Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([CH2:7][N:8](CC2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH2:4][CH2:3]1.Cl.[H][H]>CO.[C].[Pd]>[ClH:1].[CH:2]1([C:5]([CH2:7][NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C(CN(Cc1ccccc1)Cc1ccccc1)C1CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(CNCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
A total of 63.2 g of N, N-dibenzyl-aminomethyl cyclopropyl ketone hydrochloride was dissolved in 316 g of methanol, followed by dropwise addition of 11 g of 33% by weight hydrochloric acid. The inner atmosphere of the reaction system was replaced with nitrogen gas three times, 6.3 g of 5% by weight palladium-carbon was then added to the mixture, and the inner atmosphere of the reaction system was replaced with hydrogen gas three times, followed by stirring at room temperature for 2.5 hours. After the completion of the reaction, the resulting reaction mixture was filtrated using a filter aid (available from Kohjin Co., Ltd. under the trade name of “Cerafloc”), the filtrate was concentrated and thereby yielded 38.3 g of N-benzyl-aminomethyl cyclopropyl ketone hydrochloride as a colorless crystal.
Reaction SMILES: [Na].[O:2]([CH2:9][C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:11][C:10](=[O:12])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CC(=O)COc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
Sodium (6.74 g, 293 mmol) was added to EtOH at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 g, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.85 g, 54% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(CC)CC>CC(N(C)C)=O>[C:29]([O:28][C:27]([NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 90 °C
Yield: 44.9 %

Procedure:
To a mixture of methyl 2-chloro-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.227 g, 0.851 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.182 g, 0.851 mmol) in DMA (3 mL) was added Et3N (0.356 mL, 2.55 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to RT and poured onto ice. The solid was filtered and dried under high vacuum to yield the title compound as an off-white foam (170 mg). [M+H] calc'd for C22H32N6O4, 445; found, 445.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH:73]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3[OH:73])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3B3OC(C)(C)C(C)(C)O3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (450 mg, 0.449 mmol) in Acetone (6 mL) was added solution of oxone (276 mg, 0.449 mmol) in water (6 mL) and the resulting mixture was stirred at room temp for 1 h. Sat. sodium thiosulfate was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (370 mg, 0.414 mmol, 92% yield) as viscous oil. Product is a mixture of isomers LCMS (M+H)=893.4. Used as is in the next reaction without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[C:9]([O-:12])(=[S:11])[CH3:10].[K+].Cl>CN(C)C=O>[C:9]([O:12][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])(=[S:11])[CH3:10]
Reactant: FC(F)(F)CCCI
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OCCCC(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture of 23.80 g of 1-iodo-4,4,4-trifluorobutane, 100 ml of N,N-dimethylformamide and 11.42 g of potassium thioacetate was heated and stirred at 80° C. for 4 hours under a nitrogen atmosphere. A reaction vessel was cooled in an ice bath. To the reaction mixture was added an aqueous 1N hydrochloric acid solution, and the mixture was extracted with 100 ml of t-butyl methyl ether twice. Organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.20 g of 4,4,4-trifluorobutyl thioacetate represented by the formula:
Reaction SMILES: Cl[Si](C)(C)C.C(N(CC)CC)C.C([O:16][C:17]([C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:31]=1[CH2:32][O:33][CH3:34])=[CH:28][C:27]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[CH:26][CH:25]=3)=O)(C)C>C1(C)C=CC=CC=1>[CH2:36]([O:35][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]=[N:20][C:19]([CH:17]=[O:16])=[C:31]([CH2:32][O:33][CH3:34])[C:30]2=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCc1c(C=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
15 ml of chlorotrimethylsilane and 48 ml of triethylamine are added to a suspension of 24.3 g (60 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 250 ml of dry toluene. The reaction mixture is heated for one hour to 50° C. and then concentrated to half its volume. Thereafter the reaction mixture is cooled to -78° C. and, under nitrogen, 100 ml of DIBAL-H* (1-molar solution in toluene) is added within one-half hour; the mixture is stirred for another half hour at -78° C. Then the mixture is combined with 10 ml of ethanol and heated to room temperature; 200 ml of 0.5-molar sodium hydroxide solution and 200 ml of ethanol are added, and the mixture is stirred overnight. The precipitate is filtered off, washed with water, dried, and utilized in the subsequent reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cnc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A solution of 3-methylquinoline (275 mg), N-bromosuccinimide (343 mg) and 2,2′-azobis(isobutyronitrile) (31.6 mg) in carbon tetrachloride (8.0 g) was heated under reflux for 2 hours. The mixture was cooled to room temperature, and the insoluble materials were removed by filtration, and thereto was added toluene, and the mixture was concentrated under reduced pressure. To the residue was added toluene (5 mL) to give a solution of 3-bromomethylquinoline in toluene. To a 60% suspension of NaH (70 mg) in THF (2 mL) was added dropwise a solution of the compound (300 mg) obtained in Reference Example 3-2 in THF (3 mL). To the solution was added the solution of 3-bromo-methylquinoline in toluene as mentioned above, and the mixture was stirred at 35° C. for one hour. Water was added to the reaction solution, and the organic layer was separated, dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (460 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][OH:11].CC(C)=O>C(N(CC)CC)C>[OH:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: OCCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(CCO)CC1
Yield: 75 %

