Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH:15](C)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][CH:15]([CH2:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:22])[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(C)CBr
Reactant: O=C([O-])[O-]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(C)COc1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methoxy-4-nitrophenol (0.207 mg. 1.23 mmole) {Aldrich}, methyl 4-bromo-3-methylbutyrate(0.25 g. 1.35 mmole) and potassium carbonate (0.19 g. 1.35 mmole) in DMF (10 mL.) was heated and stirred at 80° C. for 8 hours. After cooling, the inorganics were filtered off, and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane and washed twice with water. After drying (MgSO4) the solvent was evaporated off to yield an oil. The oil was purified by chromatography (Varian Megabondelut silica column) using a gradient of 100% dichloromethane to 20% ethyl acetate/dichloromethane to give methyl 3-methyl-4-(2-methoxy-5-nitrophenoxy)butyrate as an oil (90 mg. 29%) ms 284(M+)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:14]3)=[C:2]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)[CH:7]=1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3-c3ccncc3)cccc2c1
Temperature: 100 °C
Yield: 6 %

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (80 mg, 0.166 mmol), potassium carbonate (115 mg, 0.832 mmol), pyridin-4-ylboronic acid (30.7 mg, 0.250 mmol), tetrakis(triphenylphosphine)palladium(0) (19.23 mg, 0.017 mmol), dioxane (1109 μl) and water (555 μl). The reaction mixture was heated in a microwave at 100° C. for 30 min. The mixture was then cooled to room temperature and the organic layer was separated from the aqueous layer by pipet. The resulting organic layer was then injected as is onto a reverse phase HPLC for purification (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were dried under a vacuum to provide 5-(4-chloro-2-(pyridin-4-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (5 mg, 0.01 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (s, 2H) 7.04 (d, J=5.98 Hz, 2H) 7.36-7.41 (m, 1H) 7.46 (d, J=8.76 Hz, 1H) 7.51-7.60 (m, 2H) 7.63-7.70 (m, 3H) 8.09 (d, J=8.33 Hz, 1H) 8.16 (s, 1H) 8.26 (d, J=5.56 Hz, 2H) 8.39 (d, J=1.71 Hz, 1H); m/z (ESI) 479.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Yield: 13.4 %

Procedure:
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile (150 mg, 0.31 mmol), 6-chloropyridazin-3-(2H)-one (62 mg, 0.47 mmol), Pd(Ph3P)2Cl2 (15 mg), and aq. Cs2CO3 solution (2 mL, 2M) in 1,4-dioxane (10 mL) was stirred at reflux for 2 h. When the reaction was finished, the mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (18.9 mg, 15%). LC-MS Method 2 tR=1.053 min, m/z=457.3; 1H NMR (CDCl3): δ1.16 (s, 3H), 1.25 (s, 3H), 1.38 (d, 3H), 2.21 (s, 2H), 2.24 (m, 1H), 2.40 (m, 2H), 2.86 (m, 1H), 5.61 (m, 1H), 6.86 (m, 2H), 6.95 (m, 1H), 7.29 (m, 5H), 7.32 (m, 2H), 7.56 (m, 1H).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[Br:12]N1C(=O)CCC1=O.ClC1C2SC=CC=2NC=1C(O)=O>>[Br:12][C:7]1[C:8]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc2sccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(O)c1[nH]c2ccsc2c1Cl
Product: O=C(O)c1[nH]c2ccsc2c1Br
Yield: 10.5 %

