Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(OC([C:11]1[CH:12]([CH3:25])[CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH+:17]([CH3:24])[C:16]=12)=O)C.Cl>CC(N(C)C)=O.CCOCC>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:25][CH:12]1[CH2:13][CH2:14][N:15]2[C:16]([NH+:17]([CH3:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=32)=[CH:11]1
Reactant: CCOC(=O)C1=C2N(CCC1C)c1ccccc1[NH+]2C
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CC1C=C2N(CC1)c1ccccc1[NH+]2C
Temperature: 25 °C

Procedure:
4-Ethoxycarbonyl-1,2-dihydro-3,5-dimethyl-5H-pyrido[1,2-a]benzimidazolium perchlorate (7.92g; 0.0213 mole) is boiled with stirring for 40 minutes in dimethylacetamide (50ml) containing concentrated HCl (3ml). During the reaction approximately half of the solution is allowed to boil away. The cooled reaction mixture is stirred overnight in a liter of ether. The ether is decanted and the residue is dissolved in hot water (300 ml) and filtered. Upon cooling to room temperature some gummy material separates on the walls of the flask. The clear solution is decanted, cooled with an ice bath, and treated with 30g of sodium perchlorate. The crude product which separates is filtered, washed with a little water then ether, and recrystallized from ethanol to give 3.28g (51.6%); m.p. 206°-210° d.
Reaction SMILES: C[SH:2].C[O-].[Na+].[Na].C12(C)C(C)(C)C(CC1)C[CH2+:8]2[CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]([O:19][CH3:20])=O>CO>[CH3:8][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]([O:19][CH3:20])=[S:2]
Reactant: COC(=O)CCCCCCC(C(=O)OC)[CH2+]1CC2CCC1(C)C2(C)C
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCC(C)C(=S)OC
Yield: 58 %

Procedure:
Methyl mercaptan (excess) is passed into a rapidly stirred solution of sodium methoxide (13.5 g., 0.25 mole) in dry methanol (200 ml.) at 0° C. to generate sodium methylmercaptide. The resulting solution is treated with dimethyl 2-bormoazelate (55.0 g., 0.186 mole), then stirred and heated at reflux under nitrogen for 5 hours. The reaction solution is concentrated in vacuo, diluted with ether and filtered. The filtrate is washed with water (until the washings are neutral), dried over sodium sulfate and distilled providing the title compound as a colorless liquid (28.4 g., 58%), bp 0.2 mm 128°-138° C.; pmr (CDCl3) δ 2.10 (s, 3H), 2.31 (t,2H), 3.20 (t,H), 3,63 (s,3H) and 3.71 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=S.[Cl:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:17][CH2:16]1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]2[O:25][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:27][N:26]=2)[CH2:19][CH2:20]1
Reactant: NNC(=O)CC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cc1nnc(Nc2ccccc2)o1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isothiocyanato-benzene (0.1 ml) and N-[1-(3,4-dichlorobenzyl)-piperidin-4-yl]-2-hydrazinocarbonyl-acetamide (0.10 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.162 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-cyclohexylcarbodiimide N-methyl polystyrene HL (0.319 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.045 g, m.pt 191-217° C., MS [M+H]+ (APCI+) 460/462).
