Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]1([C:5]2[N:6]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nc(-c2ccccc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-phenyl-1,3-thiazole (1.16 g, 5.92 mmol), 1-(tert-butoxycarbonyl)-piperazine (3.30 g, 17.8 mmol), potassium carbonate (817 mg, 5.92 mmol) and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 2 hours, poured to water, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 1.43 g (70.1%) of the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:27]
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of compound 20 (2.0 g, 8.4 mmol) in DMF (28 mL) at room temperature was added sodium hydride (235 mg, 8.8 mmol) and ethyl bromoacetate (1.03 mL, 9.2 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 2 g of 21 as a clear oil (2.73 g theoretical, 73% yield)
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:14]([C:12]1[N:11]=[C:9]2[N:8]([CH:13]=1)[C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[S:10]2)=[O:15]
Reactant: Cc1cccc2sc3nc(CO)cn3c12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc2sc3nc(C=O)cn3c12

Procedure:
2-Formyl-5-methylimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 5-methyl imidazo[2,1-b]-benzthiazole-2-methanol (2.0 g 9.1 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 700 mg (35% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 217.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](OCC)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Yield: 89.5 %

Procedure:
Ethyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 23, 2.4 g, 6.87 mmol) was dissolved in methanol (150 mL) and hydrogenated over 10% palladium on carbon (1.5 g) under 50 psi of hydrogen pressure for 2 h at room temperature. The reaction mixture was then filtered through a celite bed and the filtrate was concentrated under reduced pressure to yield 1.33 g (89.62%) of Ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate as liquid.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][CH2:12][CH2:11][C:10]2([CH3:16])[CH3:15])[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.C(OCC)C.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.[Cu](I)I>[OH:17][C:18]1[CH:27]=[C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:14]=2[O:13][CH2:12][CH2:11][C:10]3([CH3:16])[CH3:15])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cccc2c1OCCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C#CC(O)c2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.00 g (13.9 mmol) of α-ethynyl-4,4-dimethylchroman-8-methanol, 3.90 g (13.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 100 ml of triethylamine are introduced into a three-necked flask. The reaction mixture is degassed with nitrogen for 30 minutes and then 780 mg (1.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 320 mg (1.7 mmol) of copper iodide are successively added. The reaction mixture is stirred at room temperature for 4 hours and is evaporated to dryness and the residue obtained is taken up in water and ethyl ether. The organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 50% ethyl acetate and 50% heptane. 2.85 g (56%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate are collected in the form of a white solid with a melting point of 122-123° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[C:17]([C:18](OC)=[O:19])=[C:16]2[C:11]([NH:12][C:13]([CH3:24])([CH3:23])[C:14](=[O:22])[NH:15]2)=[CH:10][CH:9]=1.C(OCC)(=O)C.Cl>O1CCCC1.O>[Br:7][C:8]1[C:17]([CH2:18][OH:19])=[C:16]2[C:11]([NH:12][C:13]([CH3:24])([CH3:23])[C:14](=[O:22])[NH:15]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Nc2ccc(Br)c(CO)c2NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Litium aluminium hydride (38.5 mg, 1.01 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL) under nitrogen atmosphere. An anhydrous tetrahydrofuran solution (1.5 mL) of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 101 mg, 0.323 mmol) was added dropwise thereto at 0° C., and stirred for 1 hour at the same temperature. Ethyl acetate (10 mL), water (10 mL), and 1N aqueous hydrochloride solution (2 mL) were added thereto successively and the mixture was partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (67.4 mg) as an orange amorphous product. (Yield 74%)
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:25]([O:26][CH2:27][CH3:28])=[O:29])[CH2:2][CH2:3]1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-4-ylcarbamate (65 mg, 0.26 mmol) in DCM (1 mL) was added Na2CO3 (55.5 mg, 0.520 mmol), followed by ethyl carbonochloridate (0.028 mL, 0.29 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM, washed with 1N HCl, dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate 38A (72 mg, 0.23 mmol, 86% yield). LCMS=1.97 min [M+Na]=342.9 (Method B).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:15]2[N:14]=[N:13][NH:12][C:11]=2[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=1.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C=O)C>[CH2:22]([N:12]1[C:11]2[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[C:15]=2[N:14]=[N:13]1)[CH3:23]
Reactant: COC(=O)c1cc(N2CCCC2=O)c2nn[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nnc2c(N3CCCC3=O)cc(C(=O)OC)cc21
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
To a solution of ethyl methyl 4-(2-oxo-1-pyrrolidinyl)-1H-1,2,3-benzotriazole-6-carboxylate (D249) (400 mg, 1.54 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 68 mg, 1.69 mmol, 1.1 equiv) and the resulting mixture was stirred 5 min at this temperature. Ethyl iodide (135 μl, 1.69 mmol, 1.1 equiv) was added and the resulting solution was stirred for 2 h then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 100/0) gave methyl 1-ethyl-4-(2-oxo-1-pyrrolidinyl)-1H-1,2,3-benzotriazole-6-carboxylate (270 mg, 61%) as a pale yellow oil. [M+H]+=289.3, RT=2.47 min.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)\[CH3:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([O-:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1.[Na+]>>[CH3:1][O:2]/[N:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:30]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[CH:21]=2)[CH:26]=1)(=[O:31])=[O:32])\[CH3:5]
Reactant: CO/N=C(\C)c1ccccc1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: CO/N=C(\C)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6, Step 4 using (1E)-1-(2-iodophenyl)ethanone O-methyloxime and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (1H, s), 8.35 (1H, s), 8.29-8.27 (2H, m), 8.17 (1H, d, J=8.8 Hz), 8.02 (1H, dd, J=1.7, 8.6 Hz), 7.91 (2H, dd, J=5.5, 8.8 Hz), 7.83-7.71 (3H, m), 7.44 (1H, dd, J=1.7, 7.4 Hz), 7.37 (2H, t, J=8.8 Hz), 3.56 (3H, s), 2.14 (3H, s); m/z (ES+) 434 [MH+].
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:26]([NH2:30])(=[O:29])[CH:27]=[CH2:28]>C(O)C>[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][N:21]([CH2:28][CH2:27][C:26]([NH2:30])=[O:29])[CH2:22]2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: C=CC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)CCN1CC2CN(Cc3ccccc3)CC(C1)O2
Yield: 77.2 %

