Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH2:27])[CH3:26])[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH:27][C:29]3[C:30]4[N:38]=[CH:37][CH:36]=[CH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH3:26])[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Cc1c(F)ccc2cc([C@H](C)N)c(N3CCN(c4cnccn4)CC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(F)ccc2cc([C@H](C)Nc3ncnc4cccnc34)c(N3CCN(c4cnccn4)CC3)nc12
Yield: 46.7 %

Procedure:
Following the procedure described for Intermediate 13, Intermediate 15 (470 mg, 1.1 mmol) and TFA (3 mL) in DCM (6 mL) afforded (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine as a white foam, which was used in the next step without any further purification. Following the procedure described for Example 5, (S)-1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}-ethanamine (60 mg, 0.16 mmol), 4-chloropyrido[3,2-d]pyrimidine (33 mg, 0.19 mmol) and DIPEA (0.14 mL, 0.8 mmol) in NMP (1.2 mL) afforded the title compound (37 mg, 46%) as a brown solid. δH (DMSO-d6) 8.95-8.89 (2H, m), 8.55 (2H, d, J 14.1 Hz), 8.45 (1H, d, J 1.5 Hz), 8.19-8.14 (2H, m), 7.93-7.88 (2H, m), 7.74 (1H, dd, J 8.9, 6.3 Hz), 7.33 (1H, t, J 9.1 Hz), 5.98-5.90 (1H, m), 3.96-3.87 (2H, m), 3.87-3.75 (4H, m), 3.33-3.25 (2H, m), 2.58 (3H, d, J 2.3 Hz), 1.68 (3H, d, J 6.7 Hz). LCMS (ES+) 496 (M+H)+, RT 4.07 minutes (Method 4).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[CH2:19]([S:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:23])=[O:22])[CH3:20]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 16.5 g (0.1 mol) of ethyl 4-aminobenzoate and 16 g (0.2 mol) of pyridine in 200 mL of methylene chloride cooled to 0° C. add dropwise 13 g (0.1 mol) of ethanesulfonyl chloride. After the addition is complete stir the mixture at 20° C. for 4 hr. After this time extract the mixture with three 100 mL portions of 1N sodium hydroxide. Heat the basic extracts at reflux for 2 hr, cool to 0°-10° C. and carefully add 60 mL of concentrated hydrochloric acid. Collect the resulting precipitate to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Cl.[CH3:14][C:15]1([NH:21][C:22](=[O:24])[CH3:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>[I-].[K+].CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:18]2[CH2:19][CH2:20][C:15]([NH:21][C:22](=[O:24])[CH3:23])([CH3:14])[CH2:16][CH2:17]2)=[CH:7][CH:8]=1
Reactant: CC(=O)NC1(C)CCNCC1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1(C)CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 35.84 g of 1-(3-chloropropoxy)-4-fluorobenzene, 33 g of N-(4-methyl-4-piperidinyl)acetamide monohydrochloride, 54 ml of N,N-diethylethanamine, 0.1 g of potassium iodide and 1000 ml of N,N-dimethylformamide was stirred and heated for 1.5 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in a sodium carbonate solution in water and the product was extracted with dichloromethane. The extract was washed successively twice with water, twice with a sodium carbonate solution in water and again with water, dried, filtered and evaporated. The residue was purified by column chromatography (CHCl3 :CH3OH 95:5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 50° C., yielding 20.93 g of N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]acetamide; mp. 103.4° C. (interm. 2).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12.C1(O)C=CC=CC=1.[CH3:24][N:25]([CH2:27][CH2:28][NH2:29])[CH3:26]>CCOCC>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][NH:29][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12
Reactant: CC1(C)OCc2c1nc1ccccc1c2Cl
Reactant: CN(C)CCN
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CN(C)CCNc1c2c(nc3ccccc13)C(C)(C)OC2

Procedure:
A mixture of the starting material of formula I, 9-chloro-1,3-dihydro-3,3-dimethylfuro[3,4-b]quinoline (8.0 g, described in Example 31), phenol (15g) and the amine of formula H--Y--X, dimethylaminoethylamine (9.8 g), is heated at 150° C. for 18 hours under an atmosphere of nitrogen. Ether is added and the reaction is washed with 10% sodium hydroxide solution. The organic phase is extracted with 6 N hydrochloric acid and the aqueous phase is washed with ether. The aqueous phase is basified with 10% sodium hydroxide and extracted with ether. The organic extract is washed with water, dried, evaporated and crystallized from ethyl acetate to yield the title compound, mp 126°-127° C. The corresponding hydrochloride salt of the title compound is crystallized from ethanol, mp 182°-190° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([F:16])[CH:6]=2.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:3]=[N:4]2)=[CH:9][C:8]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(O)Cc1cc2cc(Br)cnc2cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3cc(F)c(CC(=O)O)cc3c2)cn1
Yield: 83.1 %

