Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:39])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29][C:28]=2[CH:38]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:39][C:25]2[C:24]([O:23][CH3:22])=[CH:38][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-methoxy-N-methyl-benzamide as a lyophylate (8%); 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H, exchangeable), 9.75 (bs, 1H, exchangeable), 8.74 (bs, 1H, exchangeable), 8.42 (d, J=9.35 Hz, 1H), 8.15 (s, 2H, 1 exchangeable), 7.68 (s, 1H), 7.31 (s, 1H), 7.00 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.70 (m, 2H), 3.6 (bs, water+H), 3.40 (m, 2H), 3.34 (s, 3H), 3.3-2.95 (m, 4H), 2.80 (d, J=4.04 Hz, 3H); MS (m/e) 541.37 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[F:14][CH:15]([F:23])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-:25].[K+].[K+]>>[F:14][CH:15]([F:23])[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:13])=[O:25]
Reactant: Oc1cccc(C(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1cccc(C(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 3-difluoromethylphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14]1(C2CCNCC=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OC1(C2C=CC=CC=2)CCN(CCCC[N:37]2[CH:46]([OH:47])[C:45]3[CH:48]=[CH:49][CH:50]=[C:43]4[C:44]=3[C:39](=[CH:40][CH:41]=[CH:42]4)[C:38]2=[O:51])CC1>>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:18][CH2:19][CH2:14][CH2:15][CH2:16][CH2:17][N:37]2[CH:46]([OH:47])[C:45]3[CH:48]=[CH:49][CH:50]=[C:43]4[C:44]=3[C:39](=[CH:40][CH:41]=[CH:42]4)[C:38]2=[O:51])[CH2:4][CH2:3]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C1c2cccc3cccc(c23)C(O)N1CCCCN1CCC(O)(c2ccccc2)CC1
Reactant: OC1(c2ccccc2)CCNCC1
Product: O=C1c2cccc3cccc(c23)C(O)N1CCCCCCN1CCC(O)(c2ccccc2)CC1

Procedure:
Following the procedure of example 4 but substituting 4-hydroxy-4-phenylpiperidine for the 4-phenyl-1,2,3,6-tetrahydropyridine in part (b), one obtains the titled compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23][CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[C:8]3[S:23][CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Yield: 87.5 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.120 g; 0.29 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.044 g, 0.32 mmol) to afford the title compound (0.101 g, 87%) as a white solid. MW=397.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.20-8.17 (m, 2H), 8.16-8.12 (m, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.51-7.46 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H), 3.65-3.59 (m, 2H), 3.20-3.16 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.22-2.15 (m, 2H); APCI MS m/z 398 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:31][CH2:32][C:33]([C:7]5[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=5)([OH:36])[CH2:34][CH2:35]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -75 °C
Yield: 80.9 %

Procedure:
To a cooled solution (-90° C.) of n-butyllithium (2.5M in hexane, 2.40 mL, 6.0 mmol, 1.5 eq) in tetrahydrofuran (40 mL) under nitrogen was added freshly distilled 3-bromopyridine (0.540 mL, 5.6 mmol, 1.4 eq). The metal-halogen exchange reaction was warmed to -75° C. and maintained for 1.5 h. During that time a dark green solution evolved with the appearance of fine particulate. A solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (1.35 g, 4.0 mmol) in tetrahydrofuran (10 mL) was then added dropwise with considerable lightening of the solution color to a deep yellow. The reaction was warmed to room temperature over 1 h and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (80 mL, eluent: ethyl acetate) to yield 1.35 g (81%) of the title compound as a white solid. TLC analysis (Rf 0.20, ethyl acetate). 1H NMR (D6-DMSO, 300 MHz) 8.69 (br s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.83 (dt, J=8.0 Hz, 1H), 7.29 (m, 5H), 6.95 (m, 3H), 5.05 (s, 1H), 4.35 (s, 1H), 3.41 (m, 2H), 3.34 (s, 1H), 2.75 (m, 4H), 1.92 (m, 2H), 1.62 (m, 2H) MS (CI, CH4) m/z 417 (M+1,100), 419 (36), 445 (M+29,15), 399 (15). The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with ethereal HCl, and the hydrochloride salt suspension was diluted with additional ether. The salt was filtered, washed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CCCCCC>[OH:3][C:4]1[C:13]2[C:8](=[C:9]([C:14]([F:16])([F:15])[F:17])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)c1ccccc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1O
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A solution of 2-benzoyl-3-(2-trifluoromethyl-phenylamino)-acrylic acid ethyl ester(8.2 g, 22.4 mmol) in Dowtherm (120 ml) was heated to reflux. After 4 hr, the reaction was cooled and poured in hexane. The resulting solid was filtered and washed with hexane to give (4-hydroxy-8-trifluoromethyl-quinolin-3-yl)-phenyl-methanone (4.0 g, Yield=56%); MS (ESI) m/z 318(M+H)+; Anal Calcd for C17H10F3NO2: C, 63.36; H, 3.18; N, 4.41. Found: C, 63.96; H, 3.14; N, 4.25.
Reaction SMILES: [OH:1][C:2]([CH3:20])([C:9]([CH3:19])=[CH:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:23]Br>CO.C(=O)([O-])O.[Na+].O.CO>[OH:1][C:2]1([CH3:20])[C:9]([CH3:19])([Br:23])[CH:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C(C)=CC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(O)CC(=O)OC(C=Cc2ccccc2)C1(C)Br
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
The carboxylic acid (1.09 g) prepared by hydrolyzing 12.20 g of ethyl 3-hydroxy-3,4-dimethyl-7-phenyl-4,6-heptadienoate with 4N sodium hydroxide solution in 60 ml of methanol, was dissolved in a solution of 700 mg of sodium hydrogen carbonate in 40 ml of a solvent mixture of water-methanol (1:1) and a solution of 1.06 g of bromine in 1 ml of methanol was dropwise added thereto under cooling at -30°~-35° C. After stirring for 30 minutes, the crystals produced were collected by filtration, washed with water, dried, and recrystallized from a mixture of n-hexane and ethyl acetate (5:1) to give 750 mg of the desired compound melting at 121°-123° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:20])[C@H:6]([CH3:19])[NH:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1>O.O1CCOCC1>[F:16][C:14]1[CH:15]=[C:10]([CH2:9][C:8]([NH:7][C@H:6]([C:5]([OH:20])=[O:4])[CH3:19])=[O:18])[CH:11]=[C:12]([F:17])[CH:13]=1
Reactant: COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Yield: 97.2 %

