Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]#[CH:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:23]2[N:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:24]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1

Procedure:
A mixture of the crude phenylazide (1.37 g, 11.5 mmol) from above and 1-tert-butoxycarbonyl-4-ethynyl-1,2,3,6-tetrahydropyridine (2 g, 9.6 mmol) (Example 1) in toluene (20 ml) was refluxed for 24 hours. The reaction was cooled and the solvent evaporated in vacuo. The crude residue was chromatographed on silica eluting with ethyl acetate/petrol (60°-80° C.) (1:2) to give the 1-tert-butoxycarbonyl-4-(1-phenyl-1,2,3-triazol-4-yl)-1,2,3,6-tetrahydropyridine as a tan waxy solid (853 mg, 27%), δH (CDCl3) 1.49 (9H, s, OC(CH3)3), 2.59 (2H, br s, tetrahydropyridinyl CH2), 3.67 (2H, t, J 5.2 Hz, tetrahydropyridinyl CH2), 4.12 (2H, br s, tetrahydropyridinyl CH2), 6.53 (1H, br s, tetrahydropyridinyl 5-H), 7.42-7.46 (1H, m, ArH), 7.51-7.55 (2H, m, ArH), 7.72-7.75 (2H, m, ArH), 7.87 (1H, s, triazolyl 5-H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([N:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:15])[CH2:32][CH2:31]3)[C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: CC(C)CC1(CCCCCl)C(=O)Nc2ccccc21
Product: CC(C)CC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-isobutyl-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=O)[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.C(N(CC)CC)C.[CH3:36][C:37]([NH2:40])([CH3:39])[CH3:38].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:37]([NH:40][C:25]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][C:6]=3[CH:7]=1)[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18]2)=[O:27])([CH3:39])([CH3:38])[CH3:36]
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid (486 mg, 1.28 mmol) in dichloromethane (30 ml) was added triethylamine (366 mg, 3.62 mmol), 2-methylpropan-2-amine (212 mg, 2.90 mmol) and T3P (610 mg, 1.92 mmol), and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was then quenched with water (120 ml), extracted with dichloromethane (4×60 ml), and the organic layers combined and concentrated in vacuo to afford N-tert-butyl-2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide as a yellow solid (600 mg, crude), which was used to the next step without further purification.
Reaction SMILES: Cl[CH:2]([CH2:6][O:7][CH3:8])[C:3](Cl)=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:20]2[S:21][CH:22]=[CH:23][N:24]=2)(=[O:18])=[O:17])=[CH:12][C:11]=1[OH:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[S:16]([C:13]2[CH:14]=[CH:15][C:10]3[NH:9][C:3](=[O:4])[CH:2]([CH2:6][O:7][CH3:8])[O:34][C:11]=3[CH:12]=2)(=[O:18])=[O:17])=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Reactant: COCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1Oc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc2NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To a solution of 2-chloro-3-methoxypropanoyl chloride (500 mg, 3.18 mmol) and 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (Intermediate AD; 1.04 g, 2.65 mmol) in DMF (20 mL) was added Cs2CO3 (2.59 g, 7.95 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-30% ethyl acetate in hexane) to obtain N-(4-methoxybenzyl)-2-(methoxymethyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (500 mg, 33.1%) as an off white solid. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][C:29]([S:35][CH2:36][CH2:37][OH:38])=[CH:28]2>ClCCl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][C:29]([S:35][CH2:36][CH:37]=[O:38])=[CH:28]2
Reactant: COc1ccc2ncc(SCCO)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc2ncc(SCC=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (400 mg, 0.94 mmol, 2.0 eq) is added at 0° C. to a stirred solution of 2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol (130 mg, 0.55 mmol, 1.0 eq) in dichloromethane (5 mL). The reaction mixture is stirred at room temperature for 1 hour, concentrated to give a crude product that is directly engaged in the next step (130 mg, 100%).
Reaction SMILES: [I-].[C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N+:9]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH3:25][C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Mg]Br
Reactant: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(c2ccccc2)c2ccccc2CCN1Cc1ccccc1

Procedure:
To a suspension of 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium iodide (1.0 g) in diethyl ether (10 ml) was added 3 M diethyl ether solution of methylmagnesium bromide (4.5 ml). The mixture was refluxed for 30 minutes with stirring and then poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The separated organic layer was washed with water, sodium chloride aqueous solution and dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from n-hexane to give 1-methyl-1-phenyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline (0.64 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1.S(Cl)(Cl)=O.[CH2:29](Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:29])[N:9]=1
Reactant: ClCCl
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2O
Solvent: O=S(Cl)Cl
Product: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.435 g (1 mmol) of rac-6-(2-fluorophenyl)-4-hydroxy-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine, 3 ml of thionyl chloride and 20 ml of methylene chloride was stirred at room temperature for 2 hours. After evaporation under reduced pressure, the residue was dissolved in 20 ml of methanol and the solution was :reated with 3 ml of triethylamine. After heating on the steam bath for 5 minutes, the mixture was evaporated to dryness and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from ethyl acetate to yield colorless crystals of rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with m.p. 240°-242°. The analytical sample was recrystallized from methanol/ethyl acetate and had m.p. 243°-244°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:29])[C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4]>CCOCC>[CH2:22]([N:10]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:9]1[C:8]([CH3:29])=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1scc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)csc2C(=O)O)cc1
Yield: 106 %

