Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].N12CCCN=C1CCCCC2.Br[CH2:33][CH2:34][O:35][CH3:36].O>CN(C)C=O>[CH3:36][O:35][CH2:34][CH2:33][N:10]1[C:11]2[C:12](=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]([C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[CH3:1])[C:9]1=[O:20]
Reactant: COCCBr
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COCCn1c(=O)n([C@H]2CCCC[C@H]2C)c2c3cc[nH]c3ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of rel-1-[(1S,2R)-2-Methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in N,N-dimethylformamide (0.5 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (33 μl) and 1-bromo-2-methoxyethane (21 μl). The mixture was stirred at ambient temperature for 2 hours, then 60° C. for 22 hours. To the mixture was added water. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give pale yellow solid, which was triturated and washed with diisopropyl ether to give rel-3-(2-methoxyethyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (4 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.I[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]([O:44]C)=[O:43])[CH:37]=1>>[NH2:34][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([OH:44])=[O:43])[CH:37]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:9]=1
Reactant: COC(=O)c1cc(I)ccn1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B, Step 1 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and methyl 4-iodopyridine-2-carboxylate (Combi-Blocks, Cat. No. CA-4128). LCMS (M+H)+: m/z=460.2.
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[NH2:38][C:39]1[N:44]=CC(B2OC(C)(C)C(C)(C)O2)=C[N:40]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:38][C:39]([NH2:44])=[N:40][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:35])[F:33]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cnc(N)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-aminopyrimidin-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=514, obsd.=514).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(OCC)(=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[CH:1](/[C:9]1[N:10]([C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloro-4-trifluromethyl-pyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1.C(N(CC)CC)C>ClCCl>[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:11])[CH2:13]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a solution of 1.7 mL (24 mmol) of DMSO in 30 mL of dichloromethane at −50° C. was added dropwise 5.5 mL (11.0 mmol) of 2.0 M oxalyl chloride solution in dichloromethane. After 10 min, a solution of 3.85 g (10.0 mmol) of 3-hydroxy-1-(triphenylmethyl)piperidine from Step A in 15 mL of dichloromethane was added dropwise. After 15 min, 7.0 mL (50 mmol) of triethylamine was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 0.5 h. The mixture was diluted with dichloromethane, washed sequentially with water, 5% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography (silica gel, 6% ethyl acetate/hexane) gave 1.95 g (57%) of the title compound as a white crystalline solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14](C(OCC)=O)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO.[C:28](O)([C:30](F)(F)F)=[O:29].[C:35](#[N:37])C>O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14]([C:28]4[O:29][CH:35]=[N:37][CH:30]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC#N
Reactant: CCOC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1cnco1
Reaction time: 0.05 h

Procedure:
Followed the procedure as mentioned in the synthesis of compound 3. 1H NMR: 400 MHz, DMSO-d6: δ 1.25 (d, J=6.40 Hz, 6H), 3.63-3.70 (m, 1H), 5.39 (d, J=7.60 Hz, 1H), 6.16 (s, 1H), 7.36 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.94 (d, J=8.80 Hz, 1H), 8.07 (s, 1H), 8.42 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.14 (s, 1H), 9.23 (s, 1H) LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.379 min; LCMS (ES-API), m/z 352.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 5.518 min; Purity: 99.4%.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(O[C:8](=[O:10])C)(=O)C.C([O-])=O.[Na+].[CH3:15][NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[C:22]([CH:26]=1)C(O)=O>O>[CH:8]([N:16]([CH2:17][C:18]1[CH:26]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:19]=1)[C:1]([OH:3])=[O:2])[CH3:15])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Reactant: CNCc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: CN(C=O)Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a 100 mL volume egg plant-shaped flask, there were added 4.0 mL of formic acid and 2.7 mL of acetic anhydride and the mixture was stirred at room temperature. Subsequent to this, 0.65 g of sodium formate and 5.58 g (content: 71.7 wt %) of 5-(N-methyl-aminomethyl)-2-nitrobenzoic acid were added to the foregoing mixture in two portions and then the resulting mixture was stirred at room temperature for one hour. After the confirmation of the progress of the reaction by HPLC, 32 mL of water was added thereto to separate out crystals and to form a slurry and then cooled to 9° C. and stirred overnight. The solid separated out of the reaction liquid was filtered off, washed with water, dried under reduced pressure to thus obtain 3.95 g of the title compound as a white crystalline solid (yield: 87%).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[N:25][CH:24]=3)[N:19]=2)=[O:30])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
To a stirring mixture of trans-2-phenylcyclopropylamine hydrochloride (75.3 mg, 0.431) in anhydrous DMF (1.0 mL) was added triethylamine (60.0 μL, 0.431 mmol). After 5 minutes, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) were added sequentially. The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (79.2 mg, 95%): m.p. 123-124 ° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCCN1CCOCC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 70 °C

