Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11]/[C:12](=[CH:17]\[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)/[C:13](OC)=[O:14]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:11]/[C:12](=[CH:17]\[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)/[CH2:13][OH:14]
Reactant: COC(=O)/C(C)=C/c1ccc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C/C(=C\c1ccc2ccccc2c1)CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 26 ml) was added dropwise to a solution of methyl (E)-2-methyl-3-(2-naphthyl)acrylate (3.52 g) in CH2Cl2 (100 ml) at −78° C. and the mixture was stirred at −78° C. for 1 hour. The mixture was washed with 1N HCl and brine, dried and concentrated. The residue was crystallized from CH2Cl2-hexane to give the titled compound (2.89 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:25][CH2:24][CH2:22][OH:23])=[O:8])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirring suspension of 3-cyano-4-isopropoxybenzoic acid (1.0 g, 4.8 mmol) in DCM (20 mL) was added oxalyl chloride (3.7 g, 29.2 mmol) followed by two drops DMF. The reaction mixture was stirred at 50° C. for 2 h. The mixture was concentrated and the residue re-dissolved in DCM (10 mL). Ethanolamine (0.6 g, 9.7 mmol) and TEA (1.45 g, 14.4 mmol) were added and the reaction mixture was stirred overnight at room temperature. The resulting solid was filtered, washed with water, and dried to afford 1.0 g (83%) of 3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide which was used in the next step without purification. LCMS-ESI (ink) calculated for C13H16N2O3: 248.3; found 249.0 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, CDCl3) δ 8.02-7.79 (m, 2H), 6.97-6.87 (m, 1H), 6.71 (s, 1H), 4.65 (dt, J=12.1, 6.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.56 (dd, J=10.2, 5.5 Hz, 2H), 1.96 (d, J=10.0 Hz, 1H), 1.40-1.29 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:23]=[N:24][C:25]=3[C:26]([F:29])([F:28])[F:27])=[CH:15][C:14]=2[CH3:38])[CH3:12])=[CH:6][C:5]=1[CH3:39].[OH-].[K+]>CO.C1COCC1>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[N:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[C:5]([CH3:39])[CH:6]=3)[CH3:12])=[C:14]([CH3:38])[CH:15]=2)=[C:25]([C:26]([F:28])([F:29])[F:27])[N:24]=[N:23]1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C(F)(F)F)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN(C)c2ccc(OCc3c(C(F)(F)F)nnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoic acid methyl ester (24.2 g, 40.7 mmol) in MeOH (150 mL) and THF (150 mL) is added 2N potassium hydroxide (102 mL, 203 mmol). The mixture is heated at 60° C. for 2 hours. The solvent is removed under reduced pressure. The residue is diluted with water, acidified to pH 3 with 2N HCl, and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered, and evaporated under reduced pressure to afford the title compound as a white solid that is crystallized from MeOH (20 g, 80%). ES/MS m/e 579 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)c1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)c1cc2c(cc1Cl)NCC2
Yield: 78.6 %

Procedure:
6-Chloro-5-isopropylindole (D58) (0.5 g, 2.60 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.4 g, 79%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]#[N:20])[CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:22]1[C:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]3[C:11]4[NH:10][CH2:9][CH2:8][CH2:7][C:6]=4[C:5](=[O:21])[N:4]([CH2:3][O:2][CH3:1])[C:13]=3[CH:14]=2)=[N:20][N:24]=[N:23]1
Reactant: COCn1c(=O)c2c(c3ccc(CC#N)cc31)NCCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(=O)c2c(c3ccc(Cc4nnn[nH]4)cc31)NCCC2
Temperature: 25 °C
Yield: 45.3 %

