Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC1CCCC1
Product: CCOC(=O)C1CCCC1Nc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 112.1 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (2.01 g, 12.9 mmol) in ethanol (20 mL) was treated with aniline (0.98 mL, 10.7 mmol), sodium cyanoborohydride (1.48 g, 23.6 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-cyclopentylamino-cyclopentanecarboxylic acid ethyl ester (1.40 g, 6.00 mmol, 56.1%), as a light yellow oil. LC-MS (ESI) calcd for C14H19NO2 233.14, found 234.2 [M+H+].
Reaction SMILES: F[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(C(F)(F)F)=CC=CC=2N=1.[Cl:27][C:28]1[S:29]C2C=CC(Cl)=CC=2N=1>>[Cl:27][C:28]1[S:29][C:2]2[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: FC(F)(F)c1cccc2nc(S)sc12
Product: FC(F)(F)c1cccc2nc(Cl)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2-fluoro-3-trifluoromethylaniline via 2-mercapto-7-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH3:22][N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CNc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN(c1ccccc1)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 0 °C
Yield: 46 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 56 mg, 0.198 mmol), N-methylaniline (150 μl, 1.389 mmol, Alfa Aesar, Ward Hill, Mass.), and NaHMDS (1.0M in THF; 1389 μl, 1.389 mmol) and heating at 0° C. for 1 h. Purification by silica gel (100% DCM to 3% MeOH/DCM) provided 2-(3-(methyl(phenyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.94 Hz, 2H) 3.33 (s, 3H) 3.42 (td, J=6.80, 2.45 Hz, 2H) 6.97 (br. s., 1H) 7.15 (d, J=2.15 Hz, 1H) 7.41-7.49 (m, 2H) 7.50-7.55 (m, 2H) 7.56-7.62 (m, 2H) 7.70 (dd, J=8.02, 1.17 Hz, 1H) 8.01 (dd, J=7.53, 1.27 Hz, 1H) 8.45 (s, 1H) 11.70 (br. s., 1H). MS (ESI, pos. ion) m/z: 370.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:28][CH2:29][OH:30])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][CH:19]3[CH2:18]1)[N:13]=[C:12]([CH3:27])[N:11]=2.[CH3:31]I.[H-].[Na+].Cl>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:28][CH2:29][O:30][CH3:31])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][CH:19]3[CH2:18]1)[N:13]=[C:12]([CH3:27])[N:11]=2
Reactant: Cc1nc(N2CCN3C(=O)CCC3C2)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccccc2Cl)nc2c(N3CCN4C(=O)CCC4C3)nc(C)nc21
Reaction time: 2 h

Procedure:
Charge a 100 mL flask with 2-[8-(2-chlorophenyl)-9-(2-hydroxyethyl)-2-methyl-purin-6-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one, Isomer-2 [C09111070-E] (3.3 g, 7.73 mmol) and DMF (35 mL) followed by methyl iodide (1.24 g, 8.50 mmol). Add 60% NaH (0.59 g, 13.9 mmol) in portions at 10-25° C. and stir for 2 h. Pour the mixture into water (100 mL) while stirring and extract the solution with ethyl acetate (3×50 mL). Combine the organic layers, wash with water (2×50 mL), and concentrate under vacuum to give an oil. Purify the crude by silica gel (100 g) column chromatography eluting with dichloromethane/methanol (50:1) to give a yellow solid. Redissolve the solid in ethyl acetate (40 mL) and add a solution of 1 N HCl in ethyl acetate slowly until a solid precipitates. Stir at room temperature for 2 h, filter the cake, and wash with ethyl acetate (10 mL). Dry the cake under vacuum to give 2.8 g of the title compound as an off-white solid (98.0% ee); ES/MS m/z 441.3 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(Cl)c(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (3.51 g, 25 mmol) was added dropwise to a solution of 2-chloro-5-methylphenol (3.92 g, 27.5 mmol) and triethylamine (5 mL) in dichloromethane (100 mL), The mixture was stirred for 18 hours at room temperature and concentrated under reduced pressure. Diethylether (200 mL) and water (100 mL) were added. The organic layer was separated and extracted with 2N NaOH (2×100 mL) and brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting colourless oil solidified in the freezer. Yield: 5.82 g (94%). 1H-NMR (400 MHz, CDCl3) δ=2.38 (s, 3H, —CH3), 7.05 (d, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.51-7.56 (m, 2H), 7.64-7.7.70 (m, 1H), 8.22-8.28 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=21.41, 123.97, 124.58, 128.07, 128.85, 129.15, 130.07, 130.55, 134.01, 138.38, 146.98, 164.51.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.CC1(C)C(C)(C)OB(C2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)O1.[C:27]([O-:30])(O)=[O:28].[Na+]>O1CCOCC1.CCOC(C)=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>[C:3]([O:30][C:27]([N:23]1[CH2:22][CH2:21][C:4]([OH:6])([C:3]2[CH:2]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:25][CH2:24]1)=[O:28])([CH3:8])([CH3:4])[CH3:2]
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: COC(=O)c1ccccc1Br
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Yield: 98 %

