Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17](O)[C:18]=1[CH2:19][OH:20].CI.[C:25]([O-:28])([O-])=O.[K+].[K+].[CH3:31]N(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([O:28][CH3:25])[C:18]=1[CH2:19][O:20][CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Cc1ncc(Cn2cnc3c(Cl)nc(N)nc32)c(CO)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COCc1c(Cn2cnc3c(Cl)nc(N)nc32)cnc(C)c1OC
Temperature: 50 °C

Procedure:
A mixture of 6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine, MeI, K2CO3 (excess) and DMF was heated to 50° C. for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the title compound. HPLC Rt: 5.446 min. 1H-NMR (CDCl3) δ 8.35 (s, 1H), 7.70 (s, 1H), 5.35 (s, 2H), 5.25 (s, 2H), 5.15 (s, 2H), 3.80 (s, 3H) 2.59 (s, 3H), 1.970 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1([NH:24][C:25]([C:27]2[N:28]=[CH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:6]1=[O:23])#N.Cl.[OH2:38].[CH3:39][OH:40]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([CH2:4][CH2:3][C:1]([O:40][CH3:39])=[O:38])([NH:24][C:25]([C:27]2[N:28]=[CH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[C:6]1=[O:23]
Reactant: CO
Reactant: O
Reactant: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(CCC#N)NC(=O)c1cc2ccccc2cn1
Agent: Cl
Product: COC(=O)CCC1(NC(=O)c2cc3ccccc3cn2)C(=O)N(c2ccccc2F)c2cc(OC)ccc21
Yield: 91 %

Procedure:
In 80 ml of anhydrous methanol was dissolved 23.85 g of the (+)-N-[3-(2-cyanoethyl)-1-(2-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]-3-isoquinolinecarboxamide crude product, and under ice cooling, a hydrochloric acid gas was passed through the solution until the gas was saturated. Thereafter, 1.71 ml of water was added to the solution. The reaction mixture was refluxed for 1 hour, cooled and then concentrated under reduced pressure. The residue was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic layer was separated, washed with water with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane (1:1, volume) as an eluant to afford 22.30 g of (+)-methyl 3-[l-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]propionate as a pale yellow amorphous solid (yield: 91% (from the product of Example 176 (2))). DI-MS (m/z) 513 (MH+), 426, 156, 128 (base). [α]D25 : +66.2° (c=0.402, chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:19]([NH2:21])=[O:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.O>[F:22][C:13]1[C:12]([O:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:23][C:6]=3[N:7]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:14]=1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Reactant: OB(O)c1ccncc1
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: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccncc4)ccc3s2)c1F
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 3-[(5-bromo-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide (168 mg, 0.42 mmol, 1 equiv.), 4-pyridine boronic acid (98 mg, 0.63 mmol, 1.5 equiv.) and 2M aqueous Na2CO3 solution (0.42 ml, 0.82 mmol, 2 equiv.) were suspended in dioxane (3.5 ml) and the mixture was degassed and flushed with N2. Tetrakis(triphenylphosphine)palladium(0) catalyst (37 mg, 0.031 mmol, 0.075 equiv.) was added and the reaction mixture was heated under reflux for 12 h. After cooling at r.t., the mixture was diluted with H2O and the precipitant solid was filtered and rinsed with H2O, IMS, IMS/Et2O and Et2O. Re-crystallised from CH3CN, to give the desired product as an off-white solid, 47 mg (28% yield), mp 255-258° C. HPLC-MS: m/z 398 [M+H]+, Rt=3.28 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:23]([CH2:10][C@@H:9]1[CH2:12][C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[CH2:14][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Nc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CNc1ccccc1
Yield: 81.6 %