Procedure:
Nitrogen gas was bubbled through a suspension of (3-bromo-7-fluoro-quinolin-6-yl)-acetic acid (5 g, 17.7 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (3.86 g, 18.6 mmol), potassium carbonate (7.3 g, 53 mmol) in 1,4-dioxane (50 mL) and water (20 mL) for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (II) (248 mg, 0.35 mmol) was added and the mixture heated to reflux for 3 hours. The aqueous phase was removed via pipette, diluted with 2N aqueous potassium carbonate (15 mL) and washed with ethyl acetate (2×30 mL). The aqueous phase was then acidified to pH 3 with concentrated hydrochloric acid. The formed precipitate was collected via filtration and washed with water and dried to return the title compound as a white solid (4.2 g, 14.7 mmol, 83% yield). 1H NMR 500 MHz (DMSO-d6): δ 3.84 (2H, s), 3.92 (3H, s), 7.71 (1H, d), 7.90 (1H, d), 8.10 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.18 (1H, d). ES-MS m/z: 286 (M+H+).
Reaction SMILES: C[NH2:2].[C:3]([O:13]C)(=O)[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>>[C:3]([NH2:2])(=[O:13])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CN
Product: NC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methylamine (40% in water, 3.8 equivalents) is added, at ambient temperature, methyl (S)-mandelate (1.0 equivalent; commercially available), while keeping the temperature below 30° C. and stirred at ambient temperature until full conversion is achieved. Excess methylamine is removed by azeotropic distillation. Alternatively, after neutralisation with aqueous hydrochloric acid the aqueous solution is saturated with sodium chloride and extracted several times with dichloromethane. The organic layers are combined and the water is removed by azeotropic distillation.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[C:6]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCC(=O)OCC1CO1
Reactant: CNCCO
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)OCC(O)CN(C)CCO
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was charged with 6.01 g (80 mmol) of N-methylethanolamine, 50 ml of ethanol and 22.8 g (80 mmol) of glycidyl tetradecanate, and the contents were stirred at 80° C. for 2 hours. The resultant reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel, thereby obtaining 17.5 g (yield: 60.8%) of the title compound (IIe-2).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[N:24]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
36 mg (0.90 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 173 mg (0.75 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 214 mg (0.75 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to yield 227 mg (63%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5](Cl)[CH:4]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)nc(N2CCOCC2)n1
Solvent: c1ccncc1
Product: COc1cc(N2CCNCC2)nc(N2CCOCC2)n1

Procedure:
A solution of 2,4,6-trichloropyrimidine (55 g), methanol (50 ml) and collidine (50 g) is heated in dry tetrahydrofuran (400 ml) for 48 hr. Ether is added and the precipitate is collected. The precipitate is column chromatographed on silica gel to give 6-methoxy-2,4-dichloropyrimidine. This product is mixed with morpholine in THF and stirred at 20°-25° to give 6-methoxy-2-morpholino-4-chloropyrimidine. The 6-methoxy-2-morpholino-4-chloropyrimidine is heated with piperazine in pyridine at 60° for 24 hr to give the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:17]([O:19][CH3:20])=[O:18])([O-:28])=[O:27]
Reactant: COc1ccc(O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 65.6 %

Procedure:
To a 100 mL round-bottomed flask containing potassium hydroxide (4.7 g; 82.0 mmol) dissolved in water (20 mL) was successively added 4-methoxyphenol (10.0 g; 80.6 mmol) and methyl 4-chloro-3,5-dinitrobenzoate (20.2 g; 77.5 mmol). The flask was fitted with a reflux condenser and the reaction heated at 150° C. (oil bath) for 3 hours. After cooling to room temp, the reaction mixture was transferred to a large mortar and triturated with cold 2N NaOH (100 mL) to remove unreacted phenol. The solid was collected by filtration and air-dried to give 21.5 g of crude product. Crystallization from absolute ethanol gave 17.7 g (65.6%) of pure methyl 3,5-dinitro-4-(4-methoxyphenoxy)benzoate as light yellow needles. 300 MHz 1H NMR (CDCl3) d 3.77 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.82 (m, 4H, ArH), 8.70 (s, 2H, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)([O-:12])=[O:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O