Procedure:
Methyl 2-bromobenzoate (1.816 ml, 12.936 mmol) [CAS 610-94-6] was added to a solution of 1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (4 g, 12.936 mmol) [CAS 375853-82-0] (synthesis described in WO 2004072025 A2 20040826) in 1,4-dioxane (28 ml) and an aqueous saturated solution of NaHCO3 (24 ml). The resulting solution was degassed using a stream of nitrogen and Pd(PPh3)4 (0.747 g, 0.647 mmol) was added to this solution. The reaction was then microwaved in a sealed tube at 140° C. for 5 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was collected, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 6% as eluent). The desired fractions were collected and evaporated in vacuo to yield D21 (4.04 g, 98%).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.900 g, 2.65 mmol), 4-chloro-benzylamine (0.391 mL, 3.2 mmol), and K2CO3 (0.69 g, 5.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.391 g, 41%). GC-MS: m/z 371 (M)+, 336 (M−35)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[C:6]=1[O:25][CH3:26])=[O:4].[OH-].[Na+].O.N1C2C(=CC=C3OC=CC3=2)C=C1>C(O)C.ClCCl>[CH3:26][O:25][C:6]1[C:7]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c3cc(OC)ccc3n(-c3ccccc3)c2c1OC
Agent: [Na+]
Agent: [OH-]
Agent: c1cc2ccc3occc3c2[nH]1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)c1oc(C(=O)O)c(OC)c1n2-c1ccccc1

Procedure:
A suspension of 11.5 g (0.033 mole) of 3,7-dimethoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 200 ml of 50% aqueous ethanol was treated with 25 ml of 10% aqueous sodium hydroxide solution. After stirring at reflux for 90 minutes, the reaction mixture was cooled and distributed between 750 ml of water and 250 ml of dichloromethane. The insoluble material (primarily the sodium salt of the product) was removed by filtration. The filtrate layers were separated, and the organic layer was discarded. The aqueous layer was washed several times with fresh dichloromethane, cooled in ice, and acidified with 4N hydrochloric acid. The precipitate crude product was filtered and washed with water. The original insoluble sodium salt was stirred for several hours in 400 ml of cold 1N hydrochloric acid, and the product acid was filtered, washed with water, and combined with the material obtained from acidification of the original aqueous layer. The crude yield of the furoindole acid was 9.4 g (85%) yield). A sample recrystallized from acetone/water was analytically pure, mp 148° C. (dec).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C=O.[CH3:8]OC1C=CC(O)=CC=1.[NH2:17][C:18]([NH2:20])=[O:19].Cl>C(N(CC)CC)C>[C:1]([NH:5][CH:8]=[N:17][C:18]([NH2:20])=[O:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: NC(N)=O
Reactant: C=CC(N)=O
Reactant: COc1ccc(O)cc1
Agent: C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC=NC(N)=O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
The starting material acrylamidemethyleneurea is prepared by introducing into an agitated reactor provided with a reflux condensor, the following charge: 20 parts of acrylamide, 22.8 parts of a 37% aqueous formaldehyde solution, 0.2 parts of triethylamine, and 0.01 parts of hydroquinone methyl ether. The reaction is maintained at 50° C. for one hour. In a second step, after the resultant reaction product from the first step is cooled to 10° C., there are added 67.6 parts of urea and 15 parts of concentrated hydrochloric acid. The pH of the resultant reaction milieu is then 1. The reaction milieu is agitated for 15 hours at ambient temperature, thereby forming a precipitate as the reaction proceeds. The resultant product is filtered and recrystallized in water, thereby obtaining 27.5 parts of acrylamidomethyleneurea.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>CN(C)C=O>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 34.3 g. of 2-nitrotoluene in a mixture of 37 g. of N,N-dimethylformamide diethylacetal and 100 ml. of dimethylformamide was heated under reflux for 26 hours. The dark reaction mixture was concentrated by first removing the lower boiling components on a rotary evaporator and then distilling the unreacted 2-nitrotoluene at about 75°/0.2 mm. The residual dark, red liquid (35 g., 72%), which was trans-β-dimethylamino-2-nitrostyrene, was used directly in the experiments below without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([OH:20])(=O)[CH:17]=O.ClCCCl.[CH:25]1[C:37]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:16](=[O:20])[CH:17]([C:32]3[CH:33]=[CH:34][C:35]4[CH2:36][C:37]5[C:29]([C:30]=4[CH:31]=3)=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc2c(c1)-c1ccccc1C2
Yield: 17.1 %