Procedure:
N-methylpiperazine (10 g; 100 mmol) and 2-chloroethanol (8.05 g; 100 mmol) are stirred at 100° C. for 4 h. The highly viscous reaction medium is supplemented with 250 ml of acetone and the resulting suspension is neutralized with 15 ml of triethylamine. After filtration of the triethylamine hydrochloride, the solvent is evaporated under reduced pressure. The desired compound is obtained after purification by chromatography on an alumina column (Merck®; Aluminum Oxide 90; 63-200 μm, eluent: ethyl acetate) in the form of a colorless oil. Yield: 75%
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[CH:19]([C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:27]([C:25]2[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[S:23][CH:24]=2)=[O:28])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(C(C)C)n2)c1Cl)OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1-[2-amino-3-chloro-4-(2,2-dimethoxy-ethoxy)phenyl]-ethanone (3.98 g, 14.6 mmol) and 2-isopropyl-thiazole-4-carboxylic acid (2.5 g, 14.6 mmol) was dissolved in pyridine (40 mL) and was cooled to −10° C. POCl3 (1.74 mL, 19.0 mmol) was added dropwise. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with CH3OH (5 mL). After 15 minutes, the reaction was taken up in EtOAc and extracted with 2N HCl(aq). The organic layer was dried with Na2SO4, filtered and was concentrated. 2-Isopropyl-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (5.58 g, 89%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]2.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][NH:16][C:11]=2[N:12]=[C:13]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]3)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CN1C(=O)CCc2cc(Nc3nc(NCc4ccccc4)c4c(C#N)c[nH]c4n3)ccc21

Procedure:
A solution of 4-(benzylamino)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg, 0.12 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (43 mg, 0.24 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2.5 mL) and dioxane (1.5 mL) was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 424.3 (M+H); UV 207.7, 273.1 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:29])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:32](OC(=O)C)([F:34])[F:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:29][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH3:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(C)=O)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(C)=O)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [3-(4-acetylbenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[CH:9]12[O:8][CH:12]([CH:11]=[CH:10]1)[CH:3]1[CH:2]2[C:1](=[O:7])[O:6][C:4]1=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(O3)C12
Temperature: 80 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
Maleic anhydride (30.00 g, 0.306 mol) was suspended in 150 mL of toluene and the mixture warmed to 80° C. Furan (33.4 mL, 0.459 mol) was added via syringe and the turbid solution stirred for 6 h. The mixture was then cooled to room temperature and the stirring was stopped. After 1 h the resulting white crystals were filtered off and the solid washed with 2×30 mL of petroleum ether. Obtained 44.40 g (0.267 mol, 87% yield) of the desired product as small white needless. m.p. 124-127° C. (dec.) IR (neat): 1857, 1780, 1309, 1282, 1211, 1145, 1083, 1019, 947, 920, 902, 877, 847, 800, 732, 690, 674, 633, 575 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=3.17 (s, 2H, CH), 5.45 (t, J=1.0 Hz, 2H, CHO); 6.57 (t, J=1.0 Hz, 2H, CHvinyl). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=48.85 (2C, CH), 82.35 (2H, CHO), 137.12 (2C, CHvinyl), 170.04 (2C, CO). Anal. Calcd. for C8H6O4: C, 57.84; H, 3.64. Found C, 57.74; H, 3.68.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.CCN=C=NCCCN(C)C.[Cl:28][C:29]1[C:30]([C:35](O)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1>C1C=CC2N(O)N=NC=2C=1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:10][C:35]([C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:36])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CNc1ncc(I)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CNc1ncc(I)cc1NC(=O)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 121.4 %

