Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-6-cyano-7-hydroxyquinoline (1 95 mg, 0.6 mmol), 4-(3-chloropropyl)morpholine (124 mg, 0.76 mol), (J. Amer. Chem. Soc. 1945, 67, 736), potassium carbonate (172 mg, 1.2 mmol) and DMF (5 ml) was heated at 100° C. for 6 hours. The mixture was cooled to ambient temperature, and was partitioned between water and methylene chloride. The organic layer was dried (MgSO4), insoluble materials were removed by filtration and silica (2 g) was added to the filtrate. The solvent was removed by evaporation and the powder obtained was purified by flash chromatography eluting with methylene chloride/methanol/ammonia (100/2/0.5 increasing to 100/20/1). Removal of the volatiles by evaporation gave an oil which was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-cyano-7-(3-morpholinopropoxy)quinoline (150 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([NH2:13])([CH2:11][CH3:12])[CH3:10].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]([CH2:11][CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCC(C)N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(C)Nc1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine and 3.13 mL (31.0 mmol) sec-butylamin are added to 12 mL ACN. The reaction mixture is stirred at 120° C. for 2 h, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[O:10][N:9]=[CH:8][CH:7]=1)[OH:5].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14](O)[CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:5][CH:4]([C:6]2[O:10][N:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: OC(CCCl)c1ccno1
Reactant: N#Cc1ccc(Cl)cc1O
Product: N#Cc1ccc(Cl)cc1OC(CCCl)c1ccno1

Procedure:
Prepared by the method of Example 8(a) using α-(2-chloroethyl)-5-isoxazolemethanol and 4-chloro-2-hydroxybenzonitrile.
Reaction SMILES: [CH:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[CH:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#CC2CCCCC2)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(/C=C\C2CCCCC2)cn1
Yield: 100.8 %

Procedure:
Add 5-cyclohexylethynyl-pyridine-2-carbonitrile (1.4 g, 4.16 mmol) and Lindlar's Catalyst (0.5 g) to EtOAc (20 mL). Bubble hydrogen (via balloon) through the mixture for 2 h and stir under static atmosphere of hydrogen overnight. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (0.89 g, 80%). MS (APCI+) m/z: 213 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10](=O)[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)[CH3:8]>O1CCCC1>[CH2:7]([N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:18][CH:19]=1)[CH3:8]
Reactant: CCCCCCCN(CC)C(=O)CCCc1ccc(NS(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCN(CC)CCCCc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 1.8 g (0.047 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran (THF), under nitrogen, is cooled in an ice bath. The mixture is treated with a solution of N-[4-[4-(ethylheptylamino)-4-oxobutyl]phenyl]methanesulfonamide from Preparation 25 (7.5 g, 0.0195 mol) (which has been dried by azeotrope with CCl4 and then benzene) in 100 ml of THF dropwise over 45 min. The mixture is stirred for 30 min in the cold and for 2 hrs at ambient temperature. The mixture is cooled in an ice bath and treated cautiously, dropwise, with 100 ml of saturated aqueous sodium potassium tartrate. The resultant suspension is extracted with EtOAc (3×500 ml, 2×300 ml). The pooled extract is washed with brine, dried (Na2SO4) and concentrated to give 6.67 g of a crude oil. The oil is chromatographed over 1500 ml of silica gel eluting with 0.5% NH4OH--5% MeOH/CHCl 3. Forty-five ml fractions are collected with fractions at approximately 85-136 giving the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[C:16]([N+:31]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[C:16]([NH2:31])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.45 mmol) obtained in Step 2 was dissolved in ethanol (1.0 mL), and the solution was added with iron (0.50 g, 8.9 mmol) and water (1.0 mL) under ice-cooling, followed by stirring at 40° C. for 1 hour. To the reaction mixture under ice-cooling, water was added and the mixture was neutralized. Then, the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain (E)-4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]phenyl}piperazine-1-carboxylic acid tert-butyl ester (63 mg, 34%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([NH:20][C:21]4[CH:29]=[C:28]5[C:24]([CH:25]=[N:26][NH:27]5)=[CH:23][CH:22]=4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[N:4]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:3]1.C=O.[BH3-][C:41]#N.[Na+]>CCO>[CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:41])[CH2:33][CH2:32]2)[CH2:3]1
Reactant: CC1(C)CN(CC2CCNCC2)c2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(CN2CC(C)(C)c3ccc(NC(=O)c4cccnc4Nc4ccc5cn[nH]c5c4)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[3,3-Dimethyl-1-(4-piperidylmethyl)indolin-6-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide (140 mg, Example 41) was dissolved in 10 mL EtOH. Formaldehyde (10 mL, 37%) was added, followed by 100 mg of NaCNBH3. The mixture was stirred at RT overnight, and concentrated in vacuo. The crude was extracted between saturated NaHCO3 solution and EtOAc, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. This material was further purified by preparative HPLC to yield a white solid. MS: 510 (M+1). Calc'd. for C30H35N7O−509.6.