Procedure:
Triethylamine (3.60 g, 35.7 mmol) was added slowly to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation B(iv) above; 5 g, 17 mmol) in ethanol (50 mL). Acrylamide (1.34 g, 18 mmol) was added to this mixture, which was then heated at reflux for 7 hours. The reaction mixture was then concentrated under reduced pressure. Water (50 mL) and sodium hydroxide (1 M, 150 mL) were added to the residue and the mixture extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colourless solid. This was recrystallised from ethyl acetate (50 mL) to give the sub-title compound (3.80 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5CC6CN(C(=O)OC(C)(C)C)CC6C5)c4)cc3N2)cc1OC
Yield: 54.9 %

Procedure:
Example ER-896386 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (119 mg, 0.266 mmol) and commercially available tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (226 mg, 1.06 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 5-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (94 mg, 0.146 mmol, 55% yield). Then, this intermediate was resolved into its constituent enantiomers in a manner similar to that of ER-890044 (Section A) to afford tert-butyl 5-(3-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyphexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol) and tert-butyl 5-(3-((5R,7S)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol). Then, intermediate tert-butyl 5-(34(5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yebenzoyehexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (22 mg, 0.034 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896386 (19 mg, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCC2
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(CCCN)=CCC2
Yield: 77.1 %

