Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:34][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)[C:18]([C:19]#[N:20])=[C:13]3[NH:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:39]>>[CH2:1]([N:8]1[CH2:9][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:23][CH:22]=4)[C:18]([C