Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(Cl)Cl>[C:16]([O:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1CC(O)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(=O)OC1=O
Temperature: 0 °C

Procedure:
After equipping a thoroughly dried 200 ml-volume three-necked flask with a dropping funnel, a calcium chloride tube and a nitrogen inlet tube, the system atmosphere was charged with nitrogen gas. A stirrer bar coated with Teflon™ was then added into the flask together with 50 ml of dry methylene chloride, 5.0 g (43.1 millimoles) of 2-hydroxysuccinic anhydride and 4.79 g (47.4 millimoles) of dry triethylamine, and the mixture was stirred at 0° C. under the nitrogen atmosphere. To this solution there was added, dropwise and over the period of an hour, 4.50 g (43.1 millimoles) of methacryloyl chloride that had been already placed in the dropping funnel, and then the mixture was stirred at room temperature for 2 hours. After confirming consumption of the starting materials by thin-layer chromatography, the reaction solution was transferred to a 300 ml separatory funnel and washed with 100 ml of water and saturated saline in that order. The aqueous phase was then extracted 3 times with methylene chloride. The organic layer was collected and dried over sodium sulfate anhydride. The dried organic layer was filtered with filter paper and the solvent in the filtrate was distilled off under reduced pressure. This yielded a brown oil. The oil was purified by silica gel chromatography to obtain methacryloxysuccinic anhydride as a colorless transparent oil. The yield was 6.75 g (85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]([NH2:14])=[O:13])#[CH:2]
Reactant: NC(=O)CBr
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#Cc1cccc(OCC(N)=O)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
A mixture of 3-ethynylphenol (3.31 g, 28.0 mmol), 2-bromoacetamide (2.36 g, 17.1 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (50 mL) was stirred at 70° C. for 7 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.70 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Yield: 20.5 %

Procedure:
To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550; found, 550
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:57]I.O1CCCC1>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([I:57])=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]4OC(C)(C)O[C@H]43)c2n1
Reactant: II
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(I)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 128.8 %

Procedure:
A mixture of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-N-(2,2-diphenylethyl)-2-(tributylstannyl)-9H-purin-6-amine (1.0 g, 1.12 mmol) (Preparation 4), iodine (0.43 g, 1.68 mmol) and tetrahydrofuran (30 ml) was stirred at 50° C. for 30 minutes. The mixture was cooled, dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium thiosulphate solution followed by water. The organic phase was separated, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane gradually changing to hexane:ethyl acetate (50:50, by volume) to afford the title compound (1.05 g).
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH:31]=O)=[CH:22]1.CO>COCCOC>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH2:31][C:17]#[N:18])=[CH:22]1
Reactant: Cc1ccc2c(C=O)cn(C)c2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(CC#N)cn(C)c2c1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A suspension of potassium tert-butoxide (KOtBu) (2.21 g, 19.7 mm) in DME (30 mL) was cooled to -30° C., and treated with a solution of TosMIC (1.97 g 10.1 mm). After addition was complete, the mixture was further cooled to -60° C., treated with 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.8 mm) in DME(20 mL), and stirred at that temperature for 1.5 hours. Addition of methanol (15 mL) to the cooled solution, was followed by heating to reflux temperature for 15 minutes, and evaporation of the solvent. The residue was treated with H2O (20 mL) containing acetic acid (HOAc) (0.75 mL), then extracted with CH2Cl2 (50 mL×3). The combined organic fractions were extracted with saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded (1,6-dimethyl-1H-indol-3-yl)-acetonitrile (0.86 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C.CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)[CH:11]=[N:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14]
Reactant: C1=COCCC1
Reactant: Cc1c(Br)ccc(-c2nc[nH]n2)c1F
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(-c2nncn2C2CCCCO2)c1F
Temperature: 85 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
Methanesulfonic acid (0.090 mL, 1.390 mmol) was added to a stirred solution of 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole (7.0 g, 27.3 mmol) and 3,4-dihydro-2H-pyran (12.68 mL, 139 mmol) in tetrahydrofuran (33 mL). The resulting mixture stirred at 85° C. under a reflux condenser under nitrogen for 20 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexane). Product containing fractions were combined and solvent removed under reduced pressure to afford the desired product (8.8 g, 95% yield) as a yellow solid. MS (ESI) m/z 340.0 [M]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:28])([F:27])[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:24](=[O:25])[CH2:23][CH2:22][C:19]2[CH:20]=[N:21][C:16]([C:15]([F:14])([F:27])[F:28])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)nc2)cc1OC