Procedure:
To a suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (150.0 mg, 0.3803 mmol) in dichloromethane (10 mL, was added dropwise 1.0 M of boron tribromide in dichloromethane (1.2 mL, 1.2 mmol). The mixture was stirred for 1 hour at room temperature then methanol (5 mL) was added slowly. The mixture was evaporated to dryness. Additional methanol (10 mL) was added and the mixture was evaporated to dryness. The brown solid was suspended in saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a solid. 4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol was isolated without further purification as a light brown solid (0.115 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.64 (dd, J=7.4, 0.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.00 (dd, J=7.1, 7.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 4.72 (br s, 1H), 3.09 (s, 3H). MS=381 (MH)+. 26b) A suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (50.0 mg, 0.131 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (27.0 mg, 0.145 mmol) and potassium carbonate (36.0 mg, 0.260 mmol) in acetonitrile (1 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature, diluted with acetonitrile (10 mL), filtered through a plug of diatomaceous earth and evaporated to an orange resin. The residue was purified via chromatography utilizing an ISCO automated purification apparatus with silica gel column (12 g) and 0%→10% methanol:dichloromethane solvent gradient. The title compound, [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine, was isolated as a yellow foam (0.047 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 6.73 (s, 1H), 4.12 (t, J=5.8 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.80 (t, J=5.6 Hz, 2H), 2.62-2.55 (m, 4H). MS=494 (MH)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.65 g of sodium hydride (60% in paraffin oil; 16.3 mmol) was initially charged in 25 ml of THF, and the mixture was cooled to 0° C. 4.29 g (17 mmol) of tert-butyl diethylphosphonoacetate were then slowly added dropwise. After 30 min of stirring, 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde were added. The reaction mixture was stirred at RT for 3 h, then poured into 100 ml of water and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 3.37 g (85% of theory) of the target product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCCCl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCCl)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (4.00 g, 22.39 mmol) and 5-chlorovaleryl chloride (1.30 mL, 33.6 mmol) dissolved in 150 mL of 1,2-dichloroethane was heated to reflux. After 2.8 days more 5-chlorovaleryl chloride (1.0 mL, 7.7 mmol) was added. After 16 hours more the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 3.78 g of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:27])[C:24]([OH:26])=O)=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:27])[C:24]([NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[O:26])=[N:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CN
Reactant: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CC(C(=O)NCC(C)(C)C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
A mixture of the product from Example 110 and 2,2-dimethylpropan-1-amine was processed using a method similar to that described in Example 112 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59-11.62 (bs, 1H), 8.31 (dd, J=7.8, 1.4 Hz, 1H), 8.16-8.21 (m, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.93-8.00 (m, 1H), 7.85-7.91 (m, 1H), 7.41 (s, 4H), 4.38 (q, J=6.9 Hz, 1H), 3.68 (s, 2H), 2.94 (dd, J=13.1, 6.4 Hz, 1H), 2.85 (dd, J=13.1, 6.0 Hz, 1H), 1.44 (d, J=6.9 Hz, 3H), 0.81 (s, 9H); MS (ESI+) M/Z 455 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>C(Cl)(Cl)Cl.CCCCCC>[C:23]([NH:22][CH2:21][CH2:20][CH2:19][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCNCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (481 mg) in dehydrated chloroform (3 ml) were added sodium carbonate (212 mg) and (3-bromopropyl)tritylamine (694 mg), and the mixture was stirred under reflux for 3.5 hours. To the reaction mixture were added diethyl ether and hexane, and the solution was washed with water. The mixture was extracted with 5% aqueous citric acid solution, and the aqueous layer was washed with diethyl ether. The aqueous solution was then made alkaline with sodium hydrogencarbonate followed by extraction with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-{[3-(tritylamino)propyl]amino}ethylcarbamate (410 mg) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:37](C(=O)C)[C:38](=[O:40])[CH3:39])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([NH:37][C:4]1[NH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=3)[C:12]=2[F:28])=[O:8])=[C:2]([Cl:1])[N:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)N(C(C)=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 19.8 %

Procedure:
A solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(diacetylamino)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.047 g, 0.071 mmol) and TFA (0.5 mL, 6.5 mmol) in CH2Cl2 (1.0 mL) was stirred at RT overnight. The solution was concentrated and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.007 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (br. s., 1H) 11.52 (br. s., 1H) 8.81 (br. s., 1H) 7.82 (s, 1H) 7.51-7.55 (m, 2H) 7.50 (s, 1H) 7.47
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=C=O.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][NH2:35]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:19][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:7])[C@H:9]([C:16]([NH:35][CH2:34][C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[O:18])[CH2:10]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCc1cccs1
Product: CON=C1C[C@@H](C(=O)NCc2cccs2)N(C(=O)Nc2cccc(C)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and 2-thienylmethylamine the title compound was obtained in 98% purity by LC/MS. MS(ESI+): m/z=387.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenol (200 mg, 0.58 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (283 mg, 0.87 mmol, 1.5 eq). The reaction mixture was stirred for 1 h at room temperature, then ethyl 2-bromoacetate (117 mg, 0.70 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography to give the title compound as an oil (200 mg, 80%).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2C(O)=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27](=[O:29])=O.[NH2:30][C@@H:31]1[CH2:40][CH2:39][C:38]2[C:33](=[C:34]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:35]=[CH:36][CH:37]=2)[CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:33]=2[CH2:32][C@H:31]([NH:30][C:27](=[O:29])[C:12]2[CH:11]=[CH:7][C:6]([N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)=[CH:14][CH:13]=2)[CH2:40][CH2:39]3)[CH2:42][CH2:43]1
Reactant: O=C(O)c1ccccc1-n1cccc1
Reactant: O=C=O
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(-n4cccc4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 4-(1H-pyrrol-1-ylbenzoic acid (96 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 128 mg (62% yield) of the title compound as white crystals: mp 245-247° C.; [α]21D −69° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 414 (15, M+).