Procedure:
The title compound was synthesized from 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.1 g, 0.60 mmol, 1 equiv) and N-bromosuccinimide (NBS) (0.107 g, 0.599 mmol, 1 equiv) according to the halogenation method reported for the chlorination of 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (with NCS) to 6-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid, providing the desired 6-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 71 (15.5 mg, 10.5%). LC/MS m/e 243.9 (M−H). tR of product: 2.5-2.8 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.42 (d, J=5.32 Hz, 1H), 7.01 (d, J=5.32 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20]>C(O)C.C(OCC)C.O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOc1cc(OC)ccc1C#N
Yield: 82.9 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (9.637 g, 64.61 mmol) in ethanol (50 mL) were added potassium carbonate (17.88 g, 129.2 mmol) and iodoethane (15.7 mL, 193.8 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to afford a yellow-brown paste. It was then taken in diethyl ether (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic extracts were washed with water (1×20 mL), brine (1×20 mL), and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 10–15% ethyl acetate in hexanes yielded 2-ethoxy-4-methoxy-benzonitrile as yellow solids (9.487 g, 83%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NCc1ccc(F)cc1)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-fluorobenzylamine
Reaction SMILES: [C:1]1(=O)[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCCCCC>C1C=CC=CC=1>[NH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCN1
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(N2CCOCC2)c(N=C2CCCCN2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of delta-valerolactam (24 g) in dry benzene (100 ml) was cooled to 10° C. in ice-water and treated with freshly distilled phosphorus oxychloride (22.2 ml) under nitrogen over a period of 10-15 minutes. The initial white solid formed changed to a clear yellow oil over 3 hours. A solution of 4-(2-aminophenyl)morpholine (36 g) in dry benzene (150 ml) was added and the mixture heated at 65° C. with stirring for 32 hours. The benzene layer was decanted, the oil washed twice with benzene (2×40 ml), ether (100 ml) was added and the mixture cooled in ice treated with 10% aqueous sodium hydroxide solution to alkaline pH, with stirring. The aqueous layer was extracted with ether (2×100 ml) and the combined ether extracts washed with water, brine and dried. The solution was filtered and the solvent removed to give a thick oil which solidified on trituration with hexane. The crude solid was crystallised from hot hexane to yield 4-[ 2-(2-piperidinylideneamino)phenyl]morpholine (m.p. 89°-90° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.C(N(CC)CC)C.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C[O:31][CH2:30]C1>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]>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:30]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:12]
Reactant: OCc1ccccc1
Reactant: CN1C(=O)Cc2cc(Br)ccc21
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc(C(=O)OCc3ccccc3)ccc21
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromo-1-methyl oxindole (3.75 g, 16.6 mmol) and triethylamine (3.48 mL) in THF (40 mL) was treated with benzyl alcohol (2.58 mL) and PdCl2(dppf) (300 mg), stirred under carbon monoxide (680 psi) at 130° C. for 16 hours, depressurized, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified on silica gel with 30% ethyl acetate/hexanes to provide 2.36 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[N:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][N:21]1[C:25]([CH:26]=O)=[N:24][CH:23]=[N:22]1.[O-:28][CH2:29][CH3:30].[Na+]>C(OCC)(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:26]([C:25]3[N:21]([CH3:20])[N:22]=[CH:23][N:24]=3)[C:29](=[O:28])[C:30]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: O=C1OCc2c(N=Cc3ccc(F)cc3)cccc21
Reactant: Cn1ncnc1C=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Temperature: 55 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 4-(4-fluorobenzylideneamino) isobenzofuran-1(3H)-one (5.0 g, 19.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (2.8 g, 25.5 mmol) in ethyl propionate (310 mL) was added sodium ethoxide (1.26 g, 54.9 mmol) at room temperature under nitrogen. The mixture was stirred at 55° C. for 2 hr. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (150 mL×4) and concentrated the extracts. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=20:1 to 1.5:1). A solid product was obtained (2.4 g, yield 31%). LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl>CN(C=O)C>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.44 g, 44.55 mmol), K2CO3 (13.6 g) and DMF (50 ml) was added in portions 2-dimethylaminoethylchloride hydrochloride (7.1 g). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was stripped. The residue was diluted with 1N HCl (300 ml), and extracted with ether, and the ether layer was dried over MgSO4 and stripped. The acidic aqueous layer was cooled and then treated with 8N NaOH till basic, then it was extracted with ether (3×150 ml). The ether layers were combined, dried over MgSO4, filtered and stripped to afford, as an oily liquid, 1.43 g of 3-[2-(dimethylamino)ethoxy]benzaldehyde.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15]([C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=O)C.Cl>C1COCC1.C(OCC)(=O)C.O>[O:19]1[CH:20]=[CH:21][C:17]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])=[CH:18]1
Reactant: CCOC(=O)c1ccoc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccoc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 27 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one in 40 mL of THF was treated with NaH (60 percent, 0.8 g, 36.25 mmol). After the addition of Furan-3-carboxylic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Furan-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 38 mmol) as brown solid in 27% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCOCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCO)ccc21
Reaction time: 6 h
Yield: 80 %

