Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].Cl.[OH2:16]>>[O:13]=[C:4]1[CH2:5][CH2:6][C:7]2[C:12](=[C:11]([CH2:1][C:2]([OH:14])=[O:16])[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: O=C1CCc2cccc3c2N1C(=O)C3
Reactant: O
Agent: Cl
Product: O=C(O)Cc1cccc2c1NC(=O)CC2

Procedure:
A solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2,4(1H)-dione (1.87 g, 0.01 mole) in water (10 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the starting dione can no longer be detected by thin layer chromatography). The solution is cooled, and concentrated at reduced pressure. The product is purified by flash chromatography to vield 1,2,3,4-tetrahydro-2-oxo-8-quinoline acetic acid.
Reaction SMILES: C[O:2][P:3]([CH:17]([NH:19]C(OC(C)(C)C)=O)[CH3:18])([CH2:5][C:6]([C:13]([O:15]C)=[O:14])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:4]>Cl>[NH2:19][CH:17]([P:3]([CH2:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:2])[OH:4])[CH3:18]
Reactant: CCCCCC=C(CP(=O)(OC)C(C)NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Product: CCCCCC=C(CP(=O)(O)C(C)N)C(=O)O

Procedure:
The title compound was prepared from Methyl-1-t-butoxycarbonylaminoethyl-(2-carbomethoxy-1-oct-2-enyl)phosphinate (0.176 gm, 0.45 mmol) by stirring in concentrated HCl according to Example 33. The title compound as its hydrochloride salt (0.105 gm) was obtained as a hygroscopic white powder.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH3:16])[CH2:11][OH:10]
Reactant: C/C(=C\C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C/C(=C\C[C@H](N)CO)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of (4S)-2,2-dimethyl-4-((E)-3-phenyl-but-2-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.15 g) in dioxane (10 ml) at room temperature was added a 4 M solution of hydrogen chloride in dioxane (17.4 ml solution) and stirring was continued at room temperature overnight. The mixture was taken up in ethyl acetate and washed sequentially with aqueous sodium hydroxide solution (1 N), water and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/dichloromethane gradient; eluant containing 1% aq. ammonia) to yield a yellow oil, (185 mg, 28%); MS (ISP): 192.1 ([M+H]+).
Reaction SMILES: C([Al]([CH2:6][CH3:7])CC)C.[CH:8]1([Si](C)(OC)OC)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:20]=[CH:21]C>[Ti]>[CH3:20][CH2:21][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:8][CH2:6][CH3:7]
Reactant: C=CC
Reactant: CC[Al](CC)CC
Reactant: CO[Si](C)(OC)C1CCCCC1
Agent: [Ti]
Product: CCCCCCCCCC

Procedure:
400 ml purified decane was introduced into a glass autoclave with an internal volume of 500 ml purged sufficiently with nitrogen, and the liquid phase and gaseous phase were saturated by blowing 100 liters/h propylene. Thereafter, 10 mmol triethyl aluminum, 1.0 mmol cyclohexyl methyl dimethoxy silane, and the solid titanium component (a) in an amount of 0.2 mmol in terms of titanium atom were added in this order. The mixture was polymerized at 100° C. for 2 hours while the flow rate of propylene was regulated such that the unreacted gas was not leaked out through a bubbler tube connected a purge line and the inside of the reactor was not under reduced pressure. Then, the propylene gas was replaced by a nitrogen gas with which the unreacted propylene gas was purged to terminate the reaction, to give decane slurry containing polypropylene modified at the terminal thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]#[CH:31])=[O:28])=[C:22]([F:32])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH2:33](Cl)Cl>[Au](Cl)(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[O:28][C:31]([CH3:33])=[CH:30][N:29]=4)=[C:22]([F:32])[CH:21]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: ClCCl
Reactant: C#CNC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc(Cc2ccc(OCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)cc2F)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]-N-ethynylacetamide (20 mg, 0.042 mmol) in a 10:1 solution of DCM:acetonitrile (0.55 mL) was added gold chloride (˜1.3 mg, 0.004 mmol) and the resulting mixture stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure. The material was purified using preparative RP-HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer to afford the title compound. HPLC/MS; 1.52 min (2 minute run), 471 (M+H)+. GPR119 Human EC50: 2.5 nM
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([C:33]1[S:34][C:35]([C:38]2([OH:45])[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)=[CH:36][N:37]=1)[CH3:32]>>[CH2:31]([C:33]1[S:34][C:35]([C:38]2([OH:45])[CH2:39][CH2:40][CH:41]([N:8]3[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=5)[N:18]([CH3:29])[N:17]=4)[CH2:11]3)[CH2:42][CH2:43]2)=[CH:36][N:37]=1)[CH3:32]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-(2-ethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[NH2:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)c(Cl)c1
Yield: 96.5 %