Procedure:
To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes: ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:14][C:10]1[CH:9]=[C:8]([CH:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Br)c1cccc(F)c1
Reactant: Nc1cccc(F)c1
Product: CCOC(=O)C(Nc1cccc(F)c1)c1cccc(F)c1
Yield: 99 %

Procedure:
A solution of ethyl 2-bromo-2-(3-fluorophenyl)acetate (I9) (1.80 g, 6.84 mmol) in 3-fluoroaniline (6.50 mL, 68.0 mmol) is heated at 100° C. for 5 minutes under MW irradiation (LC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is purified by flash chromatography (Hexane/EtOAc=9/1) in order to obtain 2.00 g of I10 as a yellow oil (99% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:4].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CC#N>[N:10]1([CH2:2][C:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)=[O:4])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(CBr)c1nccs1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: O=C(Cn1ccnc1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-(thiazol-2-yl)-ethanone (2.5 g; 12 mmol) in CH3CN (70 ml) was added imidazole (1.65 g; 24 mmol). After stirring at room temperature for 1 hour, the mixture was evaporated to dryness and partitioned between CH2Cl2 and water. The organics were washed with saturated NaCl and evaporated to give 2-(imidazol-1-yl)-1-(thiazol-2-yl)-ethanone as a brown solid (1.17 g; 50%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.CO>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cccc(F)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NNC(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
1,1-Dimethylethyl 2-[(6-fluoro-2-pyridinyl)carbonyl]hydrazinecarboxylate (510 mg, 2 mmol) was dissolved in 1,4-dioxane (5 mL) and treated with 4M HCl in 1,4 dioxane (5.00 mL, 20.00 mmol) at 0° C. The mixture was stirred to room temperature over 24 hr and was concentrated in vacuo, azeotroping with diethyl ether (3×50 ml) to afford a white solid. The solid was dissolved in methanol and loaded on to an SCX cartridge (Varian, 10 g), washing with methanol, and then eluting the product in free base form using 2M ammonia/methanol. The ammoniacal fractions were concentrated in vacuo to afford the product, 6-fluoro-2-pyridinecarbohydrazide (251 mg, 1.618 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>Cl>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.06 g (10.6 mmol) of 2,2,2-trifluoroethylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 1.48 g (61%) of the title compound as white crystalline solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH3:35])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>CCCCCC.C(O)C.C(O)C.O1CCCC1>[CH2:34]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:35]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
Ethyl 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (9.18 g) obtained in Example A71(5) was dissolved in hexane-ethanol (1:1, volume ratio), subjected to HPLC using CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), and eluted with hexane-ethanol (1:1, volume ratio) as a mobile phase at room temperature and at a flow rate 60 mL/min. The resulting fraction containing an optically active form having a longer retention time was concentrated to give an amorphous form (4.67 g, 99.9% ee). The obtained amorphous form (4.67 g) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), 1N aqueous sodium hydroxide solution (19.4 mL) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (30 mL) was added, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling and stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (4.21 g, 96%, 99.9% ee).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][OH:31])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CO)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and 4-(hydroxymethyl)phenylboronic acid (96 mg, 0.63 mmol) in dioxane (2.5 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (130 mg, 62%). LCMS: 504.15 (M+1)+; HPLC: 98.86% (@254 nm) (Rt; 4.240; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.39 (s, 1H), 7.37 (d, 2H), 7.21 (s, 1H), 5.85 (s, 1H), 5.20 (t, 1H, J=5.2 Hz), 4.52 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.84 (m, 2H), 3.22-3.32 (m, 2H), 3.08-3.09 (m, 2H), 3.01 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][NH:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)CCCC(C)(C)N1.Cl[C:30]1([C:36]([O:38][CH3:39])=[O:37])[C:34](=[O:35])[CH:33]=[CH:32][S:31]1>ClCCl.C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:32]3[S:31][C:30]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([OH:35])[CH:33]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reaction time: 12 h

