried over MgSO4. The residue obtained after removal of the solvent under vacuum was triturated with EtOH to afford 0.503 g of title compound (yield: 32%). Mp: 265-267° C. 1H NMR (300 MHz, d6-DMSO): δ 2.88-2.95 (m, 4H), 6.12 (s, 2H), 5.58-6.62 (dd, 1H, J=7.6 Hz, 4.7 Hz), 6.97-7.08 (m, 4H), 7.17 (d, 1H, J=1.9 Hz), 7.28 (s, 1H), 7.32 (s, 2H), 7.55 (s, 2H), 7.95-7.98 (dd, 1H, J=7.7 Hz, 1.7 Hz), 8.11-8.13 (dd, 1H, J=4.7 Hz, 1.7 Hz), 9.99 (s, 1H). M+1=469.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:6][C:5]=2[CH:1]=[C:2]1[CH3:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CCC1=O
Reactant: NCc1ccccc1
Product: Cc1cc2c(n1Cc1ccccc1)CCN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl-4-piperidone may be reacted with benzylamine to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH3:14][Mg]Br>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[CH:8][C:9]([CH:10]([OH:11])[CH3:14])=[CH:12][CH:13]=2)=[CH:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2ccsc2)nc1
Product: CC(O)c1ccc(-c2ccsc2)nc1

Procedure:
Synthesized using compound 56b (260 mg, 1.37 mmol) and methylmagnesium bromide (2.74 mL, 2.74 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Yellow solid. Yield: 240 mg, 85%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.50 (d, J=6.6 Hz, 3H), 4.90 (q, J=6.3 Hz, 1H), 7.38 (dd, J=5.0, 2.8 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.61 (dd, J=5.0, 1.3 Hz, 1H), 7.70 (dd, J=8.2, 2.2 Hz, 1H), 7.85 (dd, J=2.8, 1.3 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=25.2, 68.0, 120.4, 123.6, 126.4, 126.5, 134.3, 139.5, 142.0, 147.4, 152.9; (ESI): m/z=206.29 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@H:13]([F:15])[CH2:12][NH:11]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@H:13]([F:15])[CH2:12][N:11]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1ccc(F)c([C@H]2C[C@H](F)CN2)c1
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-67) was prepared by the method similar to that for Int-84 using (2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine hydrochloride (Int-47) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow solid. LCMS (ESI): m/z 390.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][NH:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][N:14]3[CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2noc(C3COCCN3)n2)c1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1cccc(-c2noc(C3COCCN3Cc3nccs3)n2)c1

Procedure:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-pyridin-2-ylmethyl-morpholine was obtained as described in Example 43 from (48 mg, 44%) 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine (80 mg, 0.30 mmol) with 2-thiazolecarboxaldehyde (68 mg, 0.60) and sodium triacetoxyborohydride (89 mg, 0.42 mmol). The product was purified by SPE chromatography on silica gel using 20–60% ethyl acetate in hexanes. 1H NMR (CDCl3), δ(ppm): 8.13 (s, 1H), 8.01 (d, 1H), 7.75 (d, 1H), 7.47 (m, 2H), 7.33 (d, 1H), 4.29 (m, 1H), 4.15 (m, 4H), 3.88 (m, 2H), 3.30 (m, 1H), 2.70 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:25])[C:12]([S:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1>O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:25])[C:12]([S:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cn1c(C(=O)c2ccc(Br)cc2)cnc1SCCCN1CCCCC1
Agent: O=[Mn]=O
Product: Cn1c(C(O)c2ccc(Br)cc2)cnc1SCCCN1CCCCC1
Yield: 20 %

