Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[O:6][CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][C:10]3([O:14][N:13]([CH3:15])[C:12]([NH2:16])=[N:11]3)[C:4]=2[CH:3]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:16][C:12]1[N:13]([CH3:15])[O:14][C:10]2([CH2:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][O:6][C:5]3[CH:23]=[CH:24][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])=[CH:3][C:4]2=3)[N:11]=1
Reactant: CN1OC2(CC(c3ccccc3)COc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccccc3)COc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 24.4 %

Procedure:
Pd(PPh3)2Cl2 (3 mg, 0.003 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 7-bromo-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazol]-3′-amine (77.4 mg, 0.2 mmol) in [1,4]dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol) The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile (20 mg, 24%). 1H-NMR (MeOD): 2.67 (m, 2H), 3.48 (m, 3H), 3.65 (m, 1H), 3.88 (m, 0.3H), 4.19 (m, 0.7H), 4.50 (d, 1H), 7.23 (m, 6H), 7.66 (m, 3H), 7.81 (m, 1H), 8.02 (m, 3H).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([O:16][C:17](=[O:18])[C:8]1=[CH:7]2)=[O:15].[NH2:20][C:21]([CH3:28])([CH:25]([CH3:27])[CH3:26])[C:22]([NH2:24])=[O:23]>C1COCC1>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14](=[O:15])[NH:20][C:21]([C:22](=[O:23])[NH2:24])([CH3:28])[CH:25]([CH3:27])[CH3:26])[C:8]([C:17]([OH:16])=[O:18])=[CH:7]2
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3ccc(OC(F)F)cc3cc21
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2ccc(OC(F)F)cc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 6-difluoromethoxyquinoline-2,3-dicarboxylic acid anhydride (0.037 mol) in 250 mL THF is stirred at 5° C. under nitrogen and a solution containing 2-amino-2,3-dimethylbutyramide (0.037 mol) in 50 mL THF added dropwise. After stirring at room temperature for 17 hours, the solvent is removed in vacuo to give the desired 6-difluoromethoxy-2-[(1-carbamoyl-1,2-dimethylpropyl)-carbamoyl]-3-quinolinecarboxylic acid mp 194°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].[CH3:29][NH:30][CH3:31].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC(C)(C)C(NC)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([N:30]([CH3:31])[CH3:29])=[O:9]
Reactant: CNC
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)N(C)C)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and 2M dimethylamine solution following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].CCO.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34]Cl.C(N(C(C)C)CC)(C)C>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5](=[O:10])[CH2:6]1
Reactant: COc1ccccc1OCC(O)CN1CCNCC1=O
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1=O

Procedure:
To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 (0.7 g, 0.36 mmol) and diisopropylethyl amine (0.76 g, 0.36 mmol). The reaction mixture was heated at reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 14: Mass spectrum (M+1)=442.34
Reaction SMILES: CC(C)=O.[CH3:5][O:6][CH2:7][CH:8]([OH:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH3:5][O:6][CH2:7][C:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: COCC(O)Cc1ccccc1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COCC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
20.4 ml of a Jone's reagent was slowly added dropwise into 200 ml of an acetone solution containing 5.1 g of 1-methoxy-3-phenyl-2-propanol. After stirring for 30 minutes at room temperature, 30 ml of 2-propanol was slowly added to the reaction solution. After removing the solvent, water was added thereto and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and elute with hexane/ethyl acetate (6:1), to give 3.7 g of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74–6.68 (m, 12H) 5.08–4.99 (m, 1H), 3.67–3.56 (m, br, 2H), 3.02–2.82 (br, 2H), 2.80–2.57 (m, br, 4H), 2.57–2.38 (m, br, 2H), 2.05–1.80 (m, br, 6H), 1.64–1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C32H39Cl2FN2O2.1.3EtOAc: C, 64.93; H, 7.24; N, 4.07. Found: C, 65.01; H, 6.97; N, 3.85. ESMS m/e: 537.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1(P(=O)(C2C=CC=CC=2)COC)C=CC=CC=1.[CH3:31][C:32]([CH3:38])([CH2:35][CH:36]=[CH2:37])[CH:33]=O>O>[CH3:2][O:1][CH:5]=[CH:33][C:32]([CH3:31])([CH3:38])[CH2:35][CH:36]=[CH2:37]
Reactant: C=CCC(C)(C)C=O
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: COCP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: O
Product: C=CCC(C)(C)C=COC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a freshly prepared tetrahydrofuran (300 mL) solution of lithium diisopropylamide (0.19 mol) under nitrogen at 0° C. was added dropwise in 30 minutes a tetrahydrofuran (200 mL) solution of diphenyl(methoxymethyl)phosphinoxide (49.5 g, 0.2 mol). After stirring for 15 minutes at 0° C., a tetrahydrofuran (100 mL) solution of 2,2-dimethylpent-4-enal (24.5 g, 0.22 mol) was added dropwise in 20 minutes to the cherry-colored mixture. After 15 minutes, the mixture was warmed to room temperature and then refluxed for 5 hours. The mixture was cooled to room temperature, charged with water (20 mL), and cooled at 0° C. under vigorous stirring. The resulting solid was filtered, washed with hexanes, and discarded. The filtrates were collected and distilled at 101-102° C. (155 mmHg) to give the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CN(C=O)C.O>[CH3:32][S:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1)(=[O:35])=[O:34]
Reactant: CS(=O)[O-]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CS(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4′-Bromomethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline (1.0 eq.) in DMF (0.1M) was added sodium methanesulfinate (1.3 eq.). The mixture was stirred at rt for 2 h, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EA; 1:4) and stirring in EtOAc:Hex:Et2O (1:7:2) afforded the title compound as a white solid after filtration. 1H NMR (400 MHz, acetone-d6): δ 8.96 (dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 8.08 (t, 1H), 7.81–7.75 (m, 4H), 7.63–7.59 (m, 4H), 4.48 (s, 2H), 2.90 (s, 3H), 2.75 (s, 3H), 2.03 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCCC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCCC1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:4]([Si:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([Cl:3])[Cl:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[SiH2]Cl
Reactant: C=Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(CCc1ccccc1)CCc1ccccc1
Temperature: 50 °C