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: COCCN
Product: COCCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-methoxy-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-methoxyethylamine in an analogous manner to Example 1396. Product isolated as a yellow foam (19 mg, 33%). LCMS (m/e) 525 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 6.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.50-7.40 (m, 1H), 7.37 (s, 1H), 7.30-7.22 (m, 1H), 7.15-7.0 (m, 3H), 6.70-6.61 (m, 1H), 3.72-3.65 (m, 2H), 3.62-3.55 (m, 4H), 3.41 (s, 3H), 3.38 (s, 1H), 2.99-2.88 (m, 4H), 2.84-2.73 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH3:37])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: Cc1cc[n+](CCO)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution mixture of 3a (0.12 g, 0.55 mmol), 5 (0.2 g, 0.66 mmol) and piperidine (0.1 mL) in ethanol (35 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by recrystallization from methanol to afford SLOH (0.17 g) as red solid in 62% yield. NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=6.4 Hz, 1H), 9.15 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.52 (d, J=6.4 Hz, 1H), 8.40 (m, 2H), 8.24 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 5.27 (t, J=5.6 Hz, 1H), 5.05 (t, J=4.8 Hz, 2H), 4.64 (t, J=4.8 Hz, 2H), 3.94 (m, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.11 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.8, 145.0, 142.1, 140.9, 138.1, 134.7, 128.7, 127.1, 126.8, 126.7, 126.5, 122.8, 122.2, 121.7, 120.3, 119.8, 119.2, 116.3, 114.8, 110.4, 110.3, 71.2, 69.8, 68.8, 58.9, 58.5, 58.0, 42.9. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O3 467.2342. Found 467.2340 [M+]. Calcd for C30H31ClN2O3: C, 71.53; H, 6.21; N, 5.57. Found: C, 71.04; H, 6.23; N, 5.36.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(O)CN
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a mixture of 1-aminopropan-2-ol (2 g, 26.6 mmol) and TEA (4.03 g, 39.9 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (4.36 g, 31.95 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and extracted with brine. The organic layer was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (2:1) to give ethyl 2-(2-hydroxypropylamino)-2-oxoacetate (2.19 g, 51% yield) as yellow syrup. LCMS retention time 0.348 min, LCMS MH+ 176.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1)#[N:12].N[C@H:30](C(O)=O)CCSC.[NH4+].[Cl-]>C1COCC1>[C:11]([C:13]1([CH3:30])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:15][CH2:14]1)#[N:12]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CSCC[C@H](N)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C#N)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
LiHMDS (47.6 mL, 47.6 mmol) was added dropwise via syringe to the mixture of benzyl 4-cyanopiperidine-1-carboxylate (8.00 g, 31.8 mmol, [Oakwood]) in THF (50 mL) at about −78° C. and stirred for about 1 h. Met (6.76 g, 47.6 mmol) was added dropwise via syringe at about −78° C. and the mixture was stirred overnight at rt. The solution was cooled to 0° C. and saturated aqueous NH4Cl (200 mL) was added. The mixture was extracted with DCM (3×300 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The sample was deposited onto silica gel and purified by column chromatography eluting with 10:1 pet ether/EtOAc to give benzyl 4-cyano-4-methylpiperidine-1-carboxylate (6.6 g, 74%): LC/MS (Table 2, Method i) Rt=2.03 min; MS m/z: 259 (M+H)+.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)([CH3:17])[CH2:8][CH2:9][C:10]([O:12]CCCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([N:5]=[N:6][C:7]([S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)([CH3:17])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)Sc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)N=NC(C)(CCC(=O)O)Sc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 167 grams (0.412 moles) of n-butyl 4-t-butylazo-4-(p-t-butylthiophenoxy)valerate and 34.4 grams (0.43 moles) of 50% NaOH were stirred in a 500 ml. round bottom flask, equipped with a condenser, for 4 hours at 85°-90° C. The reaction mixture was then cooled to room temperature and poured into 400 ml. water. The aqueous solution was extracted with 100 ml. of pentane to remove any unreacted ester and butyl alcohol and the pentane layer discarded. The aqueous layer was acidified to a pH of 3. The desired acid precipitated out of solution, was filtered off, washed with water and air dried. The dry product weighed 107 grams (74% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:13][C:11]1[S:10][CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=2)[N:12]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.4 mg) with purity >90%. MS (pos) m/z 431.1, 433.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=O)[C:4](=O)[CH2:3]1.O.[NH2:13][NH2:14]>CO>[CH3:1][C:2]1([CH3:11])[CH2:3][C:4]2[NH:14][N:13]=[CH:8][C:5]=2[CH2:6][CH2:7]1
Reactant: NN
Reactant: CC1(C)CCC(C=O)C(=O)C1
Solvent: CO
Solvent: O