Procedure:
The product of Example III, Step B (0.11 g) in acetone (5 mL) and DMF (5 mL) was treated with piperidine (0.22 g) and K2CO3 (1.8 g). The reaction mixture was allowed to stir for 16 h and then partitioned between EtOAc (75 mL) and aqueous (aq.) saturated (satd.) NaHCO3 (50 mL). The organic portion was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 2-5% MeOH/CH2Cl2 as the eluent to provide the title compound (0.27 g, 55%). M calc=423; M+H found=424. Step D: (4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone. The product from Example III, Step C (0.05 g) was subjected to the same conditions described in Example I, Step C (MnO2, 0.05g) to provide the title compound (0.01 g, 20%). M calc=421; M+H found=422. 1H NMR (400 MHz, CDCl3): δ 7.65 (dd, J=8.6, 2.0 Hz, 2H), 7.55 (dd, J=8.6, 2.0 Hz, 2H), 7.46 (s, 1H), 3.86 (s, 3H), 3.28 (t, J=7.1 Hz, 2H), 2.36 (tm, J=7.0 Hz, 6H), 1.91 (m, 2H), 1.55 (m, 4H), 1.40 (br m, 2H). The compound demonstrated useful biological activity when assessed with a [3H]—N-methylhistamine binding assay (see Table in Example XXV). Step E: Additional compounds prepared following Scheme I, and Example III, Steps A, B, C, and D. The following compounds of formula (I) were prepared following Scheme I and Example III, Steps A, B, C, and D; and substituting reagents, and adjusting reaction conditions as needed. The compounds were found to have useful biological activity based on the Ki (nM) value from a [3H]-N-methylhistamine binding assay.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxyphenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: tR 2.95 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.19-8.16 (m, 1H), 8.09-8.05 (m, 1H), 7.94-7.89 (m, 1H), 7.57-7.54 (m, 1H), 7.39-7.33 (m, 1H), 7.10-7.06 (m, 1H), 6.94-9-6.90 (m, 2H), 4.68 (hp, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.30 (t, 6H))
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][N:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)cnc1Cl
Temperature: 80 °C

Procedure:
0.5 g (3.38 mM) of 6-chloro-5-fluoro-3-pyridinol, 10 ml of dimethyl-formamide and 0.843 g (6.08 mM) of potassium carbonate are mixed. 0.8 ml (6.76 mM) of benzyl bromide is added and the mixture is heated at 80° C. for one hour. After hydrolysis in 100 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: pure toluene) to give the expected product in the form of a white solid with a quantitative yield.
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:6].[ClH:30].O1CCOCC1>O1CCOCC1>[ClH:30].[O:1]=[C:2]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)[CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NCC(=O)Nc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CNC(=O)[C@@H]1CCNC1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-{[(2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)amino]carbonyl}pyrrolidine-1-carboxylate (0.170 g, 0.41 mmol) in dioxane (0.5 ml), was added 4M HCl/dioxane (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated, and (3R)—N-(2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)pyrrolidine-3-carboxamide hydrochloride was obtained as a white solid and was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: c1ccc(-c2c[nH]c3ccncc23)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3cnccc32)cc1
Yield: 78.7 %

Procedure:
Add a 5 ml THF solution of 3-Phenyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 2.57 mmol, 1 eq) to a 4 ml THF solution of KotBu (303 mg, 2.70 mmol, 1.05 eq) under N2 atmosphere. Stir reaction for 10 minutes and then add a 5 ml THF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (844 mg, 2.57 mmol, 1 eq). Stir reaction for 16 hours, remove solvent on rotovap, and purify by silica gel chromatography to give N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzamide (982 mg, 79% yield). Mass Spectrum (m/e): 485.96 (MH+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(N=NC(C#N)(C)C)(C#N)C.[CH2:21]([SnH:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
A solution of 10.0 g (0.0908 mol) of 1-octyne, 60 ml of anhydrous toluene, 230 mg of azobisisobutylonitrile (AIBN), and 25 (0.0943 mol) of tri-n-butyltin hydride is refluxed under an argon atomosphere for 3 hours. The reaction mixture is cooled to ambient temperature and concentrated in vacuo. The resulting yellow liquid is distilled (bulb to bulb) to give 36.29 (99%) of the stannyl octene as a pale yellow liquid.