Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Cl.[C:20]([O-])(O)=O.[Na+]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:20])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:17][CH:18]=1
Reactant: O=C(O)C1CCNC(Cc2ccc(Cl)cc2)C1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Yield: 87 %

Procedure:
To crude 2-(4-chlorobenzyl)piperidine-4-carboxylic acid hydrochloride (5.34 g, 20.9 mmol) was added HCl (1.25 M in MeOH, 60 mL). The resulting suspension was refluxed for 2 h and then concentrated to give a slightly yellow solid. The residue was taken up in satd NaHCO3 (100 mL). The aqueous phase was extracted with DCM (×3), the combined organic layers dried with a phase separator and evaporated to yield methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.85 g, 87%) as a brown oil. MS m/z 268, 270 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
To a solution of Example 120 (0.075 g, 0.140 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 1.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solid (0.023 g, 31% yield). MP: 127-129° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.18 (s, 1H), 8.19 (s, 1H), 7.74-7.61 (m, 3H), 7.38 (q, J=7.8 Hz, 1H), 7.15 (m, 3H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.65 (d, J=10.8 Hz, 1H), 5.54 (s, 2H). Mass: 515.54 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(Cl)cc2c1=O
Yield: 84.1 %

Procedure:
12 g (40 mmol) of the product from Example A in 100 ml of pyridine are heated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours. The mixture is concentrated in vacuo, the residue is stirred with 120 ml of water and the pH is adjusted to 5 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, boiled in 80 ml of methanol and dried. 12.3 g (84% of theory) 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of melting point 295°-298° (with decomposition) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@@H:31]1[NH:36][CH2:35][CH2:34][N:33]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[CH2:35][CH2:34][N:33]([C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][C:7]([CH3:19])=[N:6][CH:5]=1.O.O.[OH-].[Li+:24]>O1CCOCC1>[Cl:18][C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[O:10][C:9]1[C:4]([C:3]([O-:20])=[O:2])=[CH:5][N:6]=[C:7]([CH3:19])[CH:8]=1.[Li+:24]
Reactant: COC(=O)c1cnc(C)cc1Oc1cc(Cl)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 420 mg (1.345 mmol) 4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in 5 mL dioxane was added 5 mL water and 85 mg (2.018 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The so-obtained light yellow solid was pure enough for the next step without further purification. MS (ESI): m/z=298.004 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:16])([O-])=O.C(O)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(-c2cccnc2)ccc1O
Reaction time: 16 h
Yield: 101.6 %

Procedure:
A mixture of 2-nitro-4-pyridin-3-yl-phenol (80 mg, 0.37 mmol), 10% Pd-C (8.0 mg), acetic acid (21 μL, 0.37 mmol) in MeOH (3.7 mL) was hydrogenated at 45 PSI at RT for 16 h. The mixture was filtered through a pad of celite and concentrate to afford 70 mg (100%) of the title compound as a brown oil: 1H NMR (CDCl3, 400 MHz) δ 8.57 (d, 1H, J=1.7 Hz), 8.30 (d, 1H, J=5.0 Hz), 7.75 (dt, 1H, J=7.9, 2.1 Hz), 7.25 (dd, 1H, J=7.9, 5.0 Hz), 6.77-6.69 (m, 2H), 3.94 (br s, 3H); 13C NMR (CDCl3, 100 MHz) δ 147.0, 146.5, 145.7, 137.6, 135.5, 134.8, 129.3, 124.0, 118.1, 115.4, 114.6; MS (Cl) m/z 187.1 (M+1); HPLC retention time=1.29 min.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: OCCCc1nc2ccccn2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCCCc1nc2ccccn2n1
Temperature: 0 °C

Procedure:
To a solution of 34.5g of 2-(3-hydroxypropyl)-s-triazolo-[1,5-a]pyridine in 500 ml of chloroform is added dropwise 77g of phosphorous oxychloride at a temperature of from 5° to 15°C. After the addition is completed, the reaction mixture is heated on a water bath for 1 hr. and then added to 300 g of ice-water. The mixture is then treated with an aqueous sodium hydroxide solution. Then the organic layer is separated from the aqueous layer, dried over anhydrous sodium sulfate and concentrated to give the residue, which is chromatographed over alumina with benzene. Twenty-three grams of 2-(3-chloropropyl)-s-triazolo[1,5-a]pyridine are obtained as colorless needles after recrystallization from cyclohexane, melting point 56.5°-57°C.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].C(Cl)Cl>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=N)NC(=N)N
Yield: 83.3 %