Procedure:
3-[5-(2-benzyloxy-ethoxy)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester (2.5 g, 5.6 mmol) was dissolved in 70% ethyl acetate/methanol (50 mL) and added under an argon atmosphere to a suspension of 10% palladium on carbon [10% w/w] (3.0 g) in the same solvent (50 mL). The reaction was placed in a Parr Hydrogenator for 6 h. The reaction was filtered through celite and the solvent was evaporated under vacuum. Purification of the crude mixture via column chromatography with silica gel, eluting with hexane/ethyl acetate gave the title compound (80% yield). 1H NMR (CDCl3), δ 7.14–7.32 (m, 7H), 6.82 (dd, 1H, J=2.3, 8.8 Hz), 6.45 (d, 1H, J=3.0 Hz), 6.07 (d, 1H, J=2.1 Hz), 6.01 (t, 1H, J=7.4 Hz), 4.03 (m, 4H), 3.91 (m, 2H), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[CH:40][CH:39]=1>CCOC(C)=O.CCCCCC>[CH2:29]([N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:38]4[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[CH:42][CH:43]=4)[C:4](=[O:31])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1)[CH3:30]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.2401 mmol) and THF (3.0 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (43 mg, 0.24 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 29% yield (0.040 g, 0.0692 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:10]([O:12][CH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[NH:15]C(=O)C(F)(F)F)=[O:11].[N:30]([O-])=O.[Na+]>O>[N+:8](=[C:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:10]([O:12][CH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[NH2:15])=[O:11])=[N-:30]
Reactant: NC(CC(F)(F)F)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=C(CC(F)(F)F)C(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a solution of O-(2-amino-4,4,4-trifluoro-1 -oxobutyl)-N-trifluoroacetyl-L-serine trifluoroacetate (500 mg) in water (5 ml) was added sodium nitrite (146 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (70 mg) was added. After stirring for 6 hours at room temperature, the mixture was chromatographed on SP (trade mark, made by MITSUBISHI CHEMICAL INDUSTRIES LTD.) (50 ml) eluting successively with water and a 9:1 mixture of water and acetone to give a crude product, which was chromatographed on preparative thin layer chromatography eluting with a 65:25:4 mixture of chloroform, methanol and water to give O-(2-diazo-4,4,4-trifluoro-1-oxobutyl)-L-serine (28 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C@@H:11]([CH2:13][OH:14])[CH3:12].Cl[C:16]1[N:21]=[C:20]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:19]=[C:18]([NH2:32])[CH:17]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN1C(=O)CCC1.C1COCC1>[Si:38]([O:14][CH2:13][C@H:11]([NH:10][C:16]1[CH:17]=[C:18]([NH2:32])[N:19]=[C:20]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:21]=1)[CH3:12])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: C[C@@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cc(Cl)nc(SCc2cccc(Cl)c2F)n1
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2cccc(Cl)c2F)n1
Reaction time: 24 h

Procedure:
N,N-Diisopropylethylamine (5.2 ml) was added to a solution of (R)-alaninol (2.56 ml) and the subtitle product of step ii) in NMP (35 ml) and stirred at 100° C. for 24 h and then 140° C. for 24 h. After cooling to ambient temperature imidazole (2.60 g) and a solution of tert-butyldimethylsilyl chloride (2.60 g) in THF (10 ml) were added and stirring maintained for 1 h. The volatiles were removed in vacuo and the residue was purified by column chromatography (1:1 Et2O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.70 g.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](CC3C=CC=CC=3)[C:16]([CH2:28][NH:29][O:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[N:15][C:14]=2[N:13]([CH3:37])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:28][NH:29][O:30][C:31](=[O:36])[C:32]([F:35])([F:33])[F:34])=[N:15][C:14]=2[N:13]([CH3:37])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CNOC(=O)C(F)(F)F)n2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CNOC(=O)C(F)(F)F)nc2n(C)c1=O
Yield: 82 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methyl-8-(N-(trifluoroacetoxy)aminomethyl)xanthine (1.0 g, 1.9 mmol) and 10% palladium on carbon (50% water, 300 mg) in glacial acetic acid (50 ml) was treated with hydrogen gas (80 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-methyl-8-(N-(trifluoroacetoxy)aminomethyl)xanthine (700 mg, 85% yield) as a white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:30])=[C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH2:27][OH:28])[C:21]=2[CH3:29])[CH:19]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:30])=[C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH:27]=[O:28])[C:21]=2[CH3:29])[CH:19]=1)[CH3:12]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(CO)c2C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOc1ccc(F)c(-c2cc(C)nc(C=O)c2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of oxalyl chloride (1.46 mL, 17.3 mmol) in DCM (50 mL) cooled to −78° C. was added dropwise, a solution of dimethyl sulfoxide (2.68 mL, 37.74 mmol) in DCM (5 mL). After addition, the solution was stirred for 15 mins. A solution of [4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]methanol (which may be prepared as described in Description 140) (4.33 g, 15.73 mmol) in DCM (10 mL) was then added dropwise over about 5 mins. The mixture was allowed to stir at −78° C. for 2 hrs. Triethylamine (8.74 mL, 62.91 mmol) was added dropwise giving a precipitate and this was allowed to warm to room temperature over one hour. The reaction mixture was washed with water and brine, dried over magnesium sulphate and evaporated. The crude residue was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (0-40%). Evaporation of desired fractions gave 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbaldehyde (D141) (2.89 g, 10.574 mmol, 67.2% yield) as a yellow solid;