Procedure:
(2S,4R)-2-Anilinomethyl-N-t-butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine (995 mg, yield: 82%) was prepared as a yellow oily substance, from (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxyprolinal (990 mg, 3 mmol) and aniline (0.3 ml, 3.3 mmol), in the same manner as in Reference Example 95-2.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C@H:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1)(O)=[O:2].Cl.[CH3:30][NH:31][CH3:32].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[CH2:14]([O:13][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([C:1](=[O:2])[N:31]([CH3:32])[CH3:30])[CH2:5][C@H:6]1[NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,2R,4S)-4-Carboxy-N1-benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-1,2-cyclohexanediamine was dissolved in dichloromethane (50 ml), and dimethylamine hydrochloride (240 mg), triethylamine (0.41 ml), 3-(3-dimethylamino-propyl)-1-ethylcarbodiimide hydrochloride (420 mg) and 1-hydroxybenzotriazole monohydrate (340 mg) were added to stir the mixture at room temperature for 1 hour. Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) were additionally added to the reaction mixture to stir the mixture at room temperature for additional 18 hours. The reaction mixture was poured into water to separate an organic layer. After the organic layer was washed with 1N hydrochloric acid and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:methylene chloride=3:47→2:23) to obtain the title compound (620 mg) as a colorless foamy substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)(Cl)Cl.O>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([NH:57][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][C:18]=2[O:23][CH3:24])=[O:42])[CH2:53][CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (89 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (118 mg, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:7][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cc(OC)cc(C(N)=O)c1
Product: COc1cc(OC)cc(-c2nc(CCl)co2)c1
Yield: 59 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,5-dimethoxybenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3,5-dimethoxyphenyl)oxazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 85-86° C.
Reaction SMILES: COC(C1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OCCCl)=O)=[C:8](C)[NH:9]C=1C)=O.[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:8][NH:9][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Product: CNCc1ccccc1

Procedure:
In 6 ml. of toluene were dissolved 2.0 g. of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester 5-methyl ester and 1.3 g. of N-methylbenzylamine and the solution thus formed was refluxed for 5 hours under heating. After the reaction was over, the reaction mixture was mixed with 30 ml. of chloroform and 10 ml. of water and then the organic layer thus formed was separated and washed with 10 ml. of 10% hydrochloric acid and then with water. The organic solvent solution thus obtained was dried over anhydrous magnesium sulfate and then the solvent was distilled away under reduced pressure. The residue was added to 10 ml. of ethyl acetate and the mixture was stirred under cooling, whereby 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-(N-benzyl-N-methylamino)ethyl ester 5-methyl ester hydrochloride was crystallized. The amount of the product thus obtained was 1.6 g. The product recrystallized from a methanol-acetone mixture had a melting point of 180°-181° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[F:20])=[C:4]([CH3:21])[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[F:20])=[C:4]([CH3:21])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(F)c1
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
The product from step (ii) (6.6 g) was added to phosphorous oxychloride (40 ml) under nitrogen. The resulting mixture was stirred at 90° C. for 15 h. The phosphorous oxychloride was evaporated under reduced pressure and the residue cautiously diluted with water (50 mL). The aqueous phase was neutralised with NaHCO3 and heated at 50° C. for 1 h. The mixture was allowed to cool and the precipitate was collected by filtration. The solid was suspended in MeCN (40 mL) and collected by filtration to give the subtitle compound as a cream solid 3.70 g that was used without further purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: Cc1cc(F)ccc1C(O)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3C)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.14 g (4.23 mmol) of the compound from Example 180A in analogy to the synthesis of the compound from Example 278. 554 mg (31% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([S:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[C:18]([CH3:21])=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCSc1nsnc1-c1ccc(C)nc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCCCSc1nsnc1-c1ccc(C)[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-6-methylpyridine (4 mmol) in acetone (5 ml) and the reaction mixture was stirred at room temperature for 20 h. Evaporation of the reaction mixture gave the crude product, which was used without further purification.
Reaction SMILES: COCCN(S(F)(F)F)CCOC.O[CH2:15][C@H:16]([NH:21][C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:23])[C:17]([O:19][CH3:20])=[O:18].BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[C:22]1[O:23][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:21]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Deoxo-flour (4.5 mL, 24.16 mmoles) was added drop-wise to a solution of (R)-benzyl 2-((S)-3-hydroxy-1-methoxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (8.5 g, 22.0 mmoles) in CH2Cl2 (150 mL) at −20° C. The solution was stirred for 30 min and BrCCl3 (7.8 mL, 79.0 mmoles) was added drop-wise followed by DBU (11.8 mL, 79 mmoles). The reaction was stirred at 2-3° C., for 10 h., quenched with Satd. Aq. NaHCO3 solution and extracted with ethyl actetate. The organic layer was concentrated and chromatographed on silica gel (10% ethyl acetate/90% chloroform) to yield 6.95 of (R)-methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4-carboxylate.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:19])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[NH:23][CH:22]=1>>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH:19][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:31])=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: N[C@@H](COCCCN1CCCCC1)c1ccccc1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: O=C(N[C@@H](COCCCN1CCCCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using coupling method A, (R)-1-phenyl-2-[3-(piperidin-1-yl)propoxy]ethylamine (218 mg, 0.83 mmol) and 3-chloro-indole-6-carboxylic acid (179 mg, 0.91 mmol) afforded, after purification (SiO2: 50% EtOAc in hexane), 115 mg (32%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.[NH2:24][C:25]1[CH:29]=[CH:28][NH:27][N:26]=1>>[C:2]([C:3]1[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[C:13]([F:23])([F:22])[F:12])[C:29]2[C:25](=[N:26][NH:27][CH:28]=2)[NH:24][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared from ethyl nipecotate, 2-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: [F:1][CH:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@@H:15]2[OH:26])[C@@:8]([OH:28])([C:9](=[O:12])[CH2:10][SH:11])[C@@H:7]([CH3:29])[CH2:6]3)[CH2:3]1.[CH:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31]>>[F:1][CH:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@H:15]2[OH:26])[C@@:8]([OH:28])([C:9](=[O:12])[CH2:10][S:11][C:38](=[O:39])[CH:33]([NH:32][CH:30]=[O:31])[CH2:34][CH2:35][S:36][CH3:37])[C@H:7]([CH3:29])[CH2:6]3)[CH2:3]1
Reactant: C[C@H]1C[C@H]2[C@@H]3CC(F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CC(F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@H](O)C[C@@]21C
Yield: 32.8 %