Procedure:
10.0 g of metformin hydrochloride and 2.40 g of sodium hydroxide were stirred in 100 ml of ethylalcohol at a temperature of 70° C., and then methylene chloride was added thereto. The produced inorganic salt was filtered, and ethyl acetate was added thereto, thus preparing metformin free-base. The produced crystal was filtered and dried in hot air, thus obtaining 6.50 g (yield: 83.4%) of metformin free-base.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (25.00 g, 145 mmol), para-methoxybenzyl chloride (24.89 g, 159 mmol), potassium iodide (2.17 g, 14.45 mmol), and potassium carbonate (39.9 g, 289 mmol) in acetone (600 mL) was heated to reflux for 18 h. The crude reaction mixture was then cooled to room temperature and filtered through a sintered glass funnel. The filtrate was concentrated in vacuo, and the white solid was recrystallized from ethanol yielding the product as a white solid (33.44 g, 79%). 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.95 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.32-7.40 (m, 4H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:3]>CO.N.[Ni]>[NH2:3][CH2:2][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C#N
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1CN

Procedure:
6.3 gm (0.02 mol) Of 1-(2-cyano-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloride were dissolved in 100 ml of methanol containing 10 ml of NH3 and the mixture was hydrogenated under normal pressure at 20°C over Raney-nickel. After separation of the catalyst, the solvent was distilled off in vacuo, and the residue was admixed with ether and water. After an addition of a small amount of NaOH the aqueous phase was separated and the organic phase was washed with water and dried over MgSO4. After distilling off the ether, a solid residue remained which was recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(2-aminomethyl- 4-chlorphenoxy)-2-hydroxy-3-tert.-butylamino propane. The base was dissolved in ethanol and ethereal HCl was added thereto. The precipitated crystals of the hydrochloride of the base were isolated to obtain 3.1 gm of the hydrochloride having a melting point of 118°-120°C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: Cc1cc(Sc2ccccc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Sc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 88.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (591.7 mg, 1.8 mmol, 1.0 equiv) and thiourea (134.3 mg, 1.8 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(phenylthio)phenyl)thiazol-2-amine (483.7 mg, 1.6 mmol) as yellow solids in 88% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.33-7.38 (m, 2 H), 7.29-7.33 (m, 3 H), 7.06 (s, 2 H), 6.89 (s, 2 H), 6.38 (s, 1 H), 2.07 (s, 6 H); ESI-MS: m/z 313.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][O:15][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC[C@@H]1COCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1COCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of (3R)-4-benzyl-3-hydroxymethylmorpholine (0.94 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil suspension, 0.22 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70° C. for 1 hour. After cooling, methyl iodide (0.31 ml) was added thereto and the mixture was stirred at 40° C. for 1 hour. After cooling, the mixture was poured into ice water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3:7) as an eluent to give (3R)-4-benzyl-3-methoxymethylmorpholine (0.88 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1Cl.Cl.Cl[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCNCCCl
Reactant: Cc1cccc(N)c1C1=CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 200 °C
Reaction time: 0.83 h
Yield: 73.5 %

Procedure:
To a mixture of 3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (663 mg, 2.72 mmol) produced in Example (71b) and 1,2-dichlorobenzene (3 mL) was added bis(2-chloroethyl)amine hydrochloride (632 mg, 3.54 mmol), followed by stirring for 5 hours and 50 minutes at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was passed through the reactor several times. The reaction mixture was cooled to room temperature, chloroform and saturated solution of sodium hydrogencarbonate were added, and the filtrate obtained by filtration through Celite was extracted with chloroform. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 625 mg of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2[nH]ncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cn[nH]c1N1CCC[C@H](N)C1
Yield: 23 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 103 as a white solid (27 mg, 23%) over two steps. 1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.48 (s, 1H), 7.86 (s, 1H), 7.54-7.49 (m, 2H), 7.28 (t, J=12 Hz, 2H), 3.19 (d, J=8 Hz, 1H), 3.09 (d, J=8 Hz, 1H), 2.82-2.77 (m, 1H), 2.67-2.60 (m, 1H), 2.43 (t, J=12 Hz, 1H), 1.84-1.81 (m, 1H), 1.75-1.55 (m, 2H), 1.15-1.08 (m, 1H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1cccc2nc(O)c(O)nc12

