Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[C:50]1([S:56]([N:8]2[CH2:12][C@@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[C@H:10]([C:22]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=[CH:31]4)[CH2:27][CH2:26][CH2:25][N:24]5[CH:23]=3)[CH2:9]2)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51909.4 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and benzenesulfonyl chloride (95 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum. The residue was dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) to yield 1-[(3R,4R)-1-benzenesulfonyl-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline as a white solid (135 mg, 57%). M.p.=115-125° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.86 (t, J=7.6 Hz, 1H), 7.75 (t, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.09 (d, J=6.4 Hz, 1H), 7.04 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.92 (dd, J=7.2, 2.0 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.79-6.74 (m, 2H), 4.00-3.90 (m, 4H), 3.78-3.69 (m, 2H), 3.39-3.29 (m, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.01 (m, 2H). LCMS: m/e 482.09 [M+H].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19]1([S:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[C:36](Cl)=[C:31]3[CH:30]=[CH:29]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:19]1([S:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[C:36]([NH:18][C@H:15]4[CH2:16][CH2:17][C@H:12]([S:9]([CH3:8])(=[O:10])=[O:11])[CH2:13][CH2:14]4)=[C:31]3[CH:30]=[CH:29]2)(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CS(=O)(=O)[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans 4-methanesulfonyl-cyclohexylamine trifluoroacetic acid salt (383 mg, 1.32 mmol), 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (536 mg, 1.60 mmol), diisopropylethylamine (0.69 mL, 4.0 mmol) in propan-2-ol (5.5 mL), were heated at 120° C. for 10 minutes using microwave irradiation. The mixture was cooled to 0° C. and filtered, the resulting solid washed with propan-2-ol and ether, then dried under vacuum to give 588 mg (93%) of trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4-methanesulfonyl-cyclohexyl)-amine as a bright yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.11 (s, 1H), 8.99 (d, 1H), 8.20 (m, 2H), 7.64 (m, 2H), 7.53 (t, 2H), 6.66 (d, 1H), 3.95 (ddd, 1H), 2.95 (m, 1H), 2.91 (s, 3H), 2.40 (m, 4H), 1.85 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1O)[CH3:12].N1CC[O:25][CH2:24]C1.C(OCC)(OCC)OCC>B(F)(F)F.CCOCC>[CH3:12][O:11][C:13]1[C:18]([O:19][CH3:20])=[C:17]2[C:16]([C:24](=[O:25])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1cccc(O)c1OC
Reactant: O=C(O)Cc1ccccc1
Reactant: C1COCCN1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(OCC)OCC
Product: COc1ccc2c(=O)c(-c3ccccc3)coc2c1OC
Temperature: 80 °C
Reaction time: 19 h
Yield: 6 %