Procedure:
A mixture of 2-[3-(7-methoxy-3,4-dihydronaphthalen-1-yl)propyl]isoindole-1,3-dione (11.8 g, 34.0 mmol.) and hydrazine monohydrate (5.1 g, 0.1 mol.) was heated in ethanol (150 ml) for one hour under reflux. The reaction mixture was ice-cooled, then resulting insolubles were filtered off. The filtrate was concentrated under reduced pressure to afford the titled compound (5.7 g, yield 77%, oily). This compound was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:21][N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: CC(C)(C)[O-]
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, methyl iodide (1.39 ml) was added, and the reaction mixture was stirred at room temperature overnight. Additional methyl iodide (0.4 ml) was added. The reaction mixture was refluxed for two hrs, cooled, and concentrated. Saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was adhered to silica, and flash chromatographed (30-60% ethyl acetate/hexane). The appropriate fractions were concentrated, and the residue was triturated with diethyl ether to give 4.21 g (80%) of 1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:58][N:59]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:61]([CH2:68]O)=[N:60]1>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:68][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:59]([CH3:58])[N:60]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cn1nc(CO)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2nn(C)c3ccccc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.47 g), tributylphosphine (1.81 mL), (1-methyl-1H-indazol-3-yl)methanol (0.51 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 47%).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:20][C:19]([Cl:21])=[CH:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C(Oc1ccc(OCC=C(Cl)Cl)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCC=C(Cl)Cl)cc1
Reaction time: 1 h
Yield: 87 %

Procedure:
A reaction vessel was charged with 44.1 g of 4-(3,3-dichloro-2-propenyloxy)phenyl benzoate and 400 ml of methanol, to which 33 g of 30% potassium hydroxide solution was slowly added dropwise under ice cooling. After stirring for 1 hour, the reaction mixture was made weakly acidic by the addition of 10% hydrochloric acid, and extracted twice with 150 ml of diethyl ether under salting out. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.0 g of 4-(3,3-dichloro-2-propenyloxy)phenol (87% yield).
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:21](Cl)=[O:22]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)=[O:22]
Reactant: O=C(Cl)Cc1cc(F)ccc1F
Reactant: Ic1cnc2c(c1)NCCN2
Product: O=C(Cc1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Yield: 14 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 2,5-difluorophenyl acetyl chloride as in General Procedure 2 to give the title compound as an off-white solid (14% yield). M.p. 152-153° C., LCMS: m/z=415.90 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.47-3.54 (m, 2H), 3.80-3.87 (m, 4H), 5.44 (bs, 1H), 6.90-7.04 (m, 3H), 8.03 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[CH:5]2.Cl[CH2:14][C:15](=O)[CH3:16].C(=O)(O)[O-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:14]=[C:15]([CH3:16])[N:12]=[C:7]1[CH:6]=[CH:5]2
Reactant: Nc1ccc2cc(I)ccc2n1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn2c(ccc3cc(I)ccc32)n1
Temperature: 25 °C

Procedure:
6-Iodo-quinolin-2-ylamine (270 mg, 1.0 mmol), chloroacetone (111 mg, 1.2 mmol), sodium bicarbonate (252 mg, 3.0 mmol), and catalytic tetrabutylammonium iodide were dissolved in 1,4-dioxane and water, and stirred at 80° C. overnight. The reaction was cooled to room temperature and concentrated, and the residue was purified by preparative HPLC to give the desired compound, 1m.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.CO[CH:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:22]=2)[C:17](=[O:29])[NH:16][C:15]1=[O:30]>CN(C)C=O>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][CH:13]=[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH:22]=3)[C:17](=[O:29])[NH:16][C:15]2=[O:30])[O:4][CH:5]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: NCc1cc(=O)c(O)co1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-n3cccc3)cc2C1=CNCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-hydroxy-pyran-4-one (106 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.80 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a beige solid, 157 mg, (55%), mp 310-2° C. dec; MS (ES+): m/z 378.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[N:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1.O>CN(C=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:16]=1
Reactant: Fc1cc(I)ccn1
Reactant: Oc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccnc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 259 mg (26.9 mmol) pyrimidin-5-ol (J. Chem. Soc. 1956, 2033) in 200 mL DMF are added 108 mg (26.9 mmol) sodium hydride (60% dispersion in mineral oil). The mixture is stirred for 20 min at r.t. After that time, 500 mg (22.4 mmol) 2-fluoro-4-iodopyridine are added and the mixture is stirred for 12 h at 80° C. Subsequently the mixture is poured into water and extracted with ethyl acetate (3×). The combined organic layers are washed with brine. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by column chromatography (silica gel; heptane/EtOAc, 100/0→40/60).