Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.BrN1C(=[O:26])CCC1=O.CC([O-])(C)C.[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]4[CH2:19][O:26]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2cc(C3CO3)ccc2ccc2ncc(Cl)cc12
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.30 g, 1.12 mmol) was dissolved in 17 mL DMSO and 3.0 mL water. N-Bromosuccinimide (0.20 g, 1.12 mmol) was added and the reaction was heated in an oil bath at 60° C. for 1 hour at which time an additional 0.1 g N-Bromosuccinimide (0.56 mmol) was added and the mixture was stirred an additional 45 min at 60° C. The resulting mixture was diluted with water and extracted with ethyl acetate three times. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was dissolved in 30 mL tetrahydrofuran and 6 mL t-BuOH. t-BuOK (2.24 mL of 1.0 M in THF, 2.24 mmol) was added dropwise and the resulting orange slurry was stirred at room temperature for 45 min. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organics were washed with brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 0-25% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.79 (d, 1H); 8.49 (d, 1H); 8.20 (d, 1H); 7.57 (d, 1H); 7.55 (dd, 1H); 7.27 (d, 1H); 7.23 (d, 1H); 3.99 (dd, 1H); 3.21 (dd, 1H); 2.84 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1COS(C)(=O)=O
Yield: 99 %

Procedure:
The product of Example 54B (4.2 g, 12 mmol) was treated with methanesulfonyl chloride according to the procedure described in Example 38G. The title compound was obtained as a brown oil (5.10, 99% yield). 1H NMR (MeOH-D4, 300 MHz) δ1.46 (s, 9H), 2.80 (m, 1H), 3.08 (s, 3H), 3.40 (m, 2H), 3.70 (m, 2H), 4.16 (m, 1H), 4.35 (m, 2H), 5.16 (s, 2H), 7.30 (m, 5H); MS (DCI/NH3) m/z 446 (M+NH4)+, 429 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][CH:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: BrC(c1ccccc1)c1cccc2ccccc12
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(NC(c3ccccc3)c3cccc4ccccc34)c2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A mixture of 2.05 g (13.0 mmol) of 2-methyl-8-aminoquinoline, 2.53 g (25 mmol) of triethylamine and 7.43 g (25 mmol) of 8 was stirred for 2 hr at 120° C. One more portion of 2.53 g of triethylamine as well as 7.43 g of 8 was added. The resulting mixture was stirred for additional 2 hr at 120° C. Finally, the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol.) to give 0.56 g (12%) of the title compound A5.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)\[CH3:13])=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>CCOCC.O1CCCC1>[CH3:24][C:20]1([CH3:25])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]2[CH:15]=[C:14](/[C:12](/[CH3:13])=[CH:11]/[C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and aluminium chloride in nitrobenzene to give (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone. Reduction of this ketone with lithium aluminium hydride in ether yields 5,6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalene-methanol which is converted by treatment with phosphorus tribromide in ether/hexane in the presence of a small amount of pyridine into 2-bromoethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. This bromoethyl compound is converted by treatment with triphenylphosphine in xylene while heating for 12 hours into [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide which, in a Wittig reaction with 4-ethoxycarbonyl-benzaldehyde, yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester of melting point 90°-91° C. This ester is reduced with lithium aluminum hydride in ether/tetrahydrofuran to give p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol of melting point 123°-124° C. (from methanol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][N:22]=1)=[CH:14]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4nccn4C)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Ethyl (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The mixture was washed with ethyl acetate, and the aqueous layer was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble substance was filtered off. The filtrate was concentrated, and the obtained yellow solid was recrystallized from ethanol to give the title compound (170 mg) as yellow crystals. MS 541 (MH+).
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[CH:18]([OH:21])[CH:19]=[CH2:20]>CCCCCC.C(Cl)Cl>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[CH:18]([CH:19]1[CH2:1][CH2:20]1)[OH:21]
Reactant: C=CC(O)c1c(F)ccc(F)c1Cl
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: ICI
Product: OC(c1c(F)ccc(F)c1Cl)C1CC1
Temperature: 25 °C

Procedure:
A 50 mL round-bottomed flask was charged with DCM (1 mL) at −30° C. under nitrogen with stirring. 1 M of diethyl zinc in hexane (1 mL) was added dropwise to the flask followed by the addition of diiodomethane (520 mg, 2.0 mmol). A solution of 1-(2-chloro-3,6-difluorophenyl)-prop-2-en-1-ol (50 mg, 0.2 mmol) in DCM was added to the reaction mixture at −20° C. with stirring. The reaction mixture was allowed to warm to rt and stirred for an additional 1 h. The reaction mixture was quenched with sat. aq. NH4Cl solution (15 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to yield a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=0.39-0.48 (m, 1H), 0.48-0.60 (m, 2H), 0.67-0.76 (m, 1H), 1.55-1.63 (m, 1H), 2.48 (dd, J=8.1, 3.5 Hz, 1H), 4.46 (t, J=8.6 Hz, 1H), 6.97-7.10 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[S:13][CH2:14][CH2:15][C:16](O)=[O:17].ClC(OCC)=O.N1C=CC=CC=1>O1CCCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:12]1[C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[NH:2][C:16](=[O:17])[CH2:15][CH2:14][S:13]1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(SCCC(=O)O)c1ccccc1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CCSC(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1

