Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH3:9])[CH2:3][CH2:4][NH:5][CH:6]([CH3:8])[CH3:7].FC1C=CC(CNC(C2C(=O)C(O)=C3C(=O)N4[C@H](C)CCN(C(C)C)[C@H]4CN3C=2)=O)=CC=1.C[O:43][C:44]([C:46]1[N:47]([CH2:72][CH:73]=O)[CH:48]=[C:49]([C:61](=[O:71])[NH:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[C:50](=[O:60])[C:51]=1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=O.C(O)(=O)C>ClCCl>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][NH:62][C:61]([C:49]2[C:50](=[O:60])[C:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:46]3[C:44](=[O:43])[N:1]4[C@H:2]([CH3:9])[CH2:3][CH2:4][N:5]([CH:6]([CH3:8])[CH3:7])[C@H:73]4[CH2:72][N:47]3[CH:48]=2)=[O:71])=[CH:69][CH:68]=1
Reactant: CC(C)NCC[C@@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: CC(C)N1CC[C@@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 56 %

Procedure:
[(3R)-3-Aminobutyl](1-methylethyl)amine. The free diamine was prepared in a similar manlier as described in example Z-29. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J=6.4 Hz, 6H), 1.06 (d, J=6.4Hz, 3H), 1.41-1.58 (m, 5H), 2.62-2.66 (m, 2H), 2.74-2.80 (m, 1H), 2.92-3.00 (m, 1H). b) (4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (26 mg, 56%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (21 mg, 90%) as an off-white solid. 1H NMR (4.00 MHz, CDCl3) δ 1.01 (d, J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H), 4.4.8 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:15]=[O:16]>CN(C)C=O>[CH2:17]([NH:14][C:15]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc(-c2ccncc2)cc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a suspension of [4-(4-pyridinyl)phenyl]amine (100 mg) in N,N-dimethylformamide (4 ml) was added (isocyanatomethyl)benzene (86 mg) and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 1-benzyl-3-[4-(4-pyridinyl)phenyl]urea (135 mg) as a yellow powder.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=O.[CH2:16]([OH:19])[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:16]1[O:19][C:10]([O:12][CH2:13][CH3:14])([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:15])[O:18][CH2:17]1
Reactant: OCCO
Reactant: CCOC(=O)CCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC1(CCCCCCCC(C)=O)OCCO1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution containing 77.5 g (362 mmol) of ethyl 9-oxodecanoate (prepared described in J. Amer. Chem. Soc., 68: 832 [1946]), 22.4 g (362 mmol) of ethylene glycol and 438 mg of p-toluenesulfonic acid in 150 ml of dry benzene was refluxed for 4.5 hr with a Dean Stark trap. A 7.0 ml portion of water (theoretical=6.5 g) collected in the trap. The solution was cooled to room temperature and then was washed with saturated aqueous sodium bicarbonate. The aqueous phase was back-extracted twice with ether. The combined ether extracts were dried over Na2SO4 and evaporated in vacuo and distilled in vacuo to give a 83.5% yield of the title compound. The product had the following physical characteristics:
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)CC>>[ClH:1].[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:19][CH:20]=1
Reactant: CCCCC=O
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Agent: Cl
Solvent: CCC=O
Product: CCCCCNCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 38 %

Procedure:
The experimental protocol used is the same as that described for Stage 399.1 of Example 399, with the compound of Example 362 and valeraldehyde replacing intermediate 355.2 and propionaldehyde respectively. A dark-coloured solid is obtained with a yield of 38%. MH+=382.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1.CCOCC>[F:13][C:10]1([F:14])[CH2:11][CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20]([OH:22])=[O:21])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: FC1(F)CC[C@@H](c2ccc(Br)cc2)C1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc([C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g (3.8 mmol) of (R)-3-(4-bromophenyl)-1,1-difluorocyclopentane (from Step B) in 15 mL of THF at −78° C. was treated with 1.6 mL (4.0 mmol) of 2.5M BuLi in hexanes. After stirring for 15 min, the reaction mixture was added to a suspension of dry ice in 200 mL of Et2O. The mixture was allowed to warm to rt. The reaction mixture was extracted with 100 mL of 1 N NaOH. After separating phases, the aqueous layer was acidified to pH 1-2 with concentrated HCl. The aqueous phase was extracted with 3×100 mL of CH2Cl2. The combined organic phases were dried and concentrated to give 0.67 g of the title compound: 1H NMR (CD3OD) δ 1.87 (m, 1H), 2.13-2.37 (m, 4H), 2.54 (m, 11H), 3.41 (m, 1H), 7.39 (d, J=8.2, 2H), 7.97 (d, J=8.2, 2H).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)[CH:15]=3)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)OCC[O:4]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[OH:32][CH2:31][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][C:10]=3[CH2:33][CH2:34][CH3:35])[CH:15]=2)[CH:28]=[CH:27][C:26]=1[CH2:29][OH:30]
Reactant: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Yield: 49.8 %

