Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[CH:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[C:35][C:2]3[CH:18]=[CH:17][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)C1CCN(Cc2ccc(I)cc2)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)C1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 2-[1-(4-iodobenzyl)piperidin-4-yl]propan-2-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 45 mg (30% of theory); melting point: 194-195° C.; C30H31ClN2O2 (M=487.04); calc.: molecular ion peak (M+H)+: 487/489; found: molecular ion peak (M+H)+: 487/489; Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: Cl.[NH2:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29].Cl[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)([C:17]([F:18])([F:19])[F:20])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 44.2 %

Procedure:
In a suspended solution of 0.13 g of N-aminomethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide hydrochloride synthesized in Synthetic Example 32 in 4 ml of dichloromethane, 0.03 g of methyl chloroformate and 0.08 g of triethyl amine were added with stirring at room temperature, and stirred at room temperature for 3 hours. After the completion of the reaction, the solvent was distilled under reduced pressure, the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.06 g of the aimed product as colorless resinous substance.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23](N)[N:24]=C2)=CC=1>>[NH2:24][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Reactant: Nc1cc2ccc(Br)cc2cn1
Product: Nc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromoisoquinolin-3-amine. +ESI (M+H) 189.2; 1H NMR (400 MHz, CD3OD, δ): 8.87 (s, 1H), 8.52 (d, J=0.78 Hz, 1H), 7.98 (dd, J=8.78, 1.76 Hz, 1H), 7.54 (d, J=8.78 Hz, 1H), 6.77 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>CN(C=O)C>[O:26]=[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) in DMF (8 ml) was added succinic anhydride (79 mg). The reaction mixture was stirred at room temperature for 2.5 hr and a precipitate was collected, washed with DMF and ethanol, then dried to give the title compound (106 mg) as a beige-coloured solid: m.p. 263°-264° C.; NMR (d6 -DMSO+CF3CO2H) δ 2.68 (4H, m), 3.80 (4H, m), 4.19 (4H, m), 7.20 (2H, d), 7.56 (2H, d), 7.82 (2H, d), 8.21 (2H, d), 9.62 (1H, s); m/Z 355 (M+H)+ ; calculated for C19H22N4 O3. 0.4 H2O: C, 63.1%; H, 6.36%; N, 15.5%; found: C, 63.1%; H, 6.4%; N, 15.7%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(O)CCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCc1ccccc1
Yield: 98.3 %

Procedure:
Into a four-necked flask provided with a thermometer and a stirrer, 150 g (1 mol) of 4-phenyl-2-butanol (XXX-35), 500 ml of toluene and 200 ml of pyridine were charged. 122.4 g (1.2 mol) of anhydrous acetic acid and 1 g of 4-dimethylaminopyridine were further added thereto to react them for 4 hours, while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid solution, extracted and fractionated, and then an organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water in the order. The thus-obtained Organic layer was concentrated under a reduced pressure to obtain 189 g of 2-acetoxy-4-phenylbutane (XXIX-35) with yield of 98.5%.
Reaction SMILES: [CH2:1]([N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26])[CH3:2]
Reactant: [H][H]
Reactant: CCn1ccc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Yield: 19.9 %

Procedure:
20 mg of palladium carbon was added to 10 ml solution of ethanol with 5 mg of 4-(2-ethyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen atmosphere. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 1 mg of the above compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH:1][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottomed flask containing 6-aminonaphthalen-2-ol (0.600 g, 3.8 mmol), in DCM (10 mL), was added p-Anisoyl chloride (0.972 g, 5.7 mmol), along with K2CO3 (1.57 g, 11.4 mmol). The mixture was stirred at ambient temperature overnight and was diluted with DCM and H2., Extraction with DCM (3×10 mL), drying of the organics over sodium sulfate, filtration, and concentration in-vacuo afforded the crude product. Recrystallization of the crude from DCM/Hexanes gave a tan colored amorphous solid, after drying (0.300 g, 1.0 mmol). MS (ESI pos. ion) m/z: 294 (M+H). Calc'd Exact Mass for C18H15NO3: 293.
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CC(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[N:26]=[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:25][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (70.8 g, 257 mmol) in IPA (2.96 L) was added thioisonicotinamide (71.1 g, 515 mmol) and the resulting mixture was refluxed for 3 days. The reaction was cooled and concentrated in vacuo and the residue was partitioned between DCM (300 ml) and saturated sodium bicarbonate solution (200 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined DCM layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude product which was purified by silica gel chromatography (ethyl acetate/DCM=0/100→40/60) followed by recrystallization from ethyl acetate/hexanes to give 33 g of the title compound as yellow crystals. (36% yield). LC/MS (FA) ES+ 359. 1H NMR (400 MHz, CDCl3) δ: 8.74-8.72 (m, 2H), 7.81-7.80 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.23 (m, 2H), 4.54 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=1)[C:44](Cl)=[O:45]>O1CCCC1>[Cl:39][CH2:40][C:41]1[CH:42]=[C:43]([C:44]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:45])[CH:47]=[CH:48][N:49]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: O=C(Cl)c1ccnc(CCl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(CCl)c3)CC4)nc12
Yield: 91.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.09 ml N-ethyldiisopropylamine and 0.017 g 2-chloromethyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.037 g (68%) (2-chloromethyl-pyridin-4-yl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=540 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC)=O.[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH2:36]>C1COCC1>[F:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34](=[NH:37])[NH:35][NH:36][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14]
Reactant: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(NN)c1cc(F)ccc1F
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=N)c1cc(F)ccc1F
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
The crude (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (4 g, 16.2 mmol) was converted to a mixed anhydride by adding Et3N (3.38 ml, 24.26 mmol), ethyl chloroformate (1.931 g, 17.79 mmol) in anhydrous THF (32.4 ml, 0.5 M) at −5° C. to 0° C. The mixture was stirred at −5° C. for 30 min. The resulting solid was filtered off and additional anhydrous THF was added to wash the precipitate. The resulting reaction solution was then added to a THF solution of 2,5-difluorobenzimido-hydrazide (2.77 g, 16.18 mmol) at −5° C. Then the reaction was gradually warmed to room temperature and stirred for overnight. Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified on silica gel column (50% EtOAc in Hexanes) to afford (R)-tert-butyl (1-(2-((2,5-difluorophenyl)(imino)methyl)hydrazinyl)-3-methoxy-3-methyl-1-oxobutan-2-yl)carbamate (1 g, 15%). LC/MS (uplc): MH+ 401.2, 0.61 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.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>[CH3:20][Si:19]([C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)([CH3:22])[CH3:21]
Reactant: C#Cc1ccc(C)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.1 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.64 g (0.0054 mole) of 4-methylphenylacetylene, 1.50 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.011 g (0.0058 mmole) of CuI, 0.103 g (0.146 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 10 ml of THF and 10 ml of triethylamine. The brown solution turned to an orange-yellow suspension when solid started to form. The mixture was stirred at room temperature under nitrogen for 3 days. It was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 25 ml of chloroform and the solution was washed two times with water (15 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.43 g (quantitative yield) of solid was obtained. 1HNMR indicated ˜10% of by product present. The solid product was used for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:24])[F:25])=[N:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylamine hydrochloride obtained by Example 57 (100 mg) and triethylamine (0.073 ml) in chloroform (10 ml) was added dropwise methanesulfonyl chloride (0.04 ml) at room temperature.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:36]>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:36])[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(N)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Temperature: 25 °C
Reaction time: 46.5 h