Reaction SMILES: ClCCl.Cl[C:5]1[N:6]=[C:7]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.C[Mg]Br.O1CC[CH2:34][CH2:33]1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([C:5]1[N:6]=[C:7]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH3:34]
Reactant: C1CCOC1
Reactant: Fc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncccc34)s2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1nc(NCc2ccc(F)cc2)sc1Cc1c[nH]c2ncccc12
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Into a round bottom flask, under an atmosphere of nitrogen, [1,1′-bis(diphenyl phosphino)ferrocene]dichloro palladium (II), complex with dichloromethane (1:1), was placed with toluene (15 mL, 140 mmol). [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (P-0156, 145 mg, 0.4 mmol) was added in 5 ml of toluene at room temperature. The mixture was stirred for 10 minutes. To the stirring reaction, a solution of 3.13 Methyl magnesium bromide in ether (1.86 mL) was added dropwise at room temperature. The opaque solution was heated to 60° C. Tetrahydrofuran (10 mL) was added to the warm solution. The mixture was heated to reflux for an additional two hours. After cooling to 0° C., the reaction was quenched with a solution of citric acid at pH 4-5 in ice-water and stirred to room temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography, eluting with a gradient of ethyl acetate:hexanes (20:100), gave a yellow solid that was further washed with ethyl acetate to give P-0162 (15 mg, 10%) as an off-white solid. MS (ESI) [M+H+]+=367.2.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Li+].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C.N#N.I[C:24]1[CH:63]=[CH:62][C:27]([CH2:28][N:29]([CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:30](=[O:53])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[C:48]([F:51])([F:50])[F:49])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>CN(C=O)C.CC(=O)OCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:58]([O:57][C:55](=[O:56])[CH2:54][N:29]([CH2:28][C:27]1[CH:62]=[CH:63][C:24]([C:1]([OH:3])=[O:2])=[CH:25][CH:26]=1)[C:30](=[O:53])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[C:48]([F:51])([F:50])[F:49])=[CH:33][CH:32]=1)([CH3:61])([CH3:60])[CH3:59]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(I)cc3)cc2)c(C(F)(F)F)c1
Reactant: O=C[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirring mixture of lithium formate (0.30 g, 5.85 mmol) and DIPEA (0.68 mL, 3.90 mmol) in DMF (3 mL) was added acetic anhydride (0.37 mL, 3.90 mmol). After 30 min, a N2 purged solution of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36 (1.33 g, 1.95 mmol) and PdCl2(dppf) (143 mg, 0.20 mmol) in DMF (2 mL) was added and the mixture heated to 110° C. for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (150 mL) and washed successively with 1N HCl (200 mL) and brine (200 mL). The organics were pre-absorbed onto silica gel then purified by chromatography (EA/isohexanes+1% AcOH) to afford a crude material that was further concentrated from toluene (20 mL). The crude solid was triturated from diethyl ether/isohexanes (10 mL:100 mL) and isolated by filtration to afford 721 mg (60%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37. LCMS-ESI (m/z) calculated for C31H31F3N2O7: 600; found 599 [M−H]−, tR=2.27 min (Method 10). 