Procedure:
This compound was prepared as described in the synthesis of analog 23. A mixture of 2.76 g of phenylacetic acid (20.08 mmol), 5.0 g of 2, 3-dimethoxylphenol (32.43 mmol) and 50 ml of boron trifluoride diethyl ether ate was stirred at 80° C. for 19 hours. Reaction mixture was then cooled to RT and washed with aqueous K2CO3 and water sequentially until pH of the filtrate approached neutrality. Product was extracted with ethyl acetate and concentrated to dryness. The residue, which contained mostly 2-hydroxy-3,4-dimethoxyphenylbenzylketone, was dissolved in 50 ml of 2-propanol and 3.0 ml of morpho line and 6.0 ml of triethyl orthoformate (36.07 mmol) were added. The mixture was stirred at 80° C. for 20 hours and evaporated to dryness. The residue was fractionated on a silica gel (chloroform-methanol system) and fractions that contained pure product were pooled, dried, and recrystallized from acetone to give 300 mg of analog 34 (crystalline plates), a yield of 6% (based on 2,3-dimethoxylphenol, w/w): mp 143-144° C. 1HNMR (DMSO-d6) δ 3.89 (8-OCH3), 3.96 (7-OCH3), 7.30 (d, 1H, J=9.03, Hz, 6-H), 7.39 (t, 1H, J=6.94 Hz, 4′-H), 7.43 (t, 2H, J=7.06, 7.72 Hz, 3′, 5′-H), 7.57 (dd, 2H, J=7.26, 1.44 Hz, 2′, 6′-H), 7.87 (d, 1H, J=8.88 Hz, 5-H), 8.50 (s, 1H, 2H). 13C NMR (DMSO-d6) δ 56.5 (—OCH3), 60.9 (—OCH3), 111.0 (C-6), 118.5 (C-10), 120.9 (C-3), 123.3 (C-1′), 127.8 (C-5), 128.1 (C-3′, 5′), 128.9 (C-2′, 6′), 131.9 (C-4′), 136.1(C-8), 149.9(C-7), 154.1 (C-2), 156.2 (C-9), 174.6 (C-4). MS (m/z) 283.3 (M+H)+, 305.4 (M+Na)+, 281.9 (M−H)−. Anal. (C17H14O4) for C, H. Cacld: 72.33, 4.99; found: 72.21, 4.97.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])[CH3:3].Br[CH2:18][CH2:19][O:20]C1CCCCO1.C(N(C(C)C)CC)(C)C.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CC#N.CCCCCC>[CH3:4][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:8]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:18][CH2:19][OH:20])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN(CCO)[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of L-phenylalanine 1,1-dimethylethyl ester (221.3 g; 1 mol), 2-(2-bromoethoxy)-tetra-hydropyran, prepared according to J. Org. Chem. 1986, 51, 752-755 (282.3 9; 1.35 mol) and diisopropylethylamine (commercial product) (175 mL; 1 mol) in CH3CN (1 L) was refluxed for 14 h. Diisopropylethylamine (commercial product) (175 mL; 1 mol) and tert-butyl bromoacetate (commercial product) (233 g; 1.2 mol) were added and the mixture refluxed for further 2 h. The solution was evaporated to give a residue which was dissolved in n-hexane (2 L) and washed with H2O (1,4L), 1 N HCl (500 mL), 1 N NaOH (100 mL) and H2O (200 mL). The solution was evaporated and the residue was dissolved in MeOH (2 L) and 2 N HCl (1 L) was added. After 2 h, 2 N NaOH (1.2 L) was added, the solution was evaporated to remove methanol and n-hexane (2 L) was added to extract the product. The organic solution was evaporated to obtain the desired product (280 g; 0.738 mol). The product was utilised for the following step without further purification.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:13][CH2:14][CH3:15])=[N:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)C.[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O>C(Cl)Cl.CCCCCC>[CH2:6]([NH:5][C:4]([NH:3][N:2]=[CH:26][C:25]1[C:24]([Cl:23])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:32])=[N:13][CH2:14][CH3:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCNC(=NCc1ccccc1)NN
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCN=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A 10.0 g. portion of 1-amino-2-benzyl-3-ethylguanidine hydroiodide in a mixture of 100 ml. each of diethyl ether, n-hexane and methylene chloride is shaken with 10 ml. of 5N NaOH. A 5.46 g. portion of 2,6-dichlorobenzaldehyde is added and the mixture is shaken and then allowed to stand at room temperature overnight. The organic layer is washed with saturated aqueous sodium chloride, passed through hydrous sodium magnesium silicate and concentrated under reduced pressure. The residue is crystallized from diethyl ether-hexane to give the desired product as a bright yellow solid, m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH:20](C(OC(C)(C)C)=O)[N:14]3[C@H:13]3[CH2:28][CH2:29][N:30]=[CH:31][C@H:12]23)[CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:12]23)[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1CSc2cc(-c3cccc(Cl)c3Cl)cc3c2N1[C@H]1CCN=C[C@H]31
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCS3)c1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl(6bR,10aS)-5-(2,3-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole carboxylate (10 mg, 0.21 mmol) in CH2Cl2 (4.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 20° C. for 1 h then concentrated in vacuo. The residue was dissolved in H2O and the solution was adjusted to pH 2 by addition of 1N HCl. The aqueous layer was washed with Et2O then basified to pH 12 by addition of 50% NaOH. The solution was extracted with CHCl3, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (79 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ1.93-2.05 (br-s, 2H), 2.65-2.99 (m, 4H), 3.01-3.25 (m, 4H), 3.44-3.68 (m, 3H), 6.88 (s, 1H), 6.90 (s, 1H), 7.18 (d, J=4.6 Hz, 2H), 7.40 (t, J=4.6 Hz, 1H) ppm.
Reaction SMILES: [Cl-:1].[Cl-].[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)=[O:19])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[BH4-].[Na+]>CO>[ClH:1].[ClH:1].[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[OH:19])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CCCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)OCO2
Reactant: [Cl-]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: OC(CCCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 182.5 %