Procedure:
The compound (65 mg, 0.23 mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (5 ml), sequentially added with sodium azide (75 mg, 1.15 mmol) and ammonium chloride (61 mg, 1.15 mmol). The resulting mixture was refluxed for 48 hours and cooled to room temperature. The mixture was washed with chloroform and the water layer was concentrated to dryness. The residue was then washend with methanol and filtered. The filtrate was purified by flash column chromatography (chloroform:methanol=5:1) to obtain the title compound (34 mg, yield: 45%, yellow solid).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Br-].[CH2:18]([Zn+])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Cc1c(Cc2ccccc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 65.8 %

Procedure:
3-Chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (400 mg, 1.66 mmol, 1 eq) is added to a solution of benzylzinc bromide (12.3 mL 0.5 M in THF, 6.64 mmol, 4 eq) and tetrakis(triphenylphosphine)palladium (100 mg, 0.08 mmol, 0.05 eq) in a microwave vial. The vial is sealed and irradiated in the microwave at 100° C. (high absorption setting) for 40 min. The reaction mixture is concentrated and purified by silica gel chromatography (5-20% EtOAc/heptane) to yield the desired compound (324 mg, 66%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](CP(=O)O)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.[CH2:18]([O:20][P:21]([C:24]1[CH:36]=[CH:35][C:27](C(OC(C)(C)C)=O)=[CH:26][CH:25]=1)(C)=[O:22])C.[OH-].[K+].Cl>O1CCOCC1>[CH3:18][O:20][P:21]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([OH:5])=[O:7])=[CH:13][CH:12]=1)([C:24]1[CH:36]=[CH:35][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: CCOP(C)(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C[PH](=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COP(=O)(c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[4-(tert-Butoxycarbonyl)phenyl]methylphosphinic acid]. tert-Butyl 4-[ethoxy(methyl) phosphoryl]benzoate (510 mg, 1.79 mmol) was made 0.25 M in dioxane and to this stirring solution was added potassium hydroxide (5.38 mL, 5.38 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was neutralized with 1 eq aq HCl then concentrated in vacuo. The residue was diluted with MeOH, the inorganic salts were filtered off and the filtrate was concentrated in vacuo. MS: cal'd 257 (MH+), exp 257 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[N:14]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1

Procedure:
3-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 1,2,3,4-tetrahydroquinoline (906 mg, 6.80 mmol) using method A to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid as an off white solid. Yield: 318 mg (44%). 1H-NMR: 8.17 (d, J=8.0 Hz, 1H), 8.06-8.04 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.15-7.05 (m, 2H), 3.80-3.76 (m, 2H), 2.40 (t, J=6.5 Hz, 2H), 1.61-1.54 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br>C(C(C)=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: Clc1ccc(OCCCBr)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
10 g of potassium carbonate was added to 30 ml of a methyl ketone solution containing 15.9 g of p-chlorophenol, and the solution was then heated with stirring at 60° C. for 1 hour. Afterward, 30 ml of a methyl ethyl ketone solution containing 50 g of 1,3-dibromopropane was added dropwise; After the addition, the solution was heated under reflux for 3 hours. The reaction solution was then cooled and a precipitate was removed therefrom, and the solution was evaporated to dryness under reduced pressure to obtain 23.2 g of 4-chlorophenoxypropyl bromide.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1csc(-c2cc[nH]c2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole (0.200 g, 0.671 mmol) in anhydrous THF (2 mL) was added TBAF (1 mL, 1 mmol of a 1M in THF) and after stirring for 20 min at rt, the reaction was complete. The reaction mixture was quenched with water (40 mL), extracted with EtOAc (3×25 mL) and washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-(1H-pyrrol-3-yl)-1,3-thiazole as a pale solid. 1H NMR (CD3Cl, 300 MHz) δ 8.20 (br, 1H) 7.63 (d, 1H), 7.28 (d, 1H), 7.06 (d, 1H), 6.73 (dd, 1H), 6.57 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH:27]=O)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][N:32]3[CH2:33][CH2:34][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][CH2:31]3)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCc1nc(N)c2c(n1)c(CCCC=O)cn2COCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc(N)c2c(n1)c(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 125.9 %

