Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:13])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A mixture of 7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.65 g), 1H-1,2,3-benzotriazol-1-ol (991 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 30 min. The mixture was cooled to 0° C., 28% aqueous ammonia (600 μL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with saturated brine (200 mL), dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography with 50% ethyl acetate-hexane mixture as an eluate to give the title compound (1.30 g, yield 79%) as a white solid. melting point 220-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[N:41]#CBr>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:41])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#CN1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[1-tert-butyloxycarbonyl-4-piperidinylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reaction with cyanogen bromide. Melting point: 245°-247° C.; Rf : 0.59 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:3)
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:46])[N:11]([C:34]6[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=6[CH:43]([CH3:45])[CH3:44])[C:12](=[O:33])[C:13]=5[CH:14]=[C:15]3[O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[CH:8][C:7]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=3)=[C:6]4[C:5]3=[CH:58][CH:59]=[CH:60][C:3]=1[C:4]=23.[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[SH:68].C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[S:68][C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:46])[N:11]([C:34]6[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=6[CH:43]([CH3:45])[CH3:44])[C:12](=[O:33])[C:13]=5[CH:14]=[C:15]3[O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[CH:8][C:7]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=3)=[C:6]4[C:5]3=[CH:58][CH:59]=[CH:60][C:3]=1[C:4]=23
Reactant: Nc1ccccc1S
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Br)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Sc6ccccc6N)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Compound 8-bromo-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (3.0 g), 2-aminobenzenthiol (0.48 g, 10% excess) and anhydrous potassium carbonate (0.24 g) were added to 30 mL of N-methyl-2-pyrrolidinone (NMP). The solution was heated rapidly and refluxed for 30 min. After a minute the liquor was added to 2% aqueous hydrochloride acid (250 ml) and after standing overnight, filtered and dried at 105° C. to give a red-blue solid of 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) with a nominal yield of 60.0%. 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) was dissolved in warm glacial acetic (12 mL) and concentration hydrochloride acid (1.3 mL) giving a fine suspension. The suspension was cooled to 0° C. and a solution of sodium nitrite (0.16 g) in water (3.6 mL) added and stirred continuously till clear. The prepared solution was added to a boiling solution of hydrated cupric sulphate (2.6 g) in water (60 mL) with good stirring within 1 hour. After boiling a further 1 hour, the solution was cooled, filtered and a blue-red solid was given. The solid was washed with a warm solution of sodium hydroxide (20 mL, 3%) three times and purified on Chromatography Column to eliminate by-products. The blue solid of 5,15-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-thioxantheno[2′,1′,9′:10,5,6]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (0.69 g) was given with a nominal yield of 34.2%. MS: base peak 884.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH2:10][CH:9]([CH:12]3[CH2:14]C3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]1[CH2:17][CH2:16][N:15]([C:4]2[C:5]3[O:11][CH2:10][C:9]4([CH2:12][CH2:14]4)[O:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=3)[N:3]=2)[CH2:20][CH2:19]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC2(CC2)O3)cn1
Temperature: 120 °C
Yield: 35.2 %