Procedure:
Under a nitrogen atmosphere, 2,6,7-trimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4 g) from Part D and ammonium acetate (40 g) were heated in a sealed tube to 150° C. After 46.5 hours, NMR analysis indicated that only 7% of the starting material remained. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and washed 3 times with 1N potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was triturated with 90/10 diethyl ether/toluene and the filtered solids were dried under vacuum at 45° C. The pale yellow solid was dissolved in 10% hydrochloric acid and extracted 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 3 times with DCM. The combined organic layers were washed once with water, 3 times with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 97/3 DCM/methanol as the eluant. The oil was then triturated with diethyl ether/toluene and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2,6,7-trimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 108.6–109.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[NH2:11].[Cl:12][CH2:13][C:14](O)=O>>[Cl:12][CH2:13][C:14]1[N:9]([CH3:10])[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=2[N:11]=1
Reactant: O=C(O)CCl
Reactant: CNc1cc(F)cc(F)c1N
Product: Cn1c(CCl)nc2c(F)cc(F)cc21
Yield: 21.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from 3,5-difluoro-N1-methylbenzene-1,2-diamine (1.50 g, 9.50 mmol) and 2-chloroacetic acid (1.3 g, 14 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 443 mg of 2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (Yield: 22%) as a purple solid.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>CN1C(=O)CCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Product: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 55.7 %

Procedure:
A solution of Intermediate 24b (593 mg, 3.45 mmol) and 4-piperidinemethanol (1.59 g, 13.8 mmol) in NMP (10 mL) was heated in the microwave at 170° C. for 3 h. The cooled mixture was applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4 2 M NH3 in MeOH. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in EtOAc, to give the title compound as a brown gum (481 mg, 56%). LCMS (Method 3): Rt 2.12 min, m/z 251 [MH+].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][C@@H:41]([CH3:45])[C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:42](=[O:43])[C@@H:41]([OH:40])[CH3:45])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Product: Nc1cccc(-c2cnc(OC3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 18A (160 mg, 0.57 mmol) was coupled with 3-aminophenylboronic acid (Lancaster, 157 mg, 1.14 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3—H2O, 90:10:1, Rf. 0.1) as solid (144 mg, yield, 86%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.21-2.29 (m, 1H), 2.74-3.04 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)c(OC)c1
Yield: 70 %

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28a (0.020 g, 0.075 mmol) was reacted with 2,4-dimethoxybenzylamine (0.25 g, 1.50 mmol) (Procedure E) to yield (2S,4R,5R)-2-benzhydryl-5-(2,4-dimethoxybenzylamino)-tetrahydropyran-4-ol, (−)-29e, 0.025 g (Yield; 70%, [α]D=(−)3.70, c=1, CHCl3).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:22]2\[C:23](=[O:28])[NH:24][C:25]3[C:21]\2=[CH:20][C:19]([F:18])=[CH:27][CH:26]=3)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCNCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: CCO
Product: CCNCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 95.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (99 g), ethanol (400 mL), 5-fluoro-2-oxindole (32 g) and pyrrolidine (1.5 g) were refluxed for 3 hours with stirring. The mixture was cooled to room temperature and the solids collected by vacuum filtration. The solids were stirred in ethanol at 60° C., cooled to room temperature and collected by vacuum filtration. The product was dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (75 g, 95% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.03 (t, 3H, CH3), 2.42, 2.44 (2×s, 6H, 2×CH3), 2.56 (q, 2H, CH2), 2.70, 3.30 (2×t, 4H, 2×CH2), 6.85, 6.92, 7.58, 7.72, 7.76 (5×m, 5H, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NH).