Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1cc(Br)cnc1N
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(2-Amino-5-bromo-pyridin-3-yl)-propan-2-ol (200 mg, 0.86 mmol), tert-butyl acrylate (628 μL, 4.3 mmol) and (i-Pr)2EtN (452 μL, 2.6 mmol) in DMF (10 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 20 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with H2O (100 mL) then extracted with ethyl acetate (2×100 mL). The combined organic fractions were dried over MgSO4, and subjected to flash chromatography on silica gel using 50% ethyl acetate:hexanes. The appropriate fractions were collected and concentrated to yield a yellow crystalline solid. Yield: 153 mg (64%); 1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.45 (d, J=15.8 Hz, 1H), 6.69 (s, 2H), 6.32 (d, J=15.8 Hz, 1H), 5.53 (s, 1H), 1.52 (s, 6H), 1.48 (s, 9H); ESI MS m/z 279 [C15H22N2O3+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:25]
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)c3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added 3-chlorobenzoic acid (17 mg, 0.11 mmol) and HATU (42 mg, 0.11 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 3-chloro-N-[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-benzamide (35 mg, 78%) as a white solid. MH+ 411.9.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[C:26](#[N:31])[CH:27]=[C:28]([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>>[CH3:29][C:28]([N:2]1[CH:3]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[N:1]1)([CH3:30])[CH2:27][C:26]#[N:31]
Reactant: CC(C)=CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 60 °C

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product.
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].C(O)(=O)C.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO>[C:16]([O:15][C:11]([NH:12][N:13]=[CH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)C=NNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 100 %

Procedure:
Pivaldehyde (52.1 g, 454 mmoles, ca. 75% solution in t-butanol) was dissolved in 120 mL methanol in a 1 L, 3-necked round bottom flask with reflux condenser, thermometer, and addition funnel. Glacial acetic acid (1 mL) was added followed by controlled addition of t-butyl carbazate (50 g, 378 mmoles), without removal of heat of the reaction. The mixture was stirred for 4 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, the residue was taken up in pentane, and the pentane was evaporated. The resultant oil crystallized upon standing to provide N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester (75.7 g, 93%). Rf=0.42 (2:1 hexanes:ethyl acetate, 1% acetic acid); 1H NMR (400 MHz, CDCl3) δ 7.6 (br s, 1H), 7.1 (s, 1H), 1.5 (s, 9H), 1.1 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18]C)[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.B(Br)(Br)Br.ClCCl.CO>ClCCl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1Cc2ccc(O)cc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.45 g (5.08 mmol) 4-fluoro-N-(5-methoxy-indan-2-yl)-benzamide were dissolved in 50 ml of dichloromethane, 13 ml (12.7 mmol) boron tribromide (1M in dichloromethane) were added, the whole was stirred for 30 min at RT. The resulting mixture was poured onto 200 ml of ice water, the organic phase was washed twice with water, dried, evaporated and the residue obtained was subjected to chromatography on silica with a mixture of dichloromethane/methanol 98:2.
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C.[C].[Pd]>[CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Ethyl 2-methyl-3-(pyridin-3-yl)acrylate (480 mg, 2.4 mmol) obtained in Step 1 of Reference Example 8-65 was dissolved in ethanol (5 mL). To this, 10% palladium carbon (92 mg) was added under an argon atmosphere, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite and the solvent in the filtrate was evaporated off under reduced pressure. Thus, ethyl 2-methyl-3-(pyridin-3-yl)propanoate (453 mg, yield: 98%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[N+:28]([C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
3-Hydroxybenzoic acid (13.8 g) in dry dimethylformamide (100 ml) was heated and stirred for 7 hours at 100° with anhydrous potassium carbonate (26 g) and 4-chloro-3-nitrobenzotrifluoride (22.5 g). The mixture was then evaporated to a small volume under reduced pressure and diluted with water. With warming, a dark solution was obtained. Acidification gave a white precipitate; this was washed with water and recrystallised from a mixture of methanol and water to give 3(2-nitro-4-trifluoromethylphenoxy) benzoic acid (24 g).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:8]1[C:14](=[O:35])[CH2:15][C@H:16]([NH:27]C(=O)OC(C)(C)C)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[ClH:36].C(OCC)C>CO>[ClH:36].[NH2:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C@H:7]1[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:35]
Reactant: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
97 mg of tert-butyl (R)-4-[(R)-2-(tert-butoxymethyl)-3-oxopiperazin-1-yl]-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate prepared in Step 8 was dissolved in 3 mL of methanol, followed by addition of 2 mL of 2N-hydrochloric acid/diethyl ether and stirring at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to afford 64 mg of the title compound as a foamy solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:11]([O-:33])=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(OCC)OCC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CC(OCC)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinoline (4.50 g, 13.7 mmol) by reaction with m-CPBA (6.0 g) to provide 1-(2,2-diethoxyethyl)-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (4.60 g, 24.1 mmol) and ammonium hydroxide solution (130 mL) to provide 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid after recrystallization from aqueous methanol, mp 148-150° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[CH3:8][C:5]1[N:4]=[N:3][C:2]([NH:10][NH2:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(NN)nn1
Yield: 80 %