Procedure:
A suspension of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butanal (268 mg, 0.704 mmol) and 4 Å molecular sieves in anhydrous dichloromethane (20 mL) was placed under nitrogen and tert-butyl piperazine-1-carboxylate (262 mg, 1.409 mmol) added. The reaction mixture was stirred at ambient temperature for 1 min then sodium triacetoxyborohydride (299 mg, 1.409 mmol) added and the reaction stirred for a further 30 min, Additional 4 Å molecular sieves were added and the reaction mixture stirred at ambient temperature for an additional 16.5 hours, The reaction mixture was filtered through celite and the cake washed with DCM. The solvent was removed in vacuo to give a viscous yellow oil. The oil was redissolved in DCM (50 mL). The organic layer was washed with saturated sodium hydrogen carbonate solution (50 mL), the layers separated and the aqueous layer back-extracted with DCM (2×25 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a yellow gum (488 mg). The sample was dissolved in dichloromethane and purified by chromatography on a silica cartridge (100 g) using a 0-10% MeOH:TBME gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow gum (338 mg).
Reaction SMILES: [CH3:1][C:2]([C:33]#[N:34])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3].Cl.C(N(CC)CC)C.[N-:43]=[N+:44]=[N-:45].[Na+].Cl>CN(C)C=O.O>[CH3:1][C:2]([C:33]1[NH:45][N:44]=[N:43][N:34]=1)([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)c1nnn[nH]1
Temperature: 125 °C
Yield: 71.1 %

Procedure:
A mixture of 1.44 g of 2-methyl-2-cyano-7-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)heptane, 4.1 g of triethylamine hydrochloride, and 1.95 g of sodium azide in 40 mL of dimethylformamide was heated in an oil bath at 125° C. for 17 hours, adding an additional 4 g of triethylamine hydrochloride and 2 g of sodium azide after 5 hours. The mixture was cooled, diluted with water, acidified with 1.0N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol to provide 1.12 g (72%) of the desired title product. NMR.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1ccc(Cl)cc1
Yield: 94 %