Procedure:
By cyclizing 3-[(2-amino-5-nitrophenyl)(2-chlorophenyl)methylthio]propionic acid hydrochloride in analogy to Example 1(c), but in tetrahydrofuran and using ethyl chloroformate and pyridine, there is obtained 6-(2-chlorophenyl)-1,3,4,6-tetrahydro-8-nitro-2H-5,1-benzothiazocin-2-one of melting point 285°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:14]1[N:19]=[N:18][C:17]([C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1.B(Br)(Br)Br>C(Cl)Cl>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[N:19]=[N:18][C:17]([C:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=4)=[CH:16][CH:15]=3)=[C:3]([OH:2])[CH:8]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)nn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(C2=CCNCC2)nn1
Temperature: -78 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
tert-Butyl 4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.12 mmol) was dissolved in DCM (0.6 mL). The solution was cooled to −78° C. and 1 M BBr3 in DCM (0.6 mL) was added dropwise. The resulting suspension was removed from the ice bath and stirred at RT overnight. The reaction was quenched with water, diluted with MeOH then adsorbed onto a MeOH conditioned SCX column. The column was washed several times (5-7 column volumes) with MeOH then eluted with 2 N NH3 in MeOH to provide the desired product, 5-(1H-pyrazol-1-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol, (9.7 mg, 0.03 mmol, 25% yield). LCMS Rt=0.49 min, M+1=320.1 (LCMS method Q). 1H NMR (DMSO-d6) δ 8.64 (d, J=2.3 Hz, 1H), 8.52 (d, J=9.5 Hz, 1H), 8.19 (dd, J=9.0, 3.0 Hz, 2H), 7.80 (d, J=1.3 Hz, 1H), 7.43-7.61 (m, 2H), 6.89-7.03 (m, 1H), 6.52-6.66 (m, 1H), 3.56-3.73 (m, 2H), 3.02-3.15 (m, 2H), 2.66-2.74 (m, 2H).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C@:4]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)OCc2ccccc2)CCC(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)O)CCC(=O)C1
Reaction time: 2 h

Procedure:
Benzyl (1S)-1-isopropyl-3-oxocyclopentanecarboxylate (1.27 g, 4.88 mmol) was combined with Pd/C (10% Degussa, 500 mg) in 20 mL of methanol and stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction had only proceeded part way (˜30% conversion) so the reaction mixture was filtered, another portion of Pd/C (500 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 h. Since the reaction had now gone to completion, the reaction mixture was filtered through celite and concentrated to afford (1S)-1-isopropyl-3-oxocyclopentanecarboxylic acid that did not require further purification. Note that the large quantities of catalyst were used because the ester obtained after chiral separation must have been poisoned by an impurity. This was unique to this particular sample. Normally much smaller quantities of catalyst are used. 1H NMR was identical to that of the racemic acid above (Step D).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.[CH3:23][O:24][C:25]([C:27]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28]1)=[O:26]>CO>[CH3:23][O:24][C:25]([C:27]1([CH2:31][NH:32][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:2])[CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: COC(=O)C1(CN)CCC1
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2ncc3cc(Oc4ccccc4)ccc3c2O)CCC1
Yield: 50.5 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (110 mg, 0.37 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid methyl ester (159 mg, 1.11 mmol, available from Ukrorgsyntez Ltd) in MeOH (2 mL) was microwaved at 150° C. for 500 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (76 mg). LC MS ESI+: 407 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14](O)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([CH2:29][CH:28]=[CH2:27])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: C=CCBr
Reactant: O=C(Nc1cc(O)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
The phenol compound obtained from Example 133 was treated with allyl bromide (1 eq.), and K2CO3 (2 eq.) in DMF at 60° C. for 24 h. After the reaction was finished, the resulting solution was directly injected on a preparative reverse phase HPLC column and fractions, which contained the desired product mass, were collected and concentrated using the Genevac system. 1H NMR (CD3OD) δ 7.98 (d, J=2 Hz, 1 H), 7.65 (dd, J=2 Hz, J=8 Hz, 1 H) 7.50 (d, J=8 Hz, 1 H), 7.38 (s, 1 H), 7.34 (s, 1 H), 6.86 (s, 1 H), 6.07 (m, 1 H), 5.42 (dq, J=2 Hz, J=17 Hz, 1 H), 5.29 (dq, J=2 Hz, J=12 Hz, 1 H), 4.61 (dt, J=2 Hz, J=5 Hz, 2 H).
Reaction SMILES: N1C2C(=C([C:10]3[N:11]=[C:12]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:13]4[S:18][C:17](C=O)=[CH:16][C:14]=4[N:15]=3)C=CC=2)C=C1.C[O-].[Na+]>CO>[N:21]1([C:12]2[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=[CH:10][N:11]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: O=Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.5 %