Procedure:
5-[4-(4-Phenyl-1-piperazinyl)butyryl]-1,3-benzodioxole dichloride (3.8 g) as prepared in Example 2 was suspended in methanol (50 ml) and 2N sodium hydroxide solution (4.5 ml) and then sodium borohydride (0.5 g) were added. The mixture was stirred for 10 hours at room temperature and the solvent was then distilled off. The residue was extracted with ethyl acetate and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. Thereafter, 20% hydrogen chloride in ethanol (4.9 ml) was added and the resulting crystals were collected by filtration and recrystallized from ethanol to give 5-[4-(4-phenyl-1-piperazinyl)-1-hydroxybutyl]-1,3-benzodioxole dihydrochloride (3.5 g, 62% yield). The characteristics of this compound are shown in Table 3 as Compound 19.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(Nc2nc(C3CCNCC3)cs2)ncc1Sc1ccnc2ccsc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2csc(Nc3cc(Oc4cccnc4C)c(Sc4ccnc5ccsc45)cn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
4-(2-Methylpyridin-3-yloxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.051 g, 0.08 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.10 mL, 0.74 mmol) and acetic anhydride (0.017 mL, 0.19 mmol) were added and the reaction was stirred at ambient temperature overnight. Saturated sodium bicarbonate solution was added, and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (0.051 g, 70% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 6.92 (d, 1H), 6.40 (d, 1H), 6.36 (s, 1H), 4.67 (m, 1H), 3.86 (m, 1H), 3.13 (m, 1H), 2.69 (m, 2H), 2.16 (s, 3H), 1.94 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](O)=[CH:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:23])/[CH:19]=[C:20](\[NH2:22])/[CH3:21].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>C(O)C>[CH3:16][O:17][C:18]([C:19]1[CH:28]([C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[C:25]([F:24])([F:34])[F:35])[C:11]2[C:10](=[O:15])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C:12]=2[NH:22][C:20]=1[CH3:21])=[O:23]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1C=C(O)CN(Cc2ccccc2)C1
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 8.5 g. of 1-benzyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine, 4.75 g. of methyl-3-aminocrotonate (97%), 6.96 g. of o-trifluoromethylbenzaldehyde and 125 ml. of ethanol was refluxed for 2 hours. The mixture was filtered while hot and the filtrate was allowed to cool to room temperature. The solid was separated by filtration. Recrystallization from ethanol afforded the title compound, m.p. 225°-227° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1c(OC)nc2nc(C(=O)O)cn2c1C
Yield: 81505.3 %

Procedure:
A mixture of 120 g (0.456 mmol) of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate and 120 g of potassium carbonate in 1200 ml of methanol and 600 ml of water was heated at reflux for 2 hours and the methanol was then evaporated. 150 ml of more water were added, and the resulting solution was acidified to a pH of 1 with concentrated HCl. The solid obtained was filtered and was washed with water, then dried under vacuum over P2O5 at 80° C. to obtain 87.43 g (82% yield) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[N:13]([CH3:19])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(C2CNC(=O)O2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)C(=O)O2)cc1OC
Reaction time: 0.67 h
Yield: 60 %

Procedure:
10 mmol of 5-(3,4-dimethoxyphenyl)-2oxazolidinone is dissolved in 20 ml. of absolute dimethylformamide and combined with 11 mmol of sodium hydride. The mixture is then stirred for 40 minutes at 40°. After cooling, 20 mmol of methyl iodide in 5 ml. of dimethylformamide is added dropwise and thereafter the reaction mixture is agitated for 6 hours at 50°. After the dimethylformamide has been removed by evaporation, the mixture is taken up in chloroform and then washed first with a small amount of water and then with saturated sodium chloride solution, dried, filtered, and concentrated. The residue is chromatographed over 60 g. of silica gel with chloroform/methanol (96:4) as the eluent. Recrystallization from ethanol produces a 60% yield of 5-(3,4-dimethoxyphenyl)-3-methyl-2-oxazolidinone, m.p. 132°-133°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.Cl[C:11]1[N:16]=[C:15]2[NH:17][N:18]=[CH:19][C:14]2=[CH:13][N:12]=1>>[NH:17]1[C:15]2=[N:16][C:11]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=3)=[N:12][CH:13]=[C:14]2[CH:19]=[N:18]1
Reactant: Nc1cnn(CCO)c1
Reactant: Clc1ncc2cn[nH]c2n1
Product: OCCn1cc(Nc2ncc3cn[nH]c3n2)cn1