Procedure:
A mixture of 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (98 mg, 0.34 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (144 mg, 0.65 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 106 as a white solid (41 mg, 35%). LCMS: RT=3.24 min, [M+H]+=343. 1H NMR (400 MHz, CDCl3): δ 9.12 (2H, s), 5.20 (2H, broad s), 4.16 (2H, s), 3.82 (8H, s), 1.29 (2H, t, J=6.89 Hz), 0.88 (2H, t, J=6.88 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18]([CH:21]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH2:3][O:2][CH3:1])([O-:20])=[O:19]
Reactant: COCOc1ccccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COCOc1ccccc1C=C[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Methoxymethoxybenzaldehyde (16.4 g) was suspended in nitromethane (54 mL), added with ammonium acetate (5.95 g), and stirred for 30 minutes at 80° C. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was suspended in water and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine in order and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residues were purified by diol silica gel column chromatography (5% ethyl acetate/hexane) to obtain the title compound (11.6 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([CH:28]=[CH2:29])=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1.I[C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1.[OH-].[Ba+2].[OH-].ClCCl>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1
Reactant: C=Cc1nn(C2CCCCO2)c2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ncc12
Reactant: Cn1cc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Ba+2]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(/C=C/c2cnn(C)c2)nn3C2CCCCO2)c1Cl
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine (0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added 4-iodo-1-methyl-1H-pyrazole (22 mg, 0.10 mmol) (Aldrich Cat. No. 683531), barium hydroxide (36 mg, 0.21 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (5.6 mg, 0.0069 mmol), and water (0.05 mL). The mixture was degassed and sealed. The mixture was stirred at 95° C. overnight. After cooling the solid was filtered off, washed with acetonitrile. The filtrate was concentrated under reduced pressure to afford the crude product which was directly used in next step reaction without further purification. LCMS (M+H)+=514.2/516.1.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].BrCC1OC(C(F)(F)F)=CC=1.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[NH:23]2.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[N:23]2[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: CCCCCI
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 1-iodopentane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 6.87-6.83 (m, 1H), 6.45 (s, 1H), 6.16 (s, 1H), 4.89 (ABq, 2H), 4.20-4.11 (m, 4H), 3.85-3.59 (m, 2H), 1.72-1.67 (m, 2H), 1.38-1.25 (m, 4H), 0.92-0.85 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 117.0, 156.4, 144.7, 144.5, 137.9, 130.13, 130.10, 126.9, 119.9, 118.1, 111.0, 107.5, 98.9, 76.8, 64.4, 63.8, 59.3, 40.5, 28.9, 27.0, 22.3, 13.9; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].N1C=CC=NC1=O.[C:25]([Mg]Br)([CH3:28])([CH3:27])[CH3:26]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH2:16][CH3:17])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: O=c1nccc[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 7-bromo-6-ethoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound A-4, 2.0 g, 6.73 mmol) in THF (20 mL), ether (20 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1])-pyrimidinone (8 mL) at −30° C. was added a solution of tert-butylmagnesium bromide (2M in ether, 13.5 mL, 27 mmol). The reaction was allowed to warm to room temperature over 5 h. The reaction was quenched with ice water and extracted with ether. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was then dissolved in methanol (20 mL). After catalytic amount of p-toluenesulfonic acid was added, the reaction was stirred at 50° C. for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 1% ethyl acetate in hexane) to afford the title compound as a pale yellow oil
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([NH:21][C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:24][C:22]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCNC(N)=O
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: CCCCNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and butyl urea.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH:22]([C:33]([OH:35])=[O:34])[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[C:16]1=[O:36].C([BH3-])#N.[Na+]>>[C:33]([CH:22]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:15]([NH:14][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:16]1=[O:36])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)([OH:35])=[O:34]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@H]1CCCCN(C(Cc2c[nH]c3ccccc23)C(=O)O)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCCCN(C(Cc2c[nH]c3ccccc23)C(=O)O)C1=O

Procedure:
Methyl 3-[3-indolyl]-2-oxopropionate (1.09 g) and α-t-Boc-L-lysine (0.246) are dissolved in ethanol solvent containing powdered 4 Å molecular sieves (1.87 g). A solution of sodium cyanoborohydride (0.189 g) in ethanol is added at room temperature over six hours. When reaction is complete, the solvent is removed and the residue is partitioned between ether and water. The aqueous layer is isolated and pH adjusted to 3.6. The crude product is extracted into ethyl acetate and purified by LH-20 chromatography. Ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-(3-indolyl)ethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponificaton of the methyl ester and subsequent formic acid treatment to remove the t-butoxycarbonyl protecting group yields 3-(S)-amino-1-[1-carboxy-2-(3-indolyl)ethyl]perhydroazepin-2-one. 2-Oxo-4-phenylbutyric acid and this caprolactam are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-(3-indolyl)ethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one. The silylated mass spectrum shows a parent ion at 693 m/e [3TMS+477 MWt], and loss of CH3 =678 m/e is observed.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1)=[CH:11][CH:10]=3.[CH2:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:18]1[C:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][C:5]2[CH:6]=[N:7][C:2]([O:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:3][C:4]=2[C:15]3=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=c1c2cc(-c3cccnc3F)ccc2oc2cnc(Cl)cc12
Reactant: CC(C)(C)CO
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)COc1cc2c(=O)c3cc(-c4cccnc4F)ccc3oc2cn1
Temperature: 95 °C
Yield: 18.8 %