Procedure:
To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin-3-yl)-hydrazine was obtained as a white crystalline solid (80% yield).
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][C:10]1[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]2=[O:21]>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][C:10]1[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]2([CH3:1])[OH:21]
Reactant: O=c1c2cc(Cl)ncc2oc2c(F)cc(Br)cc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)c2cc(Cl)ncc2Oc2c(F)cc(Br)cc21
Reaction time: 2 h

Procedure:
Methyl magnesium chloride, 22 wt % in tetrahydrofuran (6.14 mL, 18.26 mmol) was added to a solution of 7-bromo-3-chloro-9-fluoro-5H-chromeno[2,3-c]pyridin-5-one (3.0 g, 9.13 mmol) in THF (40 mL) at 0° C. After 2 hours, the reaction was quenched with saturated aqueous ammonium chloride (250 mL) and diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude product 7-bromo-3-chloro-9-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol which was used directly in the next reaction. MS m/z=346.0 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18]>CN1C(=O)CCC1.O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([CH:25]3[CH2:34][CH:26]3[CH2:27][O:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 32.9 %

Procedure:
3-Diethylaminopropyl amine (0.975 g) was added to a solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67, 0.091 g) in NMP (3 mL) and the mixture was heated at 140° C. in a sealed tube for 36 hours. After cooling, the mixture was diluted with water (2 mL) and the solution was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-[2-(3-diethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.039 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=2)=[CH:7][C:3]=1[C:4]([O:6][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=1)=[O:5]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 60 °C
Yield: 94.9 %

Procedure:
To a mixture of 2-chloro-5-hydroxybenzoic acid (500 mg, 2.9 mmol) in DMF (20 ml) were added potassium carbonate (1.0 g, 7.3 mmol, 2.5 eq) and 3-chlorobenzyl bromide (0.8 ml, 6.1 mmol, 2.1 eq). The mixture was heated at 60° C. for 2.5 hours. On cooling the mixture was diluted with ethyl acetate (300 ml) and washed with water (2×100 ml) then brine (70 ml). Organic layer dried and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 100 g silica column) eluting with 0-30% ethyl acetate in hexanes to afford the title compound as a clear oil (1.16 g). MS (ES+) m/z 421 [M+H]+ (C21H1535Cl3O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.19 (2H,s), 5.35 (2H,s), 7.26 (1H,dd, J 8.8, J 3.2), 7.40-7.56 (10H,m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1ccccc1CN1CCOCC1
Reactant: O=C1CCCCN1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(N=C2CCCCN2)c(CN2CCOCC2)c1

Procedure:
A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 48 hours to yield 4-[2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 108°-110° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cn1cc(Br)ccc1=O
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 110 °C
Yield: 72.7 %