1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 10.33 (s, 1H), 8.00-7.85 (m, 2H), 7.62 (t, J=8.5 Hz, 2H), 7.56-7.29 (m, 5H), 7.28-7.11 (m, 2H), 4.71 (s, 1H), 4.62 (s, 1H), 4.01-3.92 (m, 2H), 3.85 (s, 2H), 3.83 (s, 3H), 1.41(s, 4.5H), 1.31 (s, 4.5H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:3]1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH:12][C:23]([C:20]3[CH:21]=[CH:22][O:18][CH:19]=3)=[O:24])=[N:9][C:8]=2[C:13]2[SH:14]=[CH:15][CH2:16][CH:17]=2)=[N:3]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Cn1nnc(-c2sc(N)nc2-c2cccs2)n1
Product: Cn1nnc(-c2sc(NC(=O)c3ccoc3)nc2C2=CCC=[SH]2)n1

Procedure:
Prepared from 5-(2-methyl-2H-tetrazol-5-yl)-4-thiophen-2-yl-thiazol-2-ylamine and furan-3-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:9]([C:12]1[C:13]([NH:21][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1c(NC(=O)CC(C)(C)C)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 3,3-dimethylbutanoyl chloride (0.043 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (4 mL) and concentrated under vacuum to remove excess pyridine. The residue was crystallized from 60% ethanol-water (10 mL) to provide the title compound (40 mg). 1H NMR (300 MHz, CD3OD) δ ppm 1.13 (s, 9H) 1.31-1.53 (m, 6H) 2.33 (s, 2H) 2.95-3.24 (m, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 275 (M+H)+; Anal. Calculated for C15H22N4O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.74; H, 8.10; N, 20.46.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([Cl:10])[C:3]=1[F:11].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:12]1([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([Cl:10])[C:3]=2[F:11])[CH2:14][CH2:13]1
Reactant: Nc1cc(F)c(Br)c(F)c1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(F)c(C2CC2)c(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-chloro-3,5-difluoroaniline (5.35 g, 22.0 mmol), cyclopropylboronic acid (2.20 g, 24.0 mmol), K3PO4 (16 g, 78 mmol) and tricyclohexyl phosphine (0.623 g, 2.24 mmol) in toluene (30 mL) and water (8 mL) is degassed with N2 and heated to 100° C. Pd(OAc)2 (0.25 g, 1.16 mmol) is added. The reaction mixture is heated to 100° C. overnight, cooled and loaded directly on a column of silica gel. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-cyclopropyl-3,5-difluoro-2-chloroaniline.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:18][CH2:19][C:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.80 g, 67.1 mmol) in dichloromethane (150 mL) under nitrogen was added triethylamine (11.2 mL, 80.5 mmol. This was then cooled to 0° C. and to this was added dropwise with stirring 2-chloroacetyl chloride (6.53 mL, 80.5 mmol) in dichloromethane (50 mL) over 1 and a half hours. This was then stirred overnight warming to room temperature in the process. The reaction was then quenched by adding 1 N HCl (100 mL). This was then extracted with ethyl acetate and the ethyl acetate layers were dried with solid anhydrous magnesium sulfate powder, filtered and concentrated to give 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one as a brown oil (15.44 g). This was used without purification for the next step.
