Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15](I)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C[Si]([C:28]#[CH:29])(C)C.C(N(CC)CC)C>CN(C)C=O.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:28]#[CH:29])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(I)cc3c12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2[nH]c3cnc(C(=O)OC(C)C)c(COC)c3c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g of 6-iodo-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 30 ml of dimethylformamide in succession with 1.53 ml of trimethylsilylacetylene, 15 ml of triethylamine, 50 mg of copper (I) iodide and 100 mg of tetrakis (triphenylphosphine)-palladium (O) and heated for 3 hours under argon to 60° C. solution temperature. After removal of the solvent the residue is taken up in ethyl acetate and in succession is washed with saturated sodium bicarbonate and common salt solution. The organic phase was dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=12:1. The correspondingly combined fractions are stirred for 1 hour in 50 ml of methylene chloride with 4 ml of tetrabutylammonium fluoride at room temperature. The solution is washed with water, dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 830 mg of 6-ethinyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 191°- 193° C. (ethyl acetate/hexane) is obtained by the corresponding combination of the fractions.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:34][CH3:35])=[CH:21]/[C:22]#[C:23][C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C[O-].[Na+].[OH-].[Na+]>C1COCC1.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:34][CH3:35])=[CH:21]/[CH:22]=[CH:23]/[C:24]([C:25]([F:27])([F:26])[F:28])([OH:29])[C:30]([F:33])([F:32])[F:31])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC/C(=C\C#CC(O)(C(F)(F)F)C(F)(F)F)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: C[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1

Procedure:
1 g (1.3 mmol) of (E)-6-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1,1,1,-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol is dissolved in 10 mL of THF and then added to a suspension of 160 mg (4.2 mmol) of lithium aluminium hydride and 450 mg (8.4 mmol) of sodium methoxide in 20 mL of THF. After stirring at reflux for 2 hours, the medium is cooled and then treated with 200 μL of water, 200 μL of 15% sodium hydroxide and 600 μL of water. After filtration, the residue is purified by chromatography on silica gel (eluent: 95 heptane/5 ethyl acetate). The desired product is obtained in the form of a yellow oil (210 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C1C=CC=CN=1)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:10][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:2]([F:11])([F:12])[F:1])=[O:26])=[CH:28][CH:29]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Yield: 50.9 %

Procedure:
After 3.7 g of (R)-(+)-1,1,1-trifluoro-2-octanol and 1.2 g of triethylamine were added to 40 ml of methylene chloride to form a mixture, 40 ml of methylene chloride solution containing 4.3 g of 4-benzyloxybenzoic acid chloride was dropped with stirring to the mixture. Further, 0.5 g of dimethylaminopyridine was added and the mixture thus formed was stirred at an ambient temperature for a whole day and night. Thereafter, the reaction liquid was poured in a water tank to make it neutral. After the methylene chloride layer thus formed was extracted, the reaction liquid was dehydrated with an anhydrous magnesium sulfate. After the solvent was distilled off, the reaction product thus formed was subjected to separation and purification by a silica gel column chromatography to obtain 3.5 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), cyclohexyl alcohol (6 g, 0.06 mol), p-toluenesulfonic acid (1 g, 0.006 mol) and benzene (300 mL) was refluxed with continuous water separation for 8 hours. The mixture was cooled and washed, first with aqueous 5% Na2CO3 solution, then twice with water, then was dried overanhydrous MgSO4. Evaporation of the solvent in vacuo gave cyclohexyl 4-hydroxyphenylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:16]=2[N:17]=[C:18]([CH:20]=[O:21])[CH:19]=1)=[O:13].[OH:28]OS([O-])=O.[K+].O.CO.C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]([OH:28])=[O:21])[N:17]=[C:16]2[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:15]=12)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C=O)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C(=O)O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.515 g, 1.40 mmol) in DMF (3 mL), Oxone (0.861 g, 1.40 mmol) was added and stirred it at room temperature for 3 h. On completion of reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was as such used for next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([F:55])([CH3:54])[C:46]1=[O:56]>CC(=O)CC>[F:55][C:47]1([CH3:54])[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:45]([CH2:44][CH2:43][CH2:42][N:15]2[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][N:10]([CH2:19][C:20]4[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=4[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:11]3=[O:18])[CH2:17][CH2:16]2)[C:46]1=[O:56]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Reactant: CC1(F)C(=O)N(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C(C)(F)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.15 g, 0.34 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassium carbonate (0.070 g, 0.51 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.083 g, 0.34 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) to obtain the title compound (0.2 g, 91%); 1H NMR (DMSO-d6): δ 1.56 (s, 9H), 1.65-1.71 (m, 5H), 1.77 (t, 2H, J=7.2 Hz), 2.31-2.33 (m, 4H), 2.50-2.66 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.58 (s, 2H), 4.82 (s, 2H), 6.88-6.91 (m, 2H), 7.08-7.12 (m, 3H), 7.18 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=7.6 Hz), 7.37-7.42 (m, 2H), 7.55-7.59 (m, 2H), 7.82 (d, 1H, J=6.4 Hz); MS for C37H42F2N4O4 m/z 645.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.288 mmol), 2-chloro-5-(trifluoromethyl)pyridine (53 mg, 0.288 mmol) and potassium carbonate (80 mg, 0.576 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (85 mg, 76%) as an off white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15].C(O)=O.CO>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH:14]([NH:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:15]
Reactant: COc1cccc2c1C[C@@H](N)CC2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CO
Solvent: O=CO
Solvent: ClCCl
Product: COc1cccc2c1C[C@@H](NC=O)CC2
Reaction time: 8 h