Procedure:
30.0 g (300 millimol) of dichlorosilane, 56.5 g (543 millimol) of styrene and 50 ml of an isopropanol solution of chloroplatinic acid [H2PtCl6.6H2O (4.83×10-6 mol)] were charged in a 200 ml pressure-proof stainless steel reaction tube and reaction was carried out as in example 3 by heating in an oil bath at 50° C. for 15 hours with stirring. After reaction, the reacted liquid resinified and no diphenethyldichlorosilane was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19](Br)([F:21])[F:20].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[C:19]([F:21])[F:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid benzyl ester (0.50 g, 2.14 mmol, 1.0 eq.) in THF (20 mL) was added dibromodifluoromethane (0.90 mL, 4.5 eq.) at −30° C. followed by HMPA (1.75 mL, 4.5 eq.). The cooling bath was removed and the reaction mixture was swirled periodically. After 30 min, zinc dust (0.63 g, 4.5 eq.) and HMPA (80 μL 0.4 eq.) was added and the mixture was heated at reflux for 18 h. Upon cooling to room temperature, the residue was washed with diethyl ether several times. The combined ether washings were washed successively with saturated aqueous copper (II) sulphate, brine, dried over Na2SO4 and concentrated. The residue was purification by chromatography (20% EtOAc-hexanes) to afford 4-difluoromethylene-piperidine-1-carboxylic acid benzyl ester (0.32 g, 56%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>O>[CH3:11][N:12]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNC
Solvent: O
Product: CN(C)c1ccc(C(=O)O)cn1

Procedure:
6-Chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine 10 ml, 40% in water) were heated in a sealed pressure vessel at 130° C. for 6 h. The solvent was then removed and the residue was taken up in water and the pH was adjusted to 4–5. Extraction with dichloromethane yielded the pure intermediate depicted above (0.1 g, 20%).
Reaction SMILES: C([O:8][C:9](=[O:37])[C@@H:10]([O:34][CH2:35][CH3:36])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:35]([O:34][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:16][CH:17]=1)[C:9]([OH:37])=[O:8])[CH3:36]
Reactant: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reaction time: 3 h
Yield: 96.5 %

Procedure:
(S)-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid benzyl ester (0.1 g, 0.2 mmol) was dissolved in EtOAc (4 mL) and 10% Pd/C (0.04 g, 0.037 mmol) was added. After evacuation the reaction vessel was connected to a hydrogen line and the hydrogeneation was performed at atmospheric pressure at room temperature for 3 h. The catalyst was filtered off, washed with EtOAc and the combined organic filtrates were evaporated under reduced pressure to afford the product as a solid (0.079 g, 96.4%). 1H NMR (400 MHz, CDCl3): δ 7.98-7.99 (d, 2H), 7.42 (m, 3H), 7.23-7.25 (d, 2H), 7.02-7.04 (m, 2H), 6.71 (br s, 1H), 4.01-4.02 (m, 1H), 3.80 (s, 2H), 3.57-3.60 (m, 1H), 3.36-3.39 (m, 1H), 3.07-3.10 (m, 1H), 2.94-2.99 (m, 1H), 2.40 (s, 3H), 1.11-1.14 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5cc(F)cc(F)c5OC)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Propane sulfonyl chloride 339 (52 mg, 0.366 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 340. 1H NMR (400 MHz, CDCl3) δ: 9.68 (s, 1H), 8.53 (d, 1H), 8.17 (d, 1H), 7.84 (s, 1H), 7.73 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m, 1H), 3.95 (m, 2H), 3.68 (d, 3H), 3.01 (m, 2H), 2.94 (m, 2H), 2.36 (m, 2H), 2.14 (m, 2H), 1.86 (m, 2H), 1.06 (m, 3H) and MS ES+516.1.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C=O)C>[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15](=[O:16])[NH:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([CH3:3])[CH2:5]3)=[CH:10][CH:9]=2)[CH:18]=1)=[O:60]
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(Br)c(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(C)CC4)c2)cc1OC
Yield: 40.9 %