Product: CC1(C)CCc2cn[nH]c2C1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml) under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr. Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran (250 ml) was added dropwise over about 1 hr, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated and extracted with 2 N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained 4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux over about 1 hr, and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To a solution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole in N,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium hydroxide (121 g, 1.8 mol) at room temperature, and the mixture was stirred for about 4 hr. Then, under ice-cooling, an aqueous solution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise. Water (2 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, hexane (350 ml) was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:31]([O:30][C:28]([C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:23]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: ClCCOCCN1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of sodium hydride (0.40 g, 0.010 mol, 60% oil dispersion) and 10,11-dihydro-5H-dibenz[b,f]azepine (1.95 g, 0.010 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 3.5 h under an atmosphere of nitrogen. The reaction mixture was cooled to 100° C. and bis-2-chloro-ethyl ether (4.7 ml) was added and the mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled and water (50 ml) was added. The mixture was extracted with toluene (100 ml). The organic extract was dried over sodium sulphate and the solvent evaporated in vacuo to give 2.8 g of an oily residue containing 2-chloro-1-(2-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)ethoxy)ethane. To this oil was added ethyl (R)-3-piperidinecarboxylate (3.0 g, 0.019 mol) and the mixture was heated at 150° C. for 1.5 h. The reaction mixture was allowed to cool to 80° C. and toluene (100 ml) was added. The mixture was then allowed to cool to room temperature and a solution of potassium carbonate (1.4 g) in water (100 ml) was added. The phases were separated and the organic phase was washed successively with water, an aqueous sodium acetate solution (pH 5) and an aqueous citric acid solution (pH 5). The organic phase was then extracted with a 5% aqueous citric acid solution (50 ml). The acidic (pH 1) aqueous extract was washed with toluene (2×50 ml) and then a 4 N sodium hydroxide solution was added until pH 6-7. The aqueous mixture was extracted with toluene and the organic extract was treated with charcoal and dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.1 g (50%) of (R)-N-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[C:7]3[N:8]=[CH:9][NH:10][C:6]=3[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1nccc2[nH]cnc12
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc3[nH]cnc23)cc1

Procedure:
In step (5) of Reaction Scheme X, a 4-chloro-1H-imidazo[4,5-c]pyridine of Formula LVIII is reacted with 4-methoxybenzylamine to provide an N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine of Formula LIX. The reaction can be carried out by combining a compound of Formula LVIII with excess N-(4-methoxybenzyl)amine and excess pyridine hydrochloride in a suitable solvent such as 2,2,2-trifluoroethanol and heating (150° C.) in a microwave reactor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([OH:19])=O)=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[C:34]([Cl:35])=[CH:33][C:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:31]([F:42])[CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O>[Cl:35][C:34]1[C:29]([NH:28][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=3)[N:9]=2)=[O:19])=[CH:30][C:31]([F:42])=[C:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:33]=1
Reactant: COc1ccc(Cn2nc(C(=O)O)c3ccccc32)cc1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nn(Cc3ccc(OC)cc3)c3ccccc23)cc1F
Yield: 79.7 %

Procedure:
In methylene chloride (10 ml) was dissolved 1-(4-methoxybenzyl)-3-indazolylcarboxylic acid (630 mg, 2.23 mmol). To the resulting solution were added oxalyl chloride (292 μl, 3.53 mmol) and DMF (1 drop). The resulting mixture was stirred until the mixture became uniform. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (20 ml). Ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (517 mg, 2.23 mmol) and triethylamine (621 μl, 4.46 mmol) were added to the resulting solution. The resulting mixture was heated under reflux for 15 hours. After cooling, the reaction mixture was added with water (50 ml), followed by extraction with chloroform (200 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, ethyl (5-chloro-2-fluoro-4-(1-(4-methoxybenzyl)-3-indazolylcarbonylamino)phenyl)acetate (881 mg, 80%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[NH2:23].C(=O)([O-])O.[Na+]>C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)=[C:20]([Cl:19])[CH:21]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 3.5 hrs. The reaction mixture was allowed to cool to room temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (293 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[O:29])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Reactant: O=C(O)c1ccco1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccco3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (264 mg, 0.865 mmol), furan-2-carboxylic acid (107 mg, 0.951 mmol) and HOBT (172 mg, 1.124 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (112 mg, 0.865 mmol) and EDC (182 mg, 0.951 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc) to yield the title compound in the form of a colourless solid. 1H-NMR (400 MHz, DMSO-d6): 9.86 (br, 1H), 9.27 (br, 1H), 7.83 (d, 1H), 7.69 (m, 2H), 7.30 (m, 2H), 7.15 (dd, 1H), 6.65 (m, 1H), 4.40-4.30 (m, 2H), 3.75-3.55 (m, 2H), 1.52 (s, 3H), 1.44 (s, 9H); MS: 400 [(M+H)+].