Procedure:
As in example 6g, (-)(2S)-2-amino-8 -methoxytetralin (commercially available) (825 mg, 4.66 mmol) in 10 ml THF and 20 ml methylene chloride, was formylated with 906 mg (5.59 mmol) carbonyl diimidazole in 15 ml THF and 257 mg (5.59 mmol) formic acid in 3 ml THF. After stirring overnight, TLC analysis (silica gel; 10:90 CH3OH:CH2Cl2) indicated a major component, Rf 0.71, and absence of starting amine, Rf 0.22. The residue obtained on removal of solvent was dissolved in ethyl acetate, washed with 1N HCl, NaHCO3 solution, brine and dried (MgSO4). Filtration and removal of solvent in vacuo left a white solid, 850 mg (89%), mp 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH2:12][CH2:13][C:28]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][N:22]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Reactant: O=Cc1cnccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a solution of 4-[3-fluoro-4-(methylsulfanyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (433 mg) in ethanol (7 mL) were added pyrazine-2-carbaldehyde (182 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (41.5 mg) and triethylamine (84.1 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (438 mg, yield 75%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][OH:19])[CH2:8][C:9]=1[NH:10]2.[CH3:20][C:21]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=[CH:23][C:22]=1[N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:19][CH2:18][CH:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:2]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N:36]4[CH2:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:37]4=[O:45])[C:21]=3[CH3:20])[NH:10][C:9]=2[CH2:8]1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CO)CC3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CCC(CO)C4)cccc1N1Cc2ccccc2C1=O
Temperature: 100 °C
Yield: 58.9 %

Procedure:
A mixture of 5-bromo-2-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Intermediate 30-3(a), 80 mg, 0.248 mmol), 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one (Intermediate 50-4, 130 mg, 0.371 mmol), 2 M aqueous tripotassium phosphate (0.371 mL, 0.743 mmol), and tetrakis(triphenylphosphine)palladium (14.30 mg, 0.012 mmol) in toluene (3 mL) and ethanol (1 mL) was sealed in a vial and heated at 100° C. for 6 hrs. The mixture was cooled and diluted with EtOAc, and the solution was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 96:3.6:0.4 DCM-methanol-28% aqueous ammonium hydroxide) to provide 2-(hydroxymethyl)-5-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow solid (68 mg, 53%). 1H NMR (400 MHz, chloroform-d) δ 7.79 (1 H, d, J=7.91 Hz), 7.46-7.53 (1 H, m), 7.38-7.44 (2 H, m), 7.30 (1 H, dd, J=7.91, 3.08 Hz), 7.14-7.26 (3 H, m), 6.77 (1 H, dd, J=7.69, 2.86 Hz), 4.59-4.74 (2 H, m), 3.39-3.54 (3 H, m), 2.72-2.80 (2 H, m), 2.30-2.44 (2 H, m), 1.80-2.10 (3 H, m), 1.75 (3 H, d, J=8.35 Hz). Mass spectrum m/z 466.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[CH:12]=[C:13](N2CCCC2)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][CH2:22][O:23][C:24](/[C:26](/Cl)=[N:27]\[OH:28])=[O:25].O>ClCCl>[CH3:14][C:13]1[O:28][N:27]=[C:26]([C:24]([O:23][CH2:22][CH3:21])=[O:25])[C:12]=1[C:11](=[O:20])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: CC(=CC(=O)Nc1ccc([N+](=O)[O-])cc1)N1CCCC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(C)c1C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A suspension of 12.38 g (45 mmol) of the crude N-(4-nitrophenyl)-3-pyrrolidyl-2-butenamide in 200 ml of dry dichloromethane was cooled to 0° C. and 7.50 g (49.5 mmol) of ethyl chlorooximidoacetate were added in one portion. The reaction mixture was stirred at -5° C. to 0° C. for 2 hours and was then poured into 200 ml of water. The aqueous layer was extracted with 100 ml of dichloromethane and the combined organic extract was washed with 100 ml of 10% HCl, 5% NaHCO3 solution and then dried over MgSO4. Evaporation of the solvent gave 10.91 g (76%) of ethyl 5-methyl-4-[N-(4-nitrophenyl)]carbamoyl-3-isoxazolecarboxylate as a white crystalline solid melting at 151°-53° C. (from ethyl acetate);
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].CC1C=C(C)C=C(C)C=1[N+]1CCN(C2C(C)=CC(C)=CC=2C)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1cnc(N)c2c1sc1ccc(Cl)cc12
Agent: [Pd]
Agent: Cc1cc(C)c(N2C=[N+](c3c(C)cc(C)cc3C)CC2)c(C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cnc(N)c2c1sc1ccc(-c3ccccc3)cc12
Reaction time: 0.38 h