Procedure:
640 mg (1.4 mmol) of (4-{2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol are placed in 15 ml of acetone and 15 ml of water in a round-bottomed flask. A spatula-tip of p-toluenesulfonic acid is added and the solution is refluxed for 2 hours 30 minutes. At room temperature, it is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (30/70). 300 mg (50%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1>CN(C)C=O>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 15 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.41 g of triethylamine hydrochloride. To this solution were added 3 ml of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 16 hours at 150° C. After the reaction, dimethylformamide was removed from the reaction liquid by distillation and the residue was treated in the same manner as described in Example 7 to obtain 0.8 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. From the chloroform insoluble matter 0.6 g of the starting 5-fluorouracil was recovered. The yield of the end product was 74% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:21]([O:22][CH3:23])=[N:20][C:7]2[CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].C1C(=O)N([Cl:31])C(=O)C1>CC#N>[Cl:31][C:5]1[C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:9][CH2:8][C:7]=2[N:20]=[C:21]([O:22][CH3:23])[C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCNc1c(OC)nc2c(c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 36.5 %

Procedure:
To a solution of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (99.0 mg, 0.30 mmol) in MeCN (5 ml) was added NCS (44.0 mg, 0.33 mmol) at room temperature and the mixture was refluxed for 30 minutes. The reaction was quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 40 mg (36%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.39 (0.5H), 4.04 (0.5H), 3.94 (3H), 3.83 (1H), 3.78 (1H), 3.72 (1H), 3.45 (1H), 3.35 (2H), 3.25 (1H), 3.09 (1H), 1.19 (6H) ppm. A mixture of 4chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (37.0 mg, 0.10 mmol), K2CO3 (40 mg), MeOH (1.5 ml) and H2O (0.3 ml) was stirred for 16 h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 27 mg (93%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.85 (s, 3H), 3.47 (m, 1H), 3.23 (m, 2H), 3.16 (m, 2H), 3.08 (m, 1H), 2.89 (dd, 2H), 2.69 (dd, 1H), 1.22 (d, 3H), 1.09 (t, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[C:17]([O:22][CH3:23])=[N+:18]([O-:32])[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ncccc1COc1ccc(-c2ccc(Br)cc2)cc1
Solvent: ClCCl
Product: COc1c(COc2ccc(-c3ccc(Br)cc3)cc2)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(4′-bromo-biphenyl-4-yloxymethyl)-2-methoxy-pyridine (0.19 g, 0.51 mmol) from Step B and mCPBA (77% max., 0.25 g, 1.13 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 days. The reaction was diluted with dichloromethane and washed with aqueous Na2SO3 solution, 1N NaOH solution, water and brine. The organic layer was dried over anhydrous K2CO3 and filtered through Celite. The filtrate was concentrated under vacuo and the residue was purified by chromatography (silica gel, 10% MeOH/EtOAc) to give the desired product. MS: 386, 388 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14](CO)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OCC1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(OCC1CCNCC1)c1ccccc1
Yield: 88 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), piperidin-4-ylmethanol (1.2 mmol), Zn4(OCOCF2)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 18 hours, and as a result, piperidin-4-ylmethyl benzoate was obtained at a yield of 88%. The yield of N-benzoylpiperidin-4-ylmethyl benzoate was 12%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)[C:10](=[O:42])[CH:9]1[CH:43]([CH3:45])[CH3:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH:9]([CH:43]([CH3:45])[CH3:44])[C:10]4=[O:42])[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C(C)C)C3=O)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(C(C)C)C3=O)n(C)c2n1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.17 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 681 as an off-white solid (55 mg, 67%). LCMS (method I): RT 2.54 min, [M+H]+ 518.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-8.00 (1 H, m), 7.76-7.76 (1 H, m), 7.32-7.22 (2 H, m), 4.95-4.79 (1 H, m), 4.35 (4 H, brd s), 3.90-3.82 (7 H, m), 3.47-3.45 (3 H, m), 3.35 (2 H, q, J=7.48 Hz), 3.23-3.22 (1 H, m), 3.02 (1 H, ddd, J=12.50, 11.03, 3.93 Hz), 2.57-2.56 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.21 (1 H, t, J=7.02 Hz), 1.04 (3 H, d, J=7.12 Hz), 0.93 (3 H, d, J=6.80 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Yield: 38.7 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide (208 mg, 0.568 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (341 mg, 1.70 mmol) in n-BuOH (2 mL) was processed as described in Example 62, Step B, to provide (R)-tert-butyl 1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 39% yield).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>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.CN1CCCC1=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(O)C#Cc1cc(Cc2ccccc2)c(C#CC2(O)CN3CCC2CC3)cn1
Reaction time: 1 h