Procedure:
Dissolved 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)benzylamine dihydrochloride (36.8 mg, 0.10 mmol) in DMF (1.0 mL) and added 4-methylmorpholine (0.044 mL, 0.4 mmol). Dissolved HATU (57.0 mg, 0.15 mmol) in 1.0 mL DMF and added to the 2-bromo-4,5-dimethoxybenzoic acid (25.5 mg, 0.12 mmol) and stirred to dissolve. Added the amine to the 2-bromo-4,5-dimethoxybenzoic acid solution and shook at room temperature 48 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10% water/DMSO (900 uL). Purified by prep HPLC to give 22.0 mg of 2-bromo-4,5-dimethoxy-N-[3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 538 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]1=[O:12].CS(O[CH2:18][C@H:19]1[O:28][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[O:21][CH2:20]1)(=O)=O>O1CCOCC1>[O:21]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:28][C@@H:19]([CH2:18][NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]2=[O:12])[CH2:20]1
Reactant: NCCCN1CCC(=O)NC1=O
Reactant: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Solvent: C1COCCO1
Product: O=C1CCN(CCCNC[C@H]2COc3cccnc3O2)C(=O)N1
Yield: 16.1 %

Procedure:
A mixture of intermediate (54) (0.058 mol) in dioxane (400 ml) was stirred. A mixture of intermediate (3) (0.029 mol) and CaO (2.4 g) was added. The reaction mixture was stirred at 140° C. for 16 hours. The solvent was evaporated. DCM and water was added to the residue. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent:CH2Cl2/(CH3OH/NH3) 90/10). The product fractions were collected and the solvent was evaporated. The residue was dissolved in ethanol and converted into the ethanedioic acid salt (1:1). The formed precipitate was filtered off and dried, yielding 1.5 g of (S)-1-[3-[[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)methyl]amino]propyl]dihydro-2,4(1H,3H)-pyrimidinedione (compound 25), mp.186; [α]D20 =−37.46°, (c=26.56 mg/5 ml DMF).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(Cl)cc1Cl
Yield: 70.9 %

Procedure:
A reaction flask was loaded with 2,3,5-trichloropyridine (9.1 g) and ethanol (25 ml), followed by dropwise addition of hydrazine monohydrate (3 g) to the flask in 5 minutes with stirring. The resultant mixture was heated and stirred at 50 to 60° C. for 5 hours. Thereafter, the heating was stopped, and the reaction mixture was left to cool. The precipitated white crystals were filtrated for collection and dried to give 3,5-dichloro-2-hydrazinopyridine (6.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[Br:21]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2ccc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-n2cc(Br)c3cc(O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxyisoquinoline-1-ol was prepared as described above, followed by deprotection of the methoxy group using chlorobenzene and boron tribromide (6 equivalents, neat) added dropwise under argon atmosphere at room temperature, to obtain isoquinoline-1,6-diol (14v). Compound 14v (11.5 mmol) reacted with 4-iodoanisole (4.01 g, 17.13 mmol), copper (I) iodide (0.44 g, 2.28 mmol). L-proline (0.53 g, 4.57 mmol) and anhydrous potassium carbonate (3.16 g, 22.84 mmol) were placed in a dry 250 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The reaction flask was vacuumed and refilled with dry argon. 50 mL of anhydrous methyl sulfoxide was added via syringe. The reaction mixture was stirred and heated to 130° C. for 20 hours. 50 mL of water was added to quench the reaction, and solid precipitated out. The solid was filtered, washed with water (2×20 mL) and dried in air. This solid was purified by flash column chromatography (silica gel, ethyl acetate) to give 6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14w) a brown solid product. Compound 14w (1.8 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and septa. Acetonitrile (10 mL) was added via a syringe under argon atmosphere at room temperature. N-Bromosuccinimide or NBS (0.33 g, 1.87 mmol) was added portionwise under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was then added. The mixture was extracted with ethyl acetate (3×10 mL). Organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc=2/3 v/v) to give white solid of 4-bromo-6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14xME)