Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCc1ccc(N)cc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(N)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Isopropyl N-cyano-3 pyridinecarboximidate (1.0 g, 5.3 mmol) was dissolved in methanol (15 ml), and 2-(4-aminophenyl)ethylamine (0.80 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.88 g, 3.3 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)C(=O)O
Yield: 19.8 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3,5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 119) (512 mg, 1.0 mmol) and sodium hydroxide (1M, 10 ml, 10 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3,5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (96 mg, 20%) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:13])[C:10](Cl)=[S:11])[CH:6]=[CH:7][CH:8]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:13])[C:10](=[S:11])[O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N(C)C(=S)Cl)c1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
2.00 g of N-(3-methoxyphenyl)-N-methylthiocarbamoyl chloride, 1.44 g of β-naphthol and 1.66 g of anhydrous potassium carbonate were added to 50 ml of methyl ethyl ketone and heated to reflux for 15 hours. The reaction mixture was poured into water after it was cooled to room temperature and the products were extracted with benzene. The benzene solution was subsequently washed with water and aqueous saturated sodium chloride solution and then benzene was removed by distillation under reduced pressure after drying over anhydrous Magnesium sulfate. The residue was purified by the column chromatography (eluted with benzene on a silica gel) to give 1.45 g of O-2-naphthyl N-(3-methoxyphenyl)-N-methylthiocarbamate in crystalls (Yield: 45%). A part of the crystals was recrystallized from ethanol. Colorless crystalls having melting point of 93° to 94° C. were obtained.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[CH:9][C:10]([Cl:13])([Cl:12])[Cl:11].O>C(OCC)C>[Cl:11][C:10]([Cl:13])([Cl:12])[CH:9]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: Brc1cccs1
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: OC(c1cccs1)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
Under a dry argon atmosphere a Grignard reagent was prepared by combining 13.1 g (0.54 mole) of magnesium turnings with 86.4 g (0.53 mole) of 2-bromothiophene in dry diethyl ether. The Grignard reagent was stirred and cooled to 5° C., and 77.8 g (0.53 mole) of chloral was added slowly. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into 500 ml of cold water and extracted with three 250 ml portions of ethyl acetate. The combined organic extracts were dried with magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to yield a liquid. The liquid was distilled under reduced pressure to give 67.2 g of 2,2,2-trichloro-1-(2-thienyl)ethanol; bp 113°-115° C./19.95 pa. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) (5.27 g, 20.0 mmol), potassium carbonate (8.30 g, 60.0 mmol) and catalytic potassium iodide were suspended in butanone (100 ml). Methyl 4-(bromomethyl)benzoate (5.5 g, 24.0 mmol) dissolved in butanone (50 ml) was added dropwise after which the reaction mixture was stirred at reflux for 24 hours. The reaction mixture was cooled, the solids were filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude mixture was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:4) to afford the title compound (D3). MS (ES+) m/e 344 [(M+H)—CO2tBu]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:16][O:15][CH:5]([O:4][CH3:3])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:10][CH:9]=1
Reactant: CN(C)CCCl
Reactant: COC(CNc1ccc(O)cc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(CNc1ccc(OCCN(C)C)cc1)OC
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.57 g) was added to a solution of 4-(2,2-dimethoxyethyl-amino)phenol (4.3 g) in dimethylformamide (25 mL). After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 3.14 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated. The residue was purified by MPLC (eluent: dichloromethane/methanol/ammonia solution 95:4.9:0.1). The product with the molecular weight of 268.36 (C14H24N2O3); MS (ESI): 269 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1.[CH3:28][CH:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1C(=O)CCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:36][C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[N:15]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: CC(N)c1ccccc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.10 g, 0.26 mmol) in NMP (2 mL) is added alpha-methyl benzyl amine (0.10 mL, 0.78 mmol). After stirring 1.5 hours at 90° C., the reaction mixture is diluted with methanol (to 5 mL) and purified by reversed phase liquid chromatography (CH3CN/water/1% TFA) to afford 27 mg (23%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=5.1 Hz, 1H), 7.38-7.12 (m, 9H), 6.52 (d, J=5.1 Hz, 1H), 5.06 (q, br, 1H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 1.58 (d, J=7.0 Hz, 3H); ESI− MS: m/z (rel intensity) 446.0 (100, M+−H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: BrCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CCCc2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