Reaction SMILES: CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C([O:20][C@@H:21]1[O:26][C@H:25]([C:27]([OH:29])=[O:28])[C@@H:24]([OH:30])[C@H:23]([OH:31])[C@H:22]1[OH:32])=O.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C(F)=O>>[O:20]=[CH:21][C@@H:22]([C@H:23]([C@@H:24]([C@@H:25]([C:27]([OH:29])=[O:28])[OH:26])[OH:30])[OH:31])[OH:32]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O

Procedure:
The first chemical synthesis of retinoyl β-glucuronide was reported by us (Barua & Olson, J. Lipid Res. 26: 1277-1282, 1985), and involves a two-step procedure. Retinoyl fluoride was allowed first to react with 6,3-glucuronolactone to produce the 6,3-lactone of retinoyl glucuronic acid, which was then hydrolysed with very dilute alkali to give retinoyl β-glucuronide. The present invention is an improvement over the two-step procedure.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C@H:4]2[CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[Cl-].[NH4+]>>[C:12]([CH:9]1[CH2:8][CH2:7][CH:5]2[CH:4]([CH2:3][CH2:2][CH2:1][CH2:6]2)[C:10]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC[C@H]2CCCC[C@H]12
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)C1CCC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 19.8 %

Procedure:
Boron trifluoride-acetic acid complex (5.2 mL, 37.5 mmol) was cooled to 0° C. trans-1-Decalone (3.82 g, 25 mmol) in acetic anhydride (4.7 mL, 50 mmol) was added, and the reaction was stirred at room temperature for 3.5 hours. Saturated ammonium chloride solution (95 mL) was added, and the mixture was heated to 80° C. for 45 minutes. After cooling to room temperature, the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 10-40% ethyl acetate/hexanes gave 0.96 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15]1([C:23](Cl)=[O:24])([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[O:21]=[C:20]1[C:11]2[C:12](=[C:13]([Cl:14])[C:2]([CH3:1])=[C:3]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH:10]=2)[C:23](=[O:24])[C:15]21[CH2:19][CH2:18][CH2:17][CH2:16]2
Reactant: COC(=O)COc1cccc(Cl)c1C
Reactant: O=C(Cl)C1(C(=O)Cl)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1cc2c(c(Cl)c1C)C(=O)C1(CCCC1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of methyl (2-methyl-3-chlorophenoxy)acetate (3.7 g., 0.0172 mole) and cyclopentane-1,1-dicarbonyl chloride (3.5 g., 0.018 mole) in methylene chloride (200 ml.) is cooled to 0°C. and treated with aluminum chloride (7.2 g., 0.054 mole) in several portions during a 15 minute period. The reaction is stirred at 25°C. for 18 hours than at reflux for 5 hours, cooled and poured into 1N-hydrochloric acid. Evaporation of the methylene chloride at reduced pressure affords methyl [1',3'-dioxo-4'-chloro-5'-methyl-spiro(cyclopentane-1,2'-indan)-6'-yloxy]acetate which melts at 152°-153.5°C. after recrystallization from ethanol-water.
Reaction SMILES: [Na+].[CH2:2]([O:4][C:5]([C:7]1[CH2:8][C@@H:9]([N:20]=CC2C=CC=CC=2S([O-])(=O)=O)[C@H:10]([OH:19])[C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N)CN>C(OCC)(=O)C.O>[CH2:2]([O:4][C:5]([C:7]1[CH2:8][C@@H:9]([NH2:20])[C@H:10]([O:19][S:40]([CH3:39])(=[O:42])=[O:41])[C@H:11]([O:13][CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[CH:12]=1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N=Cc2ccccc2S(=O)(=O)[O-])C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: NCCN
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](OS(C)(=O)=O)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred suspension of 9.23 g (20 mmol) (1R,5R,6S)-2-{[3-ethoxycarbonyl-5-(1-ethyl-propoxy)-6-hydroxy-cyclohex-3-enylimino]-methyl}-benzenesulfonic acid sodium salt and 3.50 ml (25 mmol) of triethylamine in 90 ml ethyl acetate was added 1.80 ml (23 mmol) methanesulfonyl chloride at to 0 to 5° C. The resulting brown-yellowish suspension was stirred at room temperature for 2 hours, treated with 2.70 ml (40 mmol) ethylenediamine and after 10 min with 90 ml of water. After stirring the 2-phase system vigorously for 1 hour the organic phase was separated and extracted with 100 ml water and 3 times with 100 ml aqueous 1M NaHCO3 solution, dried over Na2SO4, filtered and evaporated in a rotary evaporator at 48° C./4 mbar to dryness to yield 6.36 g (91%) of (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester as an orange oil. An analytical sample of was obtained by column chromatography on silica gel using t-BuOMe containing 1% of 25% ammonia as the eluent. IR (film): 2966, 2936, 2878, 1711, 1653, 1463, 1351, 1246, 1172, 1068, 961 cm−1; MS (EI, 7o eV)): 350 (M+), 262, 224, 182, 166, 136 m/z.