Procedure:
110 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine, 53 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis(triphenylphosphine)palladium(0), 7 mg of cuprous iodide and 0.5 ml of triethylamine were added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for one hour in an oil bath kept at 100° C. After cooling as it was, it was evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 5% methanol/ethyl acetate, to synthesize 32 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[N:31]([C:10]1[C:9]([S:8][CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (24.35 g, 56.18 mmol) in DMF (200 mL) was added NaN3 (4.38 g, 67.41 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 21.04 g, 82.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.10 (m, 6H), 6.84 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[C:18]3[O:17][CH2:16][C:15](=[O:19])[C:14]=3[CH:13]=[CH:12][C:11]=2[OH:20])[CH2:3]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[N:22]1.N1CCCCC1>CO>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[C:16]2\[O:17][C:18]3[C:10]([CH2:9][N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[C:11]([OH:20])[CH:12]=[CH:13][C:14]=3[C:15]\2=[O:19])=[N:22]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: C[C@@H]1CN(Cc2c(O)ccc3c2OCC3=O)C[C@H](C)N1
Solvent: C1CCNCC1
Solvent: CO
Product: C[C@@H]1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)C[C@H](C)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.166 g, 0.601 mmol) in methanol (2.4 mL) was added with 1H-indazole-3-carbaldehyde (0.0878 g, 0.601 mmol), and piperidine (0.00512 g, 0.0601 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (8 mL), suspended in methanol, and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.197 g, 81%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][C:20]#[N:21])=[CH:16][CH:15]=1.[H-].[Na+].C(O)(=O)C>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH2:19][C:20]#[N:21])=[CH:22][CH:23]=1
Reactant: CCOC(OCC)P([O-])OCC
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 25.8 g of ethyl (diethoxymethyl)phosphonite and 18.0 g of 4-chlorocinnamonitrile in 100 ml of ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 180°-200° C./0.02 mbar, 31P=+37.9 and +37.8 ppm (CDCl3).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][C:10](=O)OC(C)(C)C)=O.C(OC=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:9]1[C:4]2[C:3](=[CH:8][CH:7]=[N:6][CH:5]=2)[CH:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=1
Reactant: CCOC=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cnccc2c1

Procedure:
A mixture of tert-butyl 4-formylpyridin-3-ylcarbamate (1.7 g, 7.65 mmol), ethyl 3-ethoxyacrylate (1.27 g, 8.8 mmol) and TFA (5.9 mL, 76.5 mmol) in CHCl3 (30 mL) is heated at reflux for 4 hr. The mixture is cooled and the solvent is removed in vacuo. The residue is dissolved in EtOAc (30 mL) and washed with saturated NaHCO3 solution (20 mL). The organic layer is dried and evaporated. Purification of the residue with flash column with hexane/EtOAc (2:1) gives the title compound as a white solid. MS (M+1): 203.1.