Procedure:
This compound is prepared by reaction of 3,4-dimethoxyphenylethylamine and 3-(6-trifluoromethyl-pyridin-3-yl)-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[Cl:17][CH2:18][CH2:19]Br>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:19][CH2:18][Cl:17])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: ClCCBr
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-chloro-2-bromo-ethane.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:30]=[N:31][C:32](F)=[CH:33][C:34]=4[CH3:35])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[C:34]([CH3:35])=[CH:33][C:32]([N:5]5[CH2:6][CH2:7][O:3][C:4]5=[O:8])=[N:31][CH:30]=4)=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of sodium hydride (168 mg, 60% in oil) in N,N-dimethylformamide (10 mL) was added oxazolidin-2-one (367 mg) under ice-cooling, and the mixture was stirred at room temperature. Thereto was added a solution of [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 139 in N,N-dimethylformamide (5 mL) and the mixture was stirred at 90° C. for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, diethyl ether was added and the mixture was stirred at room temperature. The solid was collected by filtration to give the title compound (215 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(OCC)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]=[C:12]=[O:14])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C=Nc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 203.7 %

Procedure:
To a solution of 5-aminoindane (25 g) in anhydrous diethyl ether (1250 ml), under an atmosphere of nitrogen, at 0° C. was added triphosgene (18.3 g). The mixture was stirred at 0° C. for 2 min then triethylamine (64.7 ml) was added until pH8. The mixture was stirred at 0° C. for 10 min then at. 10° C. for 10 min. The undissolved solids were filtered off and the filtrate evaporated in vacuo. The residue was distilled at 100° C./1 mbar to afford the title compound (20 g). 1H NMR (360 MHz, CDCl3) δ2.07 (2H, quin, J=7.5 Hz), 2.86 (4H, m), 6.84 (1H, dd, J=7.9 and 2.0 Hz), 6.94 (1H, s), 7.13 (1H, d, J=7.9 Hz).
Reaction SMILES: C(S[CH:5]([C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:18])[NH:6][C:7]([O:9]CC1C=CC=CC=1)=O)(C)C.[NH3:34]>>[NH2:34][CH:5]([C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23])=[O:18])[NH:6][C:7]([CH2:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:20]=1)=[O:9]
Reactant: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: N
Product: NC(NC(=O)Cc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1

Procedure:
The crude product 24 (9.3 g, 20.17 mmol) was dissolved in 133 mL of dry tetrahydrafuran. This solution was saturated with ammonia at 0° C. for 30 minutes and then mercuric chloride (6 g, 22.09 mmol) was added in one portion to the stirred solution while ammonia gas was bubbled through the solution. After bubbling ammonia gas for 2 hours at 0° C. it was bubbled for an additional hour at room temperature. The suspended solids were filtered and the solvent evaporated to yield 25 (9.7 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH2:14])[CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:7][CH2:8]1
Reactant: COc1cc(C(=O)Cl)ccc1Cl
Reactant: COC1CCN([C@@H]2CCC[C@H]2N)CC1
Product: COc1cc(C(=O)N[C@@H]2CCC[C@H]2N2CCC(OC)CC2)ccc1Cl