Procedure:
A mixture of 15.9 g (75 mmol) of 2,4-di-tert-butylphenol (97%), 12.2 g (82 mmol) of 50% aqueous glyoxylic acid, 40 mg (0.20 mmol) of p-toluenesulfonic acid monohydrate and 25 ml of 1,2-dichloroethane is refluxed for 3.5 hours under nitrogen on a water separator. The reaction mixture is thereafter concentrated on a vacuum rotary evaporator. The residue is dissolved in 30 ml of n-octane and 125 g (75 mmol) of fluorene and 3 g of Fulcat 22B are added to the solution. This reaction mixture is refluxed for 3.5 hours under nitrogen on a water separator, the cooled and filtered. The filtrate is concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethane/hexane=2:1 and subsequent crystallisation of the pure fractions from methanol yields 5.28 g (17%) of 5,7-di-tert-butyl-3-(9H-fluoren-3-yl)-3H-benzofuran-2-one, m.p. 140-153° C. (compound (121), Table 1). The product may additionally contain minor amounts of other structural isomers in accordance with the substitution at the fluorene ring.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([CH:18]([C:20]4[C:28]5[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=4)O)=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH2:18][C:20]4[C:28]5[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=5[NH:22][CH:21]=4)=[C:15]([F:17])[N:16]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ncnc2c1c(C(O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2[nH]cc(Cc3ccc(Nc4ccc(C5CC5)nc4)nc3F)c12
Temperature: 80 °C
Reaction time: 4 h
Yield: 25.2 %

Procedure:
To [6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol (73, 70 mg, 0.12 mmol) in 10.0 mL of 1,2-dichloroethane, triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.60 mL, 7.8 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4004, 11.8 mg). MS (ESI) [M+H+]+=390.9.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C@H:16]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:18]([O:17][C@H:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:12][CH2:13][NH:14][CH2:15]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@@H]1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (32 mL) of tert-butyl (S)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.62 g, 4.29 mmol) synthesized in Reference Synthesis Example 136, trifluoroacetic acid (6.5 mL) was added and the resultant mixture was stirred at room temperature for 20 hours. After completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:13].[Cl-:14].[P+]=O.[OH-].[NH4+]>CN(C)C=O>[Cl:14][C:6]1[C:5]2[C:10](=[CH:11][C:2]([I:1])=[C:3]([CH3:13])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Cc1cc2c(=O)cc[nH]c2cc1I
Reactant: [Cl-]
Agent: O=[P+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ccnc2cc1I
Temperature: 60 °C
Reaction time: 1.33 h
Yield: 98 %

Procedure:
A mixture of 7-iodo-6-methyl-1H-quinolin-4-one (5.12 g, 18.0 mmol), phosphorus oxide chloride (14 mL) and N,N-dimethylformamide (1 mL) was stirred at 60° C. for 80 min, then poured onto ice and carefully neutralized with 25% aq. ammonium hydroxide solution. The suspension was extracted three times with dichloromethane, the combined organic phase was washed with brine, dried (MgSO4), and evaporated to afford the title compound (5.33 g, 98%). Light brown solid, ISP-MS: m/e=304.1 ([M+H]+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][O:63][Si](C(C)(C)C)(C)C)[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][OH:63])[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxy-propyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (144mg) in CH2Cl2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 81 mg of the title compound. Partial 1H NMR (CDCl3, 200 MHz) d: 7.22 (d, J=9 Hz, 1H); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3 Hz, 1H); 6.89 (dd, J=3 Hz and J=9 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H); 2.00 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCN(C2C=CC(N[C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=CC=2)CC1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 72 h at rt and using 3 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2.4 equiv) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 489.1 [M+H]+; tR=3.73 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 9:1).