Procedure:
2.0 g of 2,3-dihydroxy-5-nitroquinoxaline was dissolved in 100 g of a 1:1 methanol and dioxane solvent, after which the reaction system was well purged with argon, followed by further addition of 1 g of 5% Pd/C (hydrous). Thereafter, the system was purged with hydrogen, followed by reaction at room temperature for 20 hours. After completion of the reaction, the reaction product was dispersed in a solution of 6.00 g of potassium carbonate in 130 ml of water and then dissolved therein. 35% hydrochloric acid was gradually added to the solution obtained after filtration thereby obtaining a precipitate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1=CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1=CCCCO1
Reaction time: 1 h
Yield: 112043.6 %

Procedure:
51.5 g (0.45 mol) of methanesulfonyl chloride are added dropwise to 45 g (0.39 mmol) of 6-hydroxymethyl-2,3-dihydropyran (Example 7a) and 50 g (0.5 mol) of triethylamine in 400 ml of methylene chloride at 0°-5° C. Stirring is carried out for 1 hour at 0° C. and the reaction mixture is poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water and is then dried over MgSO4 and evaporated down. 84 g of title compound are obtained as a red oil, which is used directly in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:13]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carbonyl chloride (1 eq) in anhydrous methylene chloride was added to the flask and brought to 0° C. To this was added the solution containing 4-chloropyridin-2-amine (1 eq), and diisopropylethylamine (5 eq) in anhydrous methylene chloride, which was stirred for 1 hour at 0° C. Reaction concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on silica gel, 10% methanol in methylene chloride to yield N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide as a slightly yellow crystal solid. HPLC=2.39 min; MS: MH+=254.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])=[CH:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:27])[CH:21]=[CH:22][OH:23])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C=CO)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To an ice cooled slurry of LiAlH4 (1.4 g) in dry ether (200 ml) was added a solution of ethyl 3-(4′-chloro-[1,1′-biphenyl]-4-yl)-but-2-enoate (3g, 2.8 g) in dry ether (50 ml) dropwise. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was quenched with water. A solution of 10% NaOH was added and the ether layer was decanted. The precipitate was washed with ether and the combined ether extract was concentrated. The crude product was chromatographed on silica gel to give 1.8 g (75% yield) of 3-(4′-chloro-[1,1′-biphenyl]-4-yl)-butenol (4g, formula 4, R=p-Cl—C6H4) m.p. 130-132° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCO
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCCCCO)c1ccccc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of benzoic acid (1 g), 1,5-pentanediol (5 mL) and p-toluenesulfonic acid (110 mg) was heated in an oil-bath at 100° C. overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (2×25 mL), washed with sodium carbonated (5%, 20 mL) followed by brine (15 mL). The organic layer was dried over anhyd. sodium sulfate, filtered and concentrated to give almost pure product (1.15 g, 67%).
Reaction SMILES: C([O:9][C@H:10]([CH3:31])[C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@@H:12]1[OH:30])(=O)C1C=CC=CC=1.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C.CCOC(C)=O.N>[CH3:29][O:28][CH2:27][CH2:26][O:25][C@@H:13]1[C@H:12]([O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:11]([C@@H:10]([CH3:31])[OH:9])[O:15][C@H:14]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(=O)c2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of Compound 10 (1.33 g, 3.06 mmol) and imidazole (2.09, 30.70 mmol) was dissolved in anhydrous DMF (11.4 mL). To this solution tert-butyldimethylsilyl chloride (2.31 g, 15.33 mmol) was added with stirring at room temperature for 16 h under an atmosphere of argon. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO3 (2×60 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was dissolved in methanolic ammonia (20 mL, 7 M) and stirred for 24 h at 55° C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and eluted with 50% EtOAc in hexanes to yield Compound 11 (1.21 g, 89%). ES MS m/z 455.2 [M+H]+.