Procedure:
Following the procedure of Example 1b, using trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]amine and 3-methoxy-4-chlorobenzoyl chloride there is obtained as product trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]-3-methoxy-4-chlorobenzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Product: CC(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 57.6 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with acetyl chloride (5.6 μl, 0.079 mol) via procedure V to afford 19 mg of 3-acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a white solid. MS (Q1) 458 (M)+.
Reaction SMILES: [C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 3.00 g of 4-fluorenyloxycarbonylmorpholine-2-carboxylic acid in 150 mL of acetone was added 1.77 g of potassium carbonate and 1.33 g of dimethyl sulfate. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 3.10 g of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3): δ7.76 (d, J=7.6 Hz, 2H), 7.57 (br d, J=6.6 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 4.51 (br s, 2H), 4.25 (br t, J=6.2 Hz, 1H), 3.90-4.10 (m, 4H), 3.80 (s, 3H), 3.40-3.70 (m, 1H), 3.04-3.23 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][C:25]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([O:28][C:29](=[O:30])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:27])([CH3:26])[CH3:24]
Reactant: NCCCCNC1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.4 %

Procedure:
To a solution of N-(5,6,7,8-tetrahydro-quinolin-8yl)-butane-1,4-diamine (6.77 g, 30.9 mmol) in tetrahydrofuran (155 ml) was added slowly triethylamine (4.30 ml, 30.9 mmol) and Boc-ON (7.60 g, 30.9 mmol). The mixture was stirred for 72 hours at room temperature under a N2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v). A second purification by column chromatography on silica gel (ethyl acetate) afforded the product as a brown oil (8.03 g, 80%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.60 (s, 4H), 1.78 (m, 2H), 1.99 (m, 2H), 2.78 (m, 5H), 3.15 (m, 2H), 3.77 (t, 1H), 4.87 (s, 1H), 7.07 (dd, 1H, J=7.45, 4.82 Hz), 7.83 (d, 1H, J=7.89 Hz), 8.38 (d, 1H, J=4.38 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([CH3:16])[CH3:15])#[N:13].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:21])([CH3:16])[CH3:15])#[N:13]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 3-(1-cyano-1-methylethyl)benzoic acid (9.87 g, 52.2 mmol) in toluene (150 mL) was added thionyl chloride (25.3 g, 213 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a colorless oil. To a solution of 4-methyl-3-nitroaniline (7.63 g, 50.2 mmol) in pyridine (150 mL) were added N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and 3-(1-cyano-1-methylethyl)benzoyl chloride, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL), and dried over anhydrous magnesium sulfate. After filtration through a silica gel pad, the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-(4-methyl-3-nitrophenyl)benzamide as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.C(N(CC)CC)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([NH:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48])=[O:17])=[CH:6]2
Reactant: COc1cc2cnc(C(=O)O)cc2cc1OC
Reactant: NN1CCNC1=O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2cnc(C(=O)NN3CCNC3=O)cc2cc1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-3-isoquinolinecarboxylic acid (6.99 g, 30.0 mmol) in 300 ml of N,N-dimethylformamide were added triethylamine (12.14 g, 120.0 mmol) and diphenyl chlorophosphate (80.6 g, 30.0 mmol) at 0° C. After stirring for 4 hours at 0° C., N-amino-2-oxoimidazolidine (3.03 g, 30.0 mmol) was added, and the mixture was stirred at 0° C. overnight. Ammonium salts (2.0 g) were filtered off, and the filtrate was evaporated in vacuo. The residue was triturated with a 1:1 mixture of water and ethyl acetate. The solid was filtered off and triturated twice with water at pH 8 for 3 hours. The remaining solid was filtered off, washed with water and dried in vacuo. Yield: 4.30 g; melting point 220° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3.[CH:24](=O)[CH3:25].[BH4-].[Na+].O>C(O)C>[CH2:24]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH3:25]
Reactant: COc1ccc2ccn3c(N)c(-c4ccccc4C)nc3c2c1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1c(-c2ccccc2C)nc2c3cc(OC)ccc3ccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.0 g of 3-amino-9-methoxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 26) in 100 ml of ethanol was added 3.0 ml of acetaldehyde, and the mixture was stirred at room temperature for 3 hours. After 3.3 g of sodium borohydride was added to the mixture and refluxed for 2 hours, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The crude crystal was recrystallized from petroleum ether/ethyl acetate to give 5.0 g of the title compound as colorless needles.