Procedure:
To a flask under a nitrogen atmosphere was added 6.1 g. of lithium aluminum hydride in 60 ml. of dry THF at -4° C. The resulting slurry was stirred and 20.0 g. (0.102 mole) of 4-chlorophenoxyacetic acid in 100 ml. of dry THF was added dropwise. The reaction was stirred overnight and was quenched by cautiously adding saturated aqueous sodium sulfate solution followed by ethyl acetate. The solid was removed by filtration and the aqueous phase was extracted twice with 50 ml. portions of ethyl acetate. The combined ethyl acetate solutions were washed with aqueous saturated sodium chloride solution (brine) and then dried using magnesium sulfate. Removal of the solvent resulted in 17.6 g. (94% yield) of 2-(4-chlorophenoxy)ethanol being isolated as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[N:18]=[CH:17][C:16]([O:19][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: N#Cc1ccc(F)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (500 mg, 1.671 mmol) and 6-fluoronicotinonitrile (224 mg, 1.838 mmol) in dry DMSO (5.570 mL) was added Cs2CO3 (653 mg, 2.005 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 25° C. for 16 h. The reaction was quenched with water and extracted with Et2O (3×). The combined organic layers were dried by passing through a phase separator and volatiles were removed under a gentle stream of N2. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 5-30% EtOAc/Hexanes over 8 min, 30% for 4 min) to yield the title compound as a colorless oil (667 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.2 Hz, 1H), 8.44 (dd, J=2.3, 0.7 Hz, 1H), 8.00 (dd, J=8.6, 2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.5 Hz, 1H), 7.57 (dd, J=8.6, 0.7 Hz, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.15 (dd, J=8.6, 0.7 Hz, 1H), 6.89-6.82 (m, 1H), 6.76 (ddd, J=9.8, 8.9, 2.5 Hz, 1H), 3.47 (d, J=4.9 Hz, 1H), 3.02-2.98 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −106.85 (dd, J=258.0, 8.5 Hz, 1F), −107.45-−108.24 (m, 2F), −109.31 (q, J=8.5 Hz, 1F); ESIMS m/z 402 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C@:20]1(O)[C:48]2[CH:47]=[C:46]3[N:26]([CH2:27][C:28]4[C:29]3=[N:30][C:31]3[C:32]5[C:33]=4[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=[N:36][C:37]=5[CH:38]=[CH:39][CH:40]=3)[C:25](=[O:49])[C:24]=2[CH2:23][O:22][C:21]1=[O:50])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([O:17][C@@:20]1([CH2:18][CH3:19])[C:48]2[CH:47]=[C:46]3[N:26]([CH2:27][C:28]4[C:29]3=[N:30][C:31]3[C:32]5[C:33]=4[N:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=[N:36][C:37]=5[CH:38]=[CH:39][CH:40]=3)[C:25](=[O:49])[C:24]=2[CH2:23][O:22][C:21]1=[O:50])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reactant: CN(CC(=O)O)C(=O)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.4 g (5.67 mmol) of [N-(tert-butoxycarbonyl)-glycyl]-sarcosine, which is a known substance (Helvetica Chimica Acta, 1991, 74, 197), 1.3 g (2.84 mmol) of (9S)-9-ethyl-9-hydroxy-1-pentyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione, 2.2 g (11.34 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, and 1.4 g (11.34 mmol) of 4-dimethylaminopyridine were dissolved in methylene chloride (50 mL), and then stirred at room temperature for 1.5 hours.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.[Zn]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C:22]5=[O:26])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C1CCCN1CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN5CCCC5=O)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 164 (0.5 g, 1.07 mmol) in MeOH (20 mL) was added Zinc (0.28 g, 4.28 mmol) and ammonium chloride (0.114 g, 2.139 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT and filtered. The filtrate was concentrated and the resultant oil was partitioned between water and DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to give title compound 165 (0.468 mg, 100% yield, crude) as a black solid. MS (m/z) 438.4 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16]Cl)=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+]>CN(C)C=O.CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)NCCCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1ccc(N2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1600 g of 1-(p-acetamidophenyl)-3-(2-chloroethyl) urea in 7200 ml of dimethylformamide is stirred at room temperature under an atmosphere of nitrogen. To the resulting solution is added a solution of 400 g of sodium methoxide in 2000 ml of methyl alcohol (anhydrous) in a thin stream over a 90-minute period. The temperature rises during the addition. The reaction mixture is stirred for an additional 20 minutes and then heated to 70°-75° and kept at this temperature for 1 hour. The reaction mixture is then allowed to cool slowly to 32° over a period of about 3 hours with stirring; 5000 ml of ice-water is then added rapidly. Stirring at room temperature is continued for 4 hours and the mixture is allowed to stand at room temperature overnight. The solid is filtered off and washed with 3000 ml of water and air-dried for about 2 days at room temperature to give 1-(p-acetamidophenyl)-2-imidazolidinone, m.p. 270°-273°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:9]([NH:11][C@H:12]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:16][CH:15]=[CH:14][CH2:13]2)=[O:10])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:9]([NH:11][CH:12]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:16][CH:15]3[CH:14]([O:44]3)[CH2:13]2)=[O:10])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc([C@H]2CC=CC[C@H]2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Solvent: ClCCl
Product: COc1ccc(C2CC3OC3CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Yield: 68 %

Procedure:
37.7 g of (±)-cis-3,4-bis-cyclopropylmethoxy-N-[6-(3,4-dimethoxyphenyl)cyclohex-3-enyl]benzamide (compound F1) are dissolved in 470 ml of dichloromethane and treated with 27.4 g of m-chloroperbenzoic acid. After stirring over night at room temperature, the reaction mixture is extracted with sodium hydrogencarbonate solution and water, the organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 4/4/1. 26.5 g of the title compound are obtained.