Procedure:
A vial was charged with 3-chloro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (275 mg, 0.842 mmol), neopentyl alcohol (297 mg, 3.37 mmol), Pd2 dba3 (38.5 mg, 0.042 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (67.1 mg, 0.168 mmol) and cesium carbonate (686 mg, 2.104 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Toluene (1.7 mL) was added, the vial was sealed and the reaction mixture was heated to 95° C. in an oilbath overnight. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (10-100% EtOAc/hexanes). 7-(2-Fluoropyridin-3-yl)-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one (60 mg) was obtained as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (2-hydroxy-1,1-dimethylethyl)-carbamic acid tert-butyl ester (284 mg, 1.5 mmol) in CH2Cl2 (5 mL) was added at 0° C. Dess-Martin periodane (763 mg, 1.8 mmol). After 1.5 h, a solution of 0.26M Na2S2O3 in saturated NaHCO3 (6 mL) was added and the resulting mixture was stirred for 15 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to yield (1,1-dimethyl-2-oxo-ethyl)carbamic acid tert-butyl ester as a white solid which was used in the next step without further purification.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:8]=[C:7]([Br:9])[S:6][C:5]=1[C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1.Cl>[Br:3][C:4]1[CH:8]=[C:7]([Br:9])[S:6][C:5]=1[CH:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=O)c1sc(Br)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1sc(Br)cc1Br
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.14 g, 3.7 mmol) was added portionwise to a solution of ethyl 2-(3,5-dibromothiophen-2-yl)-2-oxoacetate (7a) (0.42 g, 1.24 mmol) in anhydrous tetrahydrofuran (10 mL), previously cooled to −10° C. After 30 minutes stirring, a few drops of 1 M hydrochloric acid were added and the resulting precipitate was filtered. The filtrate was concentrated in vavuo. The residue was dissolved in brine, and extracted with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide ethyl 2-(3,5-dibromothiophen-2-yl)-2-hydroxyacetate (0.32 g, 0.93 mmol, 75%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.Br[C:17]1[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([O:29][CH3:30])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:21]([C:31]([F:34])([F:33])[F:32])[O:22]2>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>[Cl:27][C:26]1[C:17]([CH3:1])=[C:18]2[C:23](=[C:24]([O:29][CH3:30])[C:25]=1[Cl:28])[O:22][CH:21]([C:31]([F:34])([F:33])[F:32])[C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:19]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2c(Br)c(Cl)c(Cl)c(OC)c2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2c(C)c(Cl)c(Cl)c(OC)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 55 %

Procedure:
Pd(PPh3)4 (0.13 g, 0.85 mmol), K2CO3 (0.34 g, 0.85 mmol) and trimethylboroxine (0.14 g, 0.85 mmol) was added to a stirring solution of ethyl 5-bromo-6,7-dichloro-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.38 g, 0.85 mmol) dissolved in 1,4-dioxane and heated to reflux for 24 hrs. Allowed to cool to R.T., filtered through celite and washed with EtOAc. The resulting solution was condensed in vacuo and purified by flash chromatography (silica gel) and eluted with 10% EtOAc/ hexanes to yield 0.18 g (56%) of the title compound as an amorphous solid: GCMS m/z 384.0 (M+). 1H NMR (CDCl3/300 MHz) 7.92 (s, 1H), 5.80 (q, 1H, J=7.0 Hz), 4.35 (m, 2H), 3.89 (s, 3H), 2.47 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH2:20][CH3:21]>[Pd]>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:20][CH3:21]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1CC)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 d], (2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [OH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].O.Cl>CS(C)=O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:1])([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 8 h

Procedure:
87.6 g of finely powdered sodium hydroxide was added in portions over an 8-hour period to a stirred solution of 165.0 g of 2-nitro-4-(trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulfoxide at room temperature. The mixture was allowed to stand overnight, then poured into 1.5 liters of cold water. The resulting mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil formed; it was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent under reduced pressure. The residue was mixed with cold sodium hydroxide solution and the mixture was extracted with petroleum ether. The water layer was acidified with concentrated hydrochloric acid. The resulting oil was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent to give 2-nitro-4-(trifluoromethyl)phenol (6A).