Procedure:
The title compound (0.027 gm) was prepared from 6,9-difluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.06 gm) and (N-formyl-L-methionine (0.175 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ba+2].[OH-].COCCOC.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>O>[Cl:19][C:20]1[CH:25]=[C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Clc1cc(-c2ccccc2)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
A reaction vessel was charged with 0.17 g of tetrakistriphenylphosphine palladium, 0.91 g of phenylboronic acid, and 3.53 g of barium hydroxide, to which 44 ml of 1,2-dimethoxyethane, 8 ml of water, and 1.11 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 6 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.51 g of 4-chloro-6-phenylpyrimidine, m.p.: 101.3° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][C:14]3[C:15]4[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][C:35]([CH3:39])(C)[CH:36]=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][C:14]3[C:15]4[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=4[S:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:40][CH2:36][CH:35]([CH3:39])[CH3:34])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCNCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]-2-[4-(2-aminoethyl)phenyl]benzo[b]thiophene (75 mg) was dissolved in dichloromethane (3.0 mL), treated with trimethylacetaldehyde (30 μL) and sodium triacetoxyborohydride (56 mg) sequentially and allowed to stir at ambient temperature for 3 h. The reaction mixture was concentrated, and column chromatography with ET3N:EtOAc (0-5%) afforded the product (55 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH2:35])[CH3:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH:35][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:34]
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 61.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.44 g, 1.34 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.27 g, 1.61 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 0.38 g, 61.3% yield. MS: 461.9 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.40 (s, 1H), 11.31 (s, 1H), 10.92 (d, 1H, J=8.0 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.42-7.37 (m, 2H), 7.20-7.18 (m, 1H), 7.09-7.04 (m, 1H), 6.18 (d, 1H, J=8.0 Hz), 4.19-4.14 (m, 1H), 3.06 (s, 3H), 3.04-2.98 (m, 2H), 1.33 (d, 3H, J=6.0 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:23](O)=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:23]([NH2:28])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)o2)c(C)cn1
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(N)=O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.7 %

Procedure:
To a round bottom flask was added 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-1,3-oxazole-5-carboxylic acid (0.12 g, 0.33 mmol), DCM (4 mL), TBTU (0.42 g, 1.3 mmol), and TEA (0.35 mL, 2.5 mmol). The mixture was allowed to stir for 5 min at rt, and then ammonia (0.5M in dioxane, 32 mL) was added. The resulting mixture was allowed to stir at rt overnight and then concentrated. DCM and water were added. The organic solution was separated, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-1,3-oxazole-5-carboxamide (0.018 g, 15%). LCMS (FA): m/z=371.4 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1OC)([O-:3])=O.[NH2:12][NH2:13]>>[OH:3][N:1]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:13]=[N:12]1
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: NN
Product: On1nnc2ccncc21

Procedure:
3-nitro-4-methoxy pyridine is reacted with hydrazine in accordance with the procedure of Example 1 to yield the above-identified compound.