Procedure:
In the same manner as described in Example 11, 1.366 g (2.622 mmol) of the product of Example 8 provided 1.16 g (87%) of the desired carboxylic acid as a white solid after trituration with ether. Electrospray Mass Spec: 416 (M—H)—.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][Br:10])=[CH:4][C:3]=1[F:9]
Reactant: BrCCBr
Reactant: Oc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(OCCBr)ccc1Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 4-chloro-3-fluorophenol (0.30 g, 2.05 mmol), 1,2-dibromoethane (1.15 g, 6.14 mmol), sodium hydroxide (0.12 g, 3.07 mmol), and water (3 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser and warmed to an oil bath temperature of 80° C. The progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. Another portion of 1,2-dibromoethane (1.09 g, 5.8 mmol) was added, and heating was continued for 24 h. The mixture was allowed to cool to ambient temperature, diluted with 20 mL of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (2×10 mL), saturated aqueous sodium chloride (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silical gel chromatography using a gradient elution of 0-100% ethyl acetate in hexanes. The title compound was obtained as a colorless oil (0.326 g, 63% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.48 (t, 1H), 7.12 (dd, 1H), 6.86 (dd, 1H), 4.35 (t, 2H), 3.80 (t, 2H).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])=[C:25]([CH3:38])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][C:28]([CH3:34])([CH3:35])[C:29]([OH:31])=[O:30])=[C:25]([CH3:38])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
To a solution of ethyl 2-{4-[(butyl{6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)methyl]-2-methylphenoxy}-2-methylpropanoate (45 mg, 0.085 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added 2M NaOH aq. (1 mL). The resulting mixture was heated to 70° C. for 1 h and then stirred at room temperature for 18 h, before heating to 70° C. for a further 4 h. The reaction mixture was allowed to attain room temperature and the solvents removed in vacuo. The residue was acidified with 2M HCl and extracted with EtOAc (2×10 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo. Purification by aminopropyl SPE (5 g) conditioning the cartridge, loading the compound and washing with methanol before eluting using 10% NH3 in methanol. Evaporation of the methanolic ammonia yielded a white solid, which was treated with 1 M HCl (5 mL) and then extracted into CH2Cl2 (20 mL). The organic extract was dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a colourless oil (19 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:29]([N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:30][CH2:29][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Temperature: 100 °C

Procedure:
The title compound was prepared by reacting the compound of Preparation 4a supra, 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with an equimolar amount of 2-(N,N-diethylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol). The mixture was heated to 100° C. and was maintained at that temperature for about two hours. The reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
Reaction SMILES: S1C=CC(CC=[O:8])=C1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH3:17]>C(Cl)Cl.CCOCC>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]=[O:8]
Reactant: O=CCc1ccsc1
Reactant: CC(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1ccccc1Cl

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 2-chlorophenyl-ethanol. The title compound: ES-MS: 152.9 [M−H]−; single peak at tR=3.82 min (System 2); Rf=0.70 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:29])[C:10]=3[CH:30]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:29])[C:10]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C(C)C)oc2ccc(OCC3CC3)cc12
Yield: 81.6 %

Procedure:
To a mixture of methyl 5-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridine-2-carboxylate (410 mg) synthesized above, tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred with heating under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, water (4 mL) was added to the residue, 1N hydrochloric acid (2 mL) was added under ice-cooling, and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (323 mg, 80%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:10]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:9]1[N:10]=[C:11]([N:28]2[CH2:29][CH2:30][N:31]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:32][CH2:33]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piperazin-1-yl-pyrimidine trifluoroacetic acid salt (722 mg), 2-bromoacetamide (290 mg, 2.11 mmol) and potassium carbonate (871 mg, 6.30 mmol) in DMA (10 mL) is stirred at room temperature for 3 h. The reaction mixture is partitioned between EtOAc (30 mL) and water (10 mL), the organic layer is separated, washed with water (10 mL×2), brine (10 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to yield a yellow oil. Purification by chromatography on silica gel affords the title compound as a colorless oil that solidifies on standing. 1H NMR (CDCl3) δ=7.10 (d, 1H), 6.92 (br, s, 1H), 6.82 (d, 1H), 6.74 (s, 1H), 5.54 (br, s, 1H), 4.83 (s, 2H), 3.61, (m, 4H), 3.04 (s, 2H) 2.90 (m, 1H), 2.63 (m, 4H), 2.47 (s, 3H), 2.14 (s, 3H), 1.27 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-(methylamino)-3-oxopropoxy)methyl)piperidine-1-carboxylate (0.80 g, 1.95 mmol) was dissolved in a 20% solution of TFA in CH2Cl2 (20.6 mL) and stirred for about 1 h at rt until the reaction was complete. The solvent was removed by evaporation and the crude product was purified with preparative HPLC to afford 3-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)-N-methylpropanamide (542 mg, 1.75 mmol, 90% yield). MS (E/Z): 311 (M+H+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.049 mmol). The resulting mixture was stirred at 40° C. for 3 h. The solvents were evaporated and the crude material purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.4 mg (20%) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H23F5N7O (M+H)+: m/z=496.2; Found: 496.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1

Procedure:
2.87 g 1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene are dissolved in 10 ml of ethyl acetate and 5 ml of ethanol. 0.3 g 10% palladium on carbon are added and the resultant mixture is stirred under hydrogen atmosphere (1 atm) overnight. The reaction mixture is filtered over Celite and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Br:15][C:16]1[CH:22]=[C:21]([O:23][C:24]([F:26])([F:27])[F:25])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1Br

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:17])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Product: CCOC(=O)Cn1c(=O)n(Cc2ccccc2)c2cc(Cl)c(Cl)cc21

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 210 mg. (0.0007 mole) of 5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester (prepared according to the procedure described in Preparation A) and 120 mg. (0.0007 mole) of benzyl bromide were reacted to afford crude 3-benzyl-5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester, which was used as such in the next reaction step (viz., hydrolysis to the corresponding acid as hereinafter described in Example 24) without any further purification being necessary.