Procedure:
A mixture of 5-bromo-1-methylpyridin-2(1 H)-one (2.2 g, 11.7 mmol), 6-chloropyridin-3-ylboronic acid (1.57 g, 9.98 mmol), Na2CO3 (2.2 g, 20.76 mmol), and tetrakis(triphenylphosphine)palladium (0) (500 mg, 0.05 mmol) in dioxane:water (15:1, 20 ml) was degassed and heated at 110° C. in a microwave for 1 hr. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (AcOEt-Hexanes) to provide title compound, 5-(6-Chloropyridin-3-yl)-1-methylpyridin-2(1 H)-one (1.6 g, 73% yield).
Reaction SMILES: [F:1][C:2]([F:51])([C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4][C:5]([CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32]COC)=[CH:29][CH:30]=2)[O:25][CH2:24][C:23]1([C:37]1[CH:42]=[CH:41][C:40]([O:43]COC)=[CH:39][CH:38]=1)[CH3:36])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]>C(O)C.Cl.C(OCC)(=O)C>[F:51][C:2]([F:1])([C:47]([F:48])([F:49])[F:50])[CH2:3][CH2:4][C:5]([CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[O:25][CH2:24][C:23]1([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[CH3:36])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(CCCCCCCCCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1)C(=O)CCC(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCCCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a stirred solution of ethyl 2-(4,4,5,5,5-pentafluoro-1-oxopentyl)-11-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]undecanoate (128 mg, 0.17 mmol) in ethyl alcohol (5 ml), was added concentrated aqueous hydrochloric acid (10 drops) at room temperature under N2 atmosphere. The mixture was stirred at room temperature continued for 2.5 days and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. Crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate=3:2) to give ethyl 2-(4,4,5,5,5-pentafluoro-1-oxopentyl)-11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]undecanoate as a colorless glassy oil. yield: 102 mg (94%).
Reaction SMILES: C(CNCC(O[C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[C:22]([F:34])[CH:21]=2)[CH2:19][CH2:18]1)=[O:16])CNCC(=O)C)(=O)C.C([CH2:38][NH:39][CH2:40][CH:41]([O:65][C:66](=[O:68])[CH3:67])[CH2:42][NH:43][CH2:44][C:45]([C:47]1(C2C=CC(C3C=CC(Cl)=C(Cl)C=3)=C(F)C=2)CC1)=[O:46])(=O)C>CN(C1C=CN=CC=1)C>[C:45]([CH2:44][NH:43][CH2:42][CH:41]([O:65][C:66](=[O:68])[CH3:67])[CH2:40][N:39]([C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[C:22]([F:34])[CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:38])(=[O:46])[CH3:47]
Reactant: CC(=O)CNCC(CNCC(C)=O)OC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Reactant: CC(=O)CNCC(CNCC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)CNCC(CN(C)C(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)OC(C)=O

Procedure:
Note that although the procedure is similar to that utilized to synthesize C4 (second method, see Example 5), with the exception that also DMAP was added in the coupling step of Example 5 but not of Example 6, the isolated product is different, being acetic acid 1-[(acetylmethylamino)methyl]-2-{[1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarbonyl]methylamino}ethyl ester in Example 6 and 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid 2-acetylmethylamino-1-(acetylmethylaminomethyl)ethyl ester in Example 5.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1(C)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C

Procedure:
One hundred milligrams of 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-5-heptanolide was dissolved in 0.1 ml of methylene chloride and 0.63 ml of acetic anhydride, 0.56 ml of triethylamine and 1.5 mg of N,N-dimethyl-4-pyridineamine were added thereto under cooling at 0° C. After allowing to stand under ice-cooling for 4 hours, the reaction mixture was poured into ice-water and the crystals thus precipitated were recrystallized from a mixture of ethyl acetate and n-hexane (1:10) affording 68 mg of the desired compound melting at 98°-101° C.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[Li+].[CH3:16]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([F:14])[CH2:3][CH2:4][CH:5]([CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)CC1CCC(F)(F)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate (0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85 mmol, 2M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.606 mL, 9.70 mmol) was then added at −78° C. and the reaction mixture was slowly warmed to RT and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 232A as a pale yellow liquid (0.27 g, 50%). 1H NMR (300 MHz, chloroform-d) δ ppm 4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-1.11 (m, 3H).