Procedure:
To a suspension of 2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (54 mg) in anhydrous methanol (8 ml) was added phosphorus sulphone (34 mg), followed by sodium methoxide (148 ul). The reaction mixture was stirred at room temperature for 4.5 hours, then evaporated onto silica and purified by flash chromatography to give 2-(1H-indol-4-yl)-6-((E)-2-methanesulfonyl-vinyl))-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (30 mg).
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:27][CH3:28])[C:12]=2[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.C(#N)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH2:29][N:11]4[C:12]=3[C:13]([O:27][CH3:28])=[N:14]2)=[CH:21][CH:22]=1
Reactant: COc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: COc1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-4-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (23 mg, 0.05 mmol) and Pearlman's catalyst [23 mg, 20% Pd(OH)2 on carbon] in methanol (20 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 25 minutes. The reaction mixture was diluted with acetonitrile and filtered. The filtrate was concentrated under vacuum, and the residue was subjected to purification on reverse phase HPLC. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[NH:49][CH:46]3[CH2:48][CH2:47]3)[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: NC1CC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and cyclopropylamine (25% yield after two steps).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([NH:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)[C@H]1CCCN1
Reaction time: 3 h
Yield: 68.8 %

Procedure:
To tert-butyl (2R)-2-(ethylcarbamoyl)pyrrolidine-1-carboxylate (561 mg, 2.3 mmol) was added hydrogen chloride (580 μL of 4 M, 2.3 mmol) in dioxane at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 3 h. The solvent was removed under reduced pressure to obtain (2R)-N-ethylpyrrolidine-2-carboxamide (225 mg, 54%). LC/MS m/z 143.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].CC(O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(CC[N+](=O)[O-])cc1OC

Procedure:
The nitrostyrene derivative (3) is then cooled to about -10°-10° C., treated with silica gel, and reduced using 1.5-4 equivalents of a boron-based reducing agent, e.g., sodium borohydride, with 2-propanol and an inert solvent, e.g., CH2Cl2, at -10°-10° C. for 20-60 minutes to produce a nitrophenylethane derivative of formula 4 (step 2). For example, 3,4-dimethoxy-β-nitrostyrene (3) is treated with 2-propanol and SiO2 in CH2Cl2 at 0°-10° C. for 20 minutes, followed by reduction with 1.5 eq NaBH4 at 5° C. for 30 minutes to yield 2-(3,4-dimethoxyphenyl)nitroethane (4).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](Cl)=[O:43]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:42](=[O:43])[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH3:33])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: COCCOCCOCC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: COCCOCCOCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (14 mg, 31 μmol) was dissolved in abs. pyridine (0.7 ml). At room temperature, 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride (12 mg, 61 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (12.4 mg, 70% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:13][O:9][C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH3:11])=[O:10]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2CO3 and 7.6 ml (121.3 mmol) iodomethane at 0° C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 5.2 g (23.7 mmol, 98%) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Br[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: BrC=Cc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C=Cc2ccccc2)C1
Temperature: 100 °C

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (20 mg, 0.09 mmol), (2-Bromo-vinyl)-benzene (22 mg, 0.12 mmol), potassium phosphate (50 mg, 0.24 mmol), L-Proline (2 mg, 0.017 mmol), CuI (2 mg, 0.01 mmol) were stirred together in dry DMF (1 mL) at RT and N2 gas was purged into it for 5 min. The reaction mixture was heated in microwave at 100° C. for 5 h and then diluted with water. The desired compound was extracted with EtOAc, organic layer dried on anhydrous sodium sulfate, concentrated under vacuum to obtain crude compound which was purified by RHPLC to obtained 8-Chloro-2-methyl-5-styryl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off-white solid. Yield: 11 mg. 1H NMR (DMSO, TFA salt) δ (ppm): 7.90 (d, 1H), 7.80 (d, 1H), 7.65 (m, 3H), 7.42 (t, 2H), 7.30 (m, 2H), 6.98 (d, 1H), 4.60-4.30 (m, 2H), 4.0 (m, 1H), 3.70 (m, 1H), 3.25 (m, 2H), 3.02 (s, 3H).