Procedure:
To a mixture of 5-iodo-N2-methyl-pyridin-2,3-diamine (1.9 g) and pyridine (6 ml) were added WSC (1.28 g), HOBt (86 mg) and 3-chloro-pyridin-2-carboxylic acid (1.3 g), and the mixture was stirred at room temperature for 9 hours. To this reaction mixture was added water, and the mixture was filtered to collect the precipitated powder. The collected powder was washed with chloroform to give 3-chloro-pyridin-2-carboxylic acid (5-iodo-2-methylamino-pyridin-3-yl)-amide (3.6 g), which is hereinafter referred to as “intermediate compound (M20-7)”.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:13]([NH:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:13]([N+:20]([O-:21])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: ONCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(C=[N+]([O-])Cc2ccccc2)cc1

Procedure:
Using 4-acetamidobenzaldehyde and N-benzylhydroxylamine (prepared from the hydrochloride salt by treatment with K2CO3) and following the procedures described herein, the title compound was prepared as a yellow powder, m.p. 230.7-237.7° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH2:14][CH2:15][CH2:16][CH3:17])C(N)=O)=[CH:6][CH:5]=1.[CH3:24][N:25]([CH3:28])[CH:26]=[O:27]>>[CH3:24][N:25]([CH3:28])[C:26](=[O:27])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCC(Cn1cncn1)(C(=O)N(C)C)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 45.1 %

Procedure:
To a 100 mL 3 neck flask stirring under nitrogen was charged 1.5 g (0.9375 mole) 60% sodium hydride (prewashed with hexanes) in 50 mL of dimethyl formamide. To the slurry was charged 3.83 g (0.0125 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexanamide in 50 mL of dimethyl formamide. The mixture was sitrred at room temperature for 3 hours then quenched by adding 20 mL of water and 75 mL of ether. The ether was washed with 50 mL water and the aqueous phase was extracted with 50 ml ethyl acetate. The ether was dried and concentrated and gave 1.88 g (45.1% yield) of product as an oil, Example 160 of Table 1.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=1[CH3:17])(=[O:9])[CH3:8]>>[CH2:15]([C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][O:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:17])[N:12]=1)[CH3:16]
Reactant: Brc1ccoc1
Reactant: CCc1nc(C)c(C(C)=O)o1
Product: CCc1nc(C)c(C(C)(O)c2ccoc2)o1

Procedure:
Starting with 3-bromofuran and 5-acetyl-2-ethyl-4-methyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: [O:1]=[C:2]([CH3:13])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:14]N1C(=O)CCC1=O.C(OCC)(=O)C>C1COCC1>[Cl:14][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:3][C:2](=[O:1])[CH3:13])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Cn1ccc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Cn1cc(Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-oxopropyl)indole from Example 3, Step 1 (800 mg, 4.6 mmol) in dry THF (20 mL) was added in one portion at r.t. N-chlorosuccinimide (680 mg, 5.1 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was then added (200 mL) and the organic phase was washed successively with 1N HCl, saturated NaHCO3, brine, dried and evaporated. The crude product was purified by flash chromatography eluting with 25% EtOAc in hexanes to yield the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH2:56][CH2:57]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a 300 mL round-bottomed flask was added 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (5 g, 9.73 mmol), dichloromethane (100 mL) and glacial acetic acid (0.6 mL, 10 mmol). This mixture was cooled to 0° C. using an ice bath and biphenyl-2-ylcarbamic acid 1-(9-oxononyl)piperidin-4-yl ester (4.6 g, 9.73 mmol) was added with stirring. This mixture was stirred at 0° C. for 30 minutes and then sodium triacetoxyborohydride (6.15 g, 29 mmol) was added in portions over 15 minutes. The reaction mixture was stirred at 0° to 10° C. for 2 hours and then aqueous saturated sodium bicarbonate solution (50 mL) was added and this mixture was stirred for 15 minutes. The layers were then separated and the organic layer was washed with 5% aqueous sodium chloride solution (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.5 g, 80% purity by HPLC), which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1>C1CCCCC1.ClCCl>[NH2:12][C:10]1[N:11]=[C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH3:19])=[CH:16][C:3]=2[OH:2])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCc1ccc(Oc2cccc(N)n2)c(OC)c1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCCc1ccc(Oc2cccc(N)n2)c(O)c1
Yield: 4.3 %

Procedure:
According to the procedure of example 5(b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for 6-(2-methoxy-4-propylphenoxy)pyridin-2-amine (125 mg, 0.48 mmol), the title compound (5 mg; 4%) was prepared as a clear oil, after preparative TLC (cyclohexane/dichloromethane).