Procedure:
A mixture containing 1-amino-8-chloro[1]benzothieno[3,2-c]pyridine-4-carboxamide (Example 1), phenylboronic acid (1.9 equiv), 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride (0.2 equiv), cesium carbonate (2.4 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv) in dioxane (0.3 M) was placed in a microwave reactor at 120° C. for 23 min. The resulting mixture was extracted with EtOAc-DMSO and H2O. The organic phase was separated and purified by flash chromatography (EtOAc to 10% MeOH in EtOAc) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(OCC)(=O)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-fluoro-2-nitro-phenol (464 mg, 2.95 mmol), benzyl bromide (0.37 ml, 3.10 mmol) and cesium carbonate (1.055 g, 3.24 mmol) in MeCN (10 mL) was stirred room temperature under argon for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 2-benzyloxy-4-fluoro-1-nitro-benzene.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.O>[CH2:29]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([F:11])([F:12])[F:13])=[O:7])=[CH:20][CH:21]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
To a mixture of the 1,1,1-trifluoro-2-octyl 4-hydroxybenzoate prepared above (0.53 g) and triethylamine (0.18 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of 4-n-octyloxybiphenyl-4'-carboxylic acid chloride (0.73 g) in methylene chloride (10 ml). After the mixture was left to stand until it reached room temperature, it was stirred overnight. The mixture was poured in water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, the residue was purified by silica-gel column chromatography to obtain the titled compound (0.4 g, [α]D20 =+32.2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=C)[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.C[OH:14].ClCCl>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:14])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: CO
Reactant: C=Cc1nc(Cl)nc(Cl)c1OC
Solvent: ClCCl
Product: COc1c(Cl)nc(Cl)nc1C=O

Procedure:
A solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (6.64 g, 32.5 mmol, prepared by Example 2), in methanol:dichloromethane (1:4, 300 mL), was cooled to −78° C. in a dry ice/acetone bath. Ozone was bubbled into the reaction until the starting material was no longer present according to thin layer chromatography (TLC). Dimethyl sulfide (6 mL) was added. The mixture was concentrated on a rotary evaporator at 0° C. to remove the dichloromethane. This provided an unpurified material comprising the title compound. The title compound was not isolated from the unpurified material.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9]Br.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[C:1]([O:4][CH2:9][CH:8]([O:11][CH3:12])[O:7][CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(CBr)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(COC(C)=O)OC
Temperature: 134 °C
Reaction time: 16 h

Procedure:
A mixture of sodium acetate (1.0 g, 12.19 mmol), bromoacetaldehyde dimethyl acetal (1.43 mL, 12.19 mmol), and tetrabutylammoniumbromide (1.96 g, 6.09 mmol) in 8 mL of anhydrous CH3CN was stirred at 134° C. for 16 h in a sealed tube. It was cooled to room temperature, water was added and the mixture extracted with Et2O (3×100 mL). The combined organic phases were washed with saturated NaCl (1×75 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 40-60% ethyl acetate/hexanes to give the product 43b (product is volatile, some of the product is lost during the evaporation of solvents). 1H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 3.36 (s, 6H), 4.08 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H).