Procedure:
22.1 g of 3,4-dichloro-nitrobenzene and 70 g of toluene are placed in an agitator autoclave, and the catalyst suspension is flushed in with 4 g of water. Hydrogenation subsequently takes place at a temperature of 100° C. and at a hydrogen pressure of 5 bar. When the hydrogen uptake is complete, the autoclave is cooled and rendered inert with nitrogen. The catalyst is filtered off and washed with toluene. After working up by distillation, 18.0 g of 3,4-dichloroaniline (yield 96.8% of theory) are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.06 g, 0.15 mmol, obtained in example 90) and DMAP (0.001 g, 0.0058 mmol) in pyridine (0.6 mL), methanesulfonyl chloride (0.017 mL, 0.22 mmol) was added under argon atmosphere and cooled with an ice bath (0.017 mL, 0.22 mmol). This was stirred overnight at room temperature. The solvent was concentrated. The residue was dissolved in CHCl3 and saturated NaHCO3 was added. The phases were separated. The organic phase was dried over Na2SO4 and concentrated. The crude product obtained was purified by chromatography on silica gel using EtOAc as solvent, and 70 mg of the title compound was obtained (yield: 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>CC(O)C>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1ccccc1F
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Solvent: CC(C)O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3F)c2c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (80 mg, 0.293 mmol, 1.0 eq.) and 2-fluoroaniline (65 mg, 0.58 mmol, 2 eq.) in i-PrOH (5 mL) was stirred at 85° C. for 18 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with H2O (10 ml) and diethyl ether (10 mL). After drying, the crude product was purified by PREP-HPLC (Condition C: Gradient: B=5%-50%, Target Peak: at 7.2 min) to give 16.5 mg of N-(2-fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine as a yellow solid, yield 16.4%. LCMS m/z=347.0 (M+1) (Method A) (retention time=1.31 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.33 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.80 (d, J=1.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.58 (dd, J=8.8, 1.2 Hz, 1H), 7.44-7.35 (m, 3H), 3.97 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH:12]=[CH:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CCCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C=CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a cold (0° C.) solution of 2-methoxy-pyrrolidine-1-carboxylic acid benzyl ester (example 4, step 4, 500 mg, 1.0 eq.) in dichloromethane was added N-diisopropylethyl-amine (0.5 mL, 1.36 eq.) and trimethylsilyltrifluoromethanesulfonate (0.51 mL, 1.3 eq.). The reaction mixture was stirred at 0° C. for 30 min and partitioned between dichloromethane and an aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and evaporated in vacuo and purified on silica eluting with 19:1 cyclohexane/ethyl acetate to yield 325 mg (75%) of the desired product as a colourless oil. MS (m/e): 204.5 (MH+, 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>S(Cl)(Cl)=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]2)=[O:17])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](CCCCCC(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@H](CCCCCC(=O)OOC(=O)CCCCC[C@H]2CC[C@H](OC(C)=O)CC2)CC1
Reaction time: 72 h

Procedure:
trans-6-(4-Acetoxycyclohexyl)hexanoic acid (4.8 g) is dissolved in thionyl chloride (5 ml), and the solution is allowed to stand at room temperature for 3 days. The excess thionyl chloride is distilled off under reduced pressure togive a crude acid chloride. This product is dissolved in petroleum ether (40 ml), and ice-water (20 ml) is added. Thereafter, sodium peroxide (3 g) is added portionwise with ice-cooling and stirring. The mixture is extracted with chloroform and the extract is washed with saturated aqueous sodium chloride and dried over calcium chloride. The solvent is then distilled off under reduced pressure to give bis[trans-6-(4-acetoxycyclohexyl)hexanoyl]peroxide.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:24].[CH:25]([NH2:27])=O.CC(C)([O-])C.[K+]>C(O)C.C(O)(=O)C>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C:6]1[N:27]=[CH:25][NH:24][C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: [NH4+]
Reactant: NC=O
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1cc(Cc2cccc(C(F)(F)F)c2)nc[nH]1
Temperature: 100 °C

Procedure:
Ethyl-(3-trifluoromethylphenyl)acetoacetate (15.3 g, 0.056 mol) is added to a solution of ammonium acetate (21.6 g, 0.28 mol) in ethanol (100 ml) and the mixture is refluxed for 3 hours. The solution is concentrated under reduced pressure and then suspended in ethyl acetate. The suspension is washed with water and saturated brine and the organic layer concentrated. The material is then dissolved in dimethylsulfoxide (125 ml) and formamide (20 ml) and potassium tert-butoxide (1.28 g, 0.011 mol) are added. The solution is heated for 18 hours at 100° C. Upon cooling the solution is poured into ice (1000 ml) and glacial acetic acid (20 ml). The resulting solid is collected and air dried. The material is then triturated with diethyl ether and is air dried to give 6-(3-trifluoromethylbenzyl)pyrimidin-4-one (7.20 g).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[O:39]([C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=[O:50])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[OH:50][CH:49]([C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=1)[C:35]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=1)[C@@H:8]1[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]1[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)c3cccc(Oc4ccccc4)c3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(Hydroxy-((3-phenoxy)phenyl)methyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3-phenoxybenzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc(N)c2)cc1
Yield: 93.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl)amine (2.70 g) [prepared as described in step (a) above] in methanol (100 ml), nickel chloride hexahydrate (3.37 g) and sodium borohydride (1.13 g) were reacted, to afford the title compound (2.32 g) as a yellow oil.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH:11]([OH:13])[CH3:12].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:13][CH:11]([CH3:12])[CH2:10][NH2:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)CN
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(CN)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (2.6 g 17 mmol) was dissolved in DCM (20 mL). 1-Amino-propan-2-ol (1.2 g, 16 mmol), triethylamine (2.2 mL, 16 mmol) and a catalytic amount of DMAP were added. The reaction mixture was stirred for 16 h. Water (10 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The product was isolated as an oil. Yield: 2.4 g, 80%.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:23].[Mn+2:24].[Cl-:25]>CO>[Cl:23][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]1[Cl:25].[Mn+2:24]
Reactant: c1ccc(CC2CNCCNCCNCCNCCN2)cc1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)Cc1ccccc1
Yield: 89 %