Procedure:
The title compound was made following the procedure in Example 1 (Step ii) using 2-(4-amino-1H-pyrazol-1-yl)ethanol and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine to form 2-(4-((1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol. This was followed by the procedure in Example 1 (Step i) using 4-(3-(bromomethyl)-2,4-difluorophenyl)morpholine. 1H NMR (d6-DMSO) δ 9.86 (s, 1H), 8.88 (s, 1H), 8.17 (br s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.14-6.97 (m, 2H), 5.56 (s, 2H), 4.88 (t, 1H), 4.18-4.09 (m, 2H), 3.77-3.73 (m, 2H), 3.70 (t, 4H), 2.92 (t, 4H); LC-MS method B, (ES+) 457.2, RT=6.98 min.
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].BrC1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>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].C1(C)C=CC=CC=1>[CH3:15][C:10]1[CH:9]=[C:18]([CH:17]([CH3:1])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(C)C(=O)c2ccccc2)c1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
A dry Schlenk tube was charged with Pd2 (DBA)3 (4.6 mg, 0.005 mmol) and sodium tert-butoxide (125 mg, 1.3 mmol). The tube was then evacuated and filled with argon. Toluene (1 mL), 5-bromo-m-xylene (185 mg, 0.136 mL, 1.0 mmol) and propiophenone (161 mg, 0.160 mL, 1.2 mmol) were sequentially added with a syringe, and the tube was sealed and heated in an, oil bath at 80° C. for 12 h. The mixture was cooled, and partitioned between ether and water. The aqueous layer was extracted twice with ether, and the combined organics were dried over Na2SO4, filtered and concentrated. Chromatography on silica gel, eluting first with hexane, then 4:1 toluene:hexane, gave 0.185 g (79%) of α-(3,5-dimethylphenyl)propiophenone, a clear oil. 1H NMR (CDCl3, 300 MHz) δ 7.96 (m, 2H); 7.48 (m, 1H); 7.38 (m, 214); 6.89 (s, 2H); 6.83 (s, 2H); 4.60 (q, 1H, J=6.9 Hz); 2.26 (s, 6H); 1.50 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC#N
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 144 h

Procedure:
To 1 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 930 mg of methylsulfonylacetonitril and 1.6 g of triethylamine. After 24 hours another 1 g of methylsulfonylacetonitril and 0.3 g of triethylamine was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (4a). Yield 1.1 g of (4a), m.p. 206° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccn2)CC1
Yield: 7 %

Procedure:
A solution of 2-chloro-isonicotinonitrile (2.00 g, 14.43 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.18 g, 15.88 mmol, 1.1 equiv; commercially available) in DMAc (10 mL) was heated by microwave irradiation to 150° C. for 30 min. The solvent was evaporated under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) to yield 0.30 g (7%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25-1.42 (m, 2H), 1.43 (s, 9H), 1.93-1.97 (m, 2H), 2.83-2.93 (m, 2H), 3.71-3.81 (m, 1H), 3.97-4.02 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.51 (s, 1H), 6.66 (d, J=5.2 Hz, 1H), 8.11 (d, J=5.2 Hz, 1H). MS (ISP): 303.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Yield: 78 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 16.1 mmol) and DIPEA (3.1 ml, 18.0 mmol) were dissolved in DCM (32 ml) and cooled in ice bath. To the above stirred mixture was added a solution of chloroacetyl chloride (1.33 ml, 16.7 mmol) at 0° C. Three hours later, the mixture was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography using EA/PE (4/1) as eluent to afford the title compound (3.3 g, yield 78.0%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CC2
Reactant: OCCS
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CC2
Temperature: 25 °C

Procedure:
In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5 H-dibenzo[a,d]-cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.