Procedure:
A solution of 10.0 g (46 mmol) of 1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, ethyl ester [J. Chem. Soc., 2518 (1962)] and 50 ml of sulfuric acid is stirred in an ice bath and a cold mixture of 9.75 ml of 70% nitric acid and 9.75 ml of sulfuric acid is added dropwise over 10 minutes. The reaction solution is stirred with ice bath cooling for 1 hour and then is poured into ice and water with stirring. The resulting solid is collected by filtration and washed with water and ethanol. After drying, 10.7 g of the requisite ester is obtained, mp>310° C. The structure is assigned by an unequivocal synthesis from the condensation of 2-amino-5-nitro-benzaldehyde and diethyl malonate to give the same 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 41 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and o-tolylboronic acid (8 mg, 0.06 mmol). The title compound was obtained in 41% yield (8.1 mg). MS (ESI+) calcd mass for C18H15N5O2S2 397.066716, found 397.066896.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[F:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]2[CH2:40][O:39]2)=[CH:34][CH:33]=1>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:40][C@H:38]([OH:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(F)cc3)cc2)CC1
Yield: 21 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.400 g, 0.95 mmol) was reacted with (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.119 g, 0.713 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.085 g, 0.15 mmol).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]([NH:13][C:14]([NH2:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([NH:13][C:14]([NH:16][C:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)(C)NC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)NC(=O)NC1=CC(=O)CCC1
Yield: 66.7 %

Procedure:
To a solution of 11.2 g of 1,3-cyclohexanedione in 250 ml of benzene is added 11.6 g tert-butylurea and 100 mg of p-toluenesulfonic acid. The solution is heated at reflux under nitrogen with water removal for three hours. At the end of this period the solution is cooled and the precipitated product removed by filtration. The precipitate is recrystallized from acetonitrile to give 14 g of 1-tert-butyl-3-(3-oxo-1-cyclohexene-1-yl)urea, m.p. 223°-225° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25][C:26]4[NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[N:27]=4)[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:10][CH2:9]1.ClC1C=CC=C(C(OO)=[O:44])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO.CO>[CH2:10]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25]([C:26]4[NH:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[O:44])[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:8][CH2:9]1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a toluene (30 ml)/methanol (3 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (290 mg, 0.73 mmol) obtained in the step (9h), a toluene/methanol (10:1) solution of 3-chloroperbenzoic acid (174 mg, 0.65 mmol as the content was regarded as 65%) was added at −70° C. in a nitrogen atmosphere. After the mixture was stirred at −50° C. for one hour, a saturated aqueous solution of sodium hydrogen carbonate was added. After the mixture was warmed to room temperature, the mixture was extracted with ethyl acetate twice. Organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate, ethyl acetate/methanol=9/1). Fractions containing the title compound was collected by use of ethyl acetate and concentrated. After diethyl ether was added to the residue, the solvent was distilled off to obtain the title compound (230 mg, yield: 76.2%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:19]([N:18]([C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Clc1nc2ncccc2o1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro[1,3]oxazolo[4,5-b]pyridine as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:11]
Reactant: Cc1cccc(Br)n1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A52, using 2-bromo-6-methylpyridine. ESI-MS (m/z): 338 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1.[BH4-].[Na+].O>C(O)C>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1cc(Cl)cnc1N
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of t-butyl (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoate (500 mg, 2.0 mmol) in ethanol (10 ml) at RT was added sodium borohydride (317 mg, 8.4 mmol) portionwise and the mixture stirred for 16 h. After the addition of water, the ethanol removed in vacuo and the mixture extracted with diethyl ether. The ethereal extracts were dried over MgSO4, evaporated to dryness and purified by column chromatography upon silica gel using hexane—EtOAc (7:3) as eluant to give t-butyl 3-(2-amino-5-chloro-3-pyridinyl)propanoate as a colourless oil (340 mg, 1.3 mmol).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:6]([OH:23])=[O:5])=[CH:14][CH:13]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 101.3 %

Procedure:
To a solution of 3-(4-cyanophenyl)-2-(R,S)-cyclohexyl-propionic acid t-butyl ester (8.2 g, 26.2 mmol) in dichloromethane (70 ml) was added trifluoroacetic acid (14.1 ml, 183.0 mmol) with stirring at room temperature. A gentle gas evolution ensued. After 69 h, solvent and excess trifluoroacetic acid were evaporated under reduced pressure. The solid was taken up in ethyl acetate and washed with water and brine, then dried (magnesium sulfate), filtered, and evaporated to dryness. The crude product was dissolved in methanol, treated with decolorizing carbon, filtered through celite, and concentrated. The resultant solid was recrystallized from toluene to afford the desired product as an off-white powder (6.83 g, 58%). mp.: 115-117° C., MS m/z: 258 (M+H)+.