Procedure:
A solution of 2-phenylmethyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 6D (1.5 g, 4.9 mmole) and anhydrous manganese(II) chloride (0.62 g, 4.9 mmole) in anhydrous methanol was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and the solvent removed in vacuo. The yellow gummy solid was purified by stirring vigorously in acetone to give 1.89 g (89% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 395/397 [(M-Cl)+, 100/31]; Anal. calcd. for C17H31Cl2MnN5 : C, 47.34; H, 7.24; Cl, 16.44; N, 16.24. Found: C, 46.84; H, 7.51; Cl, 16.38; N, 15.86.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[N:31](COCC[Si](C)(C)C)[CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl.CCO>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(CCN3CCOCC3)CC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CCN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide (650 mg, 1.05 mmol) (as prepared in the previous step) in 10 mL of DCM was added 0.3 mL of EtOH and 3.0 mL of TFA, and the reaction was allowed to proceed for 2 h at 25° C. The reaction was diluted with 10 mL of EtOH and concentrated. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 9 min to give 600 mg (80%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.04 (s, 1H), 7.24 (dd, 1H), 7.14 (d, 1H), 5.84 (m, 1H), 3.84 (m, 4H), 3.76 (m, 2H), 3.50 (m, 2H), 3.30-3.10 (m, 4H), 2.92 (m, 5H), 2.30 (m, 4H), 2.20-2.00 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H36N6O2, 489.2. found 489.2.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[CH2:6][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:18]I>C(#N)C>[CH:1]1([NH:4][C:5](=[O:17])[CH2:6][N:7]([CH3:18])[C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(CN[C@@H]1C[C@H]1c1ccccc1)NC1CC1
Solvent: CC#N
Product: CN(CC(=O)NC1CC1)[C@@H]1C[C@H]1c1ccccc1
Yield: 81.9 %

Procedure:
To a solution of N-cyclopropyl-N-methyl-trans-2-(phenylcyclopropyl amino)acetamide (example 1, 240 mg, 1 mmol) in acetonitrile (10 mL), methyl iodide (140 mg, 1 mmol) was added and the solution was refluxed for 1 h. The mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (DCM:MeOH, 10:1) to afford the title compound as a white solid (200 mg, 57%). 1HNMR (CDCl3) δ (ppm): 0.44 (s, 2H), 0.73 (dd, 2H), 0.93 (m, 1H), 1.02 (m, 1H), 1.89 (m, 1H), 2.04 (m, 1H), 2.29 (s, 3H), 2.67 (m, 1H), 3.13 (m, 2H), 6.84 (br, 1H), 6.98 (d, 2H), 7.11 (q, 1H), 7.14 (m, 2H), 7.18 (d, 2H). MS (M+H): 244.7.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20]Br)=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[C:22]([O:25][CH2:20][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[Br:19])[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]2)(=[O:24])[CH3:23]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CBr)c(Br)cc21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Under a nitrogen stream, to a solution of 1-benzenesulfonyl-6-bromo-5-bromomethyl-1H-indole (14 mg, 0.03 mmol) in DMF (0.2 mL) was added sodium acetate (4 mg, 0.05 mmol), and the resultant mixture was then stirred for 2 hours at 80° C. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (2:5)), to thereby obtain the titled compound (11 mg, 85%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)([OH:22])[C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[CH:12]=1
Reactant: CN1CCC(Cl)CC1
Reactant: COc1cc2cc(Cl)ccc2c(=O)c2ncccc12
Solvent: C1CCOC1
Product: COC1=Cc2cc(Cl)ccc2C(O)(C2CCN(C)CC2)c2ncccc21
Yield: 52.8 %

Procedure:
Add a 1.5 M Grignard solution of N-methyl 4-chloropiperidine (150 mL, 22.5 mmol) in THF dropwise over a 7 minute period to 5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00 g, 18.4 mmol) in THF (70 mL) at 0° C. and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH4Cl (pH 8) and extract (3×) with CHCl3. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Purify via flash chromatography (CH3OH 5% in CH2Cl2) to give the title compound (3.60 g, 53%) as a solid. The solid may be recrystallized from isopropyl ether to give a white powder (mp 168°-170° C.).