Procedure:
To a mixture of 21.2 g of 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridine and 11.36 g of 2,2,6,6-tetramethylpiperidine in 2 l dichloromethane was slowly added a solution of 8.77 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 300 ml chloroform at 30-40° C. The reaction mixture was stirred for 12 h, washed with water (2×200 ml) and concentrated under vacuum. The residue was purified by flash chromatography (eluents: ethyl acetate/methanol/triethylamine) two times and after precipitation from ethyl acetate/n-hexane the title compounds were obtained as a mixture of regioisomers.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([CH:14]=O)[CH:5]=1)([O-:3])=[O:2].[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[N+:1]([C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([CH:14]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1cc2c(c([N+](=O)[O-])c1)OCCO2
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc3c(c([N+](=O)[O-])c2)OCCO3)N1
Temperature: 77 °C
Yield: 5.3 %

Procedure:
A mixture of 8-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (Intermediate 45) (110 mg, 0.529 mmol), 1,2-diphenylethanone (103.8 mg, 0.529 mmol), urea (95.2 mg, 1.587 mmol), and concentrated hydrochloric acid (0.1 mL) in ethanol (10 mL) was refluxed at 77° C. for 63 h. Volatiles were removed, and purified by preparative HPLC to give Compound 89 (12.1 mg, yield 5.5%). 1H NMR (CD3OD 400 MHZ): δ 7.32 (s, 1H), 7.14 (s, 5H), 7.06 (s, 1H), 6.95-6.94 (m, 3H), 6.78-6.76 (m, 2H), 5.20 (s, 1H), 4.26-4.24 (m, 4H); MS (ESI): m/z 430.0 [M+H]+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16])([O-])=O.O.C(O)(=O)C>CCO.[Pd]>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:16][CH:15]=[CH:14]2
Reactant: N#CCc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc2[nH]ccc2c1
Yield: 65.1 %

Procedure:
A mixture of 4-Nitrobenzotrifluoride (25.0 g, 131 mmol) and 4-chlorophenoxyacetonitrile (24.1 g, 144 mmol) in dry DMF (200 mL) was added dropwise over 1 h to a stirred solution of potassium tert-butoxide (32.3 g, 288 mmol) in dry DMF (200 mL) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 3 h then poured into a mixture of ice water (200 mL) and 5 N aqueous HCl (200 mL). The resulting mixture was extracted with dichloromethane (3×300 mL). The combined extracts were washed with 10% aqueous NaOH, 5 N HCl, brine, dried over sodium sulfate, and concentrated in vacuo to give the crude (2-nitro-5-trifluoromethylphenyl) acetonitrile. The crude (2-nitro-5-trifluoromethylphenyl) acetonitrile (24.6 g, 107 mmol) was dissolved in 9:1 EtOH:H2O (300 mL) and glacial acetic acid (3.0 mL). This mixture was hydrogenated over 10% Pd/C (10.0 g) at 50 psi for 16 h at room temperature. The reaction was filtered through celite and evaporated in vacuo. The residue was partitioned between saturated aqueous sodium carbonate and dichloromethane (2×200 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 20:1, 9:1, 5:1) to afford 12.9 g (65% yield) of 5-trifluoromethyl-1H-indole as a yellow solid: 1H NMR (400 MHz, CDCl3) 8.34, (1H, br s), 7.95 (1H, s), 7.45 (2H, m), 7.32 (1H, m), 6.65 (1H, m); MS m/e 184 (M−H)−. Anal calcd. for C9H6F3N.0.15 H2O: C, 57.55; H, 3.38; N, 7.46. Found: C, 57.25; H, 2.98; N, 7.29.