According to Scheme 22 Method A: To a solution of 5-bromo-2-methoxypyridine (1 eq, 2.70 mmol, 0.50 g) in THF (4.4 mL) at −78° C. under nitrogen was added dropwise n-butyl lithium (1 eq, 2.5M in hexanes, 2.70 mmol, 1.10 mL). The reaction mixture was stirred at −78° C. for 30 min. and 1-(3-bromopropyl)benzene (1 eq, 2.70 mmol, 0.40 mL) in solution in THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min. and then allowed to warm to room temperature for 1 hour. The reaction was quenched at 0° C. with water and extracted with Et2O. The organic phase was dried over Na2SO4, filtered and solvent was removed under reduced pressure leaving an orange oil. This residue was purified by flash chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 97.5/2.5), yielding the title compound (0.46 mmol, 0.10 g, 17%) as a colorless semi-solid.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:42][CH:41]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)[NH:40][C:39]2=[O:49])[CH2:34][CH2:33]1.[O:50]1CCC[CH2:51]1>>[O:24]=[C:3]1[C@H:2]([NH:1][C:51]([N:32]2[CH2:33][CH2:34][CH:35]([N:38]3[CH2:42][CH:41]([C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)[NH:40][C:39]3=[O:49])[CH2:36][CH2:37]2)=[O:50])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1NC(c2ccncc2)CN1C1CCNCC1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2CC(c3ccncc3)NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (49 mg, 0.146 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (0.020 mL, 0.146 mmol) were added to a solution of p-nitrophenylchloroformate (29 mg, 0.146 mmol) in tetrahydrofuran (5 mL) at 0 oC. After 1 h, 1-piperidin-4-yl-4-pyridin-4-ylimidazolidin-2-one (36 mg, 0.146 mmol) and additional triethylamine (0.040 mL, 0.292 mmol) were added and the reaction warmed to ambient temperature. After 16 h, the reaction was concentrated and partitioned between dichloromethane and saturated sodium bicarbonate. The organics were washed with water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane→15% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (36 mg). MS 606.2 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])[CH3:2].[NH2:23][N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)[CH3:21])[N:15]=1)[CH3:13])[CH3:2]
Reactant: Nn1cccc1
Reactant: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 16 h

Procedure:
Monoimine 2-[1-(2,6-diethylphenylimino)ethyl]-6-acetylpyridine (8, 1.5 g, 5.1 mmol) and 1-aminopyrrole (460 mg, 5.6 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 845 mg (46%) of mixed diimine 13.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@:22]([OH:32])([C@H:29]([SH:31])[CH3:30])[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[S:11])[S:31][C@@H:29]([C@:22]([C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[F:14])([OH:32])[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH3:30]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: S=C(Cl)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](SC(=S)Nc1ccc(Cl)cc1Cl)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
2,4-Dichloroaniline (0.85 g) was allowed to react with thiophosgen (0.4 ml), followed by the reaction with (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.5 g) by the same manner as in Example 5. The compound (23), i.e., [(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl] N-(2,4-dichlorophenyl)dithiocarbamate (0.08 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.CO[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:29]Br)=O)=[CH:23][CH:22]=1.Cl.[C:32](OCC)(=[O:34])C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:27]([C:24]1[CH:23]=[CH:22][CH:21]=[C:26]([O:34][CH3:32])[CH:25]=1)=[CH:29]2
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: COc1cccc(-c2cc3cc(OC)ccc3[nH]2)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a boiling mixture of p-anisidine (2.46 g, 20 mmol, 6.66 eq) and N,N-dimethylaniline (3.5 ml) is slowly added dropwise 2-bromo-4-methoxyacetophenone (0.7 g, 3 mmol, 1 eq) dissolved in ethyl acetate (12 ml). After the addition is complete, the reaction mixture is stirred at 180° C. for 2 h. To the cooled mixture are added ethyl acetate and 2 M HCl. The aqueous phase is extracted with ethyl acetate several times, and the combined organic phases are washed with a saturated NaCl solution, dried over MgSO4, filtered and evaporated to dryness on a rotary evaporator. Purification by column chromatography (eluent dichloromethane/hexane 7/3) yields the desired product in a yield of 15% (760 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[OH:23])=[N:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[O:23][CH3:24])=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(Cl)cnc(-c3cccc(Cl)c3O)c2c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(Cl)cnc(-c3cccc(Cl)c3OC)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A mixture of methyl 4-chloro-1-(3-chloro-2-hydroxyphenyl)isoquinoline-7-carboxylate (150 mg), potassium carbonate (119 mg), iodomethane (245 mg), and DMF (3 mL) was stirred at room temperature for one day. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-chloro-1-(3-chloro-2-methoxyphenyl)isoquinoline-7-carboxylate (130 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([F:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:19]C(F)(F)S(O[Si](C)(C)C)(=O)=O.F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C1(C)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:10][F:19])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(=O)c1cc(Br)cnc1F
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(CF)c1cc(Br)cnc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (200 mg, 0.92 mmol) and triethylamine (140 μl, 1.01 mmol) in toluene (2 mL) was treated with trimethylsilyl trifluoromethanesulfonate (182 μl, 1.01 mmol) under nitrogen atmosphere. The reaction mixture was heated to 80° C. for 2 h, the upper toluene phase was isolated (e.g. by decanting) and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in acetonitrile (2 mL) and added to a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-(2.2.2)octane bis(tetrafluoroborate) (325 mg, 0.92 mmol) in acetonitrile (2 mL) at room temperature. After 1 h, the solvent was removed under reduced pressure. The residue was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure to obtain 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.72 mmol, 79% yield, 90% purity) as a light yellow solid. This material was used in the next step without purification. MS m/z=237.9 [M+H]+. Calculated for C7H4BrF2NO: 236.01.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:30])[N:12]([CH2:19][CH:20]1[NH:29][CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21]1)[C:13]2=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:30])[N:12]([CH2:19][CH:20]1[CH2:21][C:22](=[O:23])[CH2:27][CH2:28][NH:29]1)[C:13]2=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc(OCc3ccccc3)c2C(=O)N1CC1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCNC(CN2C(=O)c3cccc(OCc4ccccc4)c3C2=O)C1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of the above 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (0.22 g, 0.54 mmol) in 1,4-dioxane (4 ml) was added 4N hydrochloric acid (4 ml) and the reaction stirred in a 65° C. (oil bath) for 6 h. The mixture was basified with saturated sodium bicarbonate until pH=8 and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as an oil. Which was used without further purification or characterization.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl-:20].[C:22]([CH2:21][N+:2]([CH3:1])([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCCCCCCCCCCCCCN(C)C
Reactant: CCOC(=O)CCl
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CC(=O)OCC
Product: [Cl-]

Procedure:
0.5 mol of dimethyl-cetylamine known under the trademark "Armeen DM 16D" is heated at 90°-95° C. for 11/2 hours with 0.5 mol of ethyl monochloroacetate and 40 g of absolute alcohol. Carboethoxymethyl-dimethyl-cetyl-ammonium chloride is obtained.
Reaction SMILES: [CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>C(O)C.CC(OC)(C)C>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCCC=O)C1CCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: CC(CCCCO)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
5-Cyclopentylhexanal (4.2 g; 25 mmol) in ethanol (40 ml) was added to sodium borohydride (1.2 g; 32 mmol) suspended in the same solvent (50 ml) at 10° C. The reaction mixture was stirred at room temperature for 2 hours and then 1 N HCl (50 ml) was added dropwise at 0° C. The mixture was diluted with MTBE (150 ml), the organic layer separated, washed with brine (3×250 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (125° C./0.2 torr) to give 3.4 g (80% yield) of 5-cyclopentylhexan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (96 mg, 0.19 mmol), 2-(tert-butoxycarbonylamino)acetic acid (51 mg, 0.29 mmol) and HBTU (110 mg, 0.29 mmol) in DMF (1.0 mL) was added DIEA (63 L, 0.38 mmol). The mixture was stirred at RT for 30 min. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and water to give (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 83%). LRMS (M+Na+) m/z 663.2.
Reaction SMILES: C1CC1.[CH2:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:8])[OH:7].[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([O:7][C:6]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:8])[CH:5]=[CH2:4])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: C1CC1
Product: C=CC(C)(CCC=C(C)C)OC(C)=O

Procedure:
The cyclopropane derivative of linalool was then reacted with acetyl chloride to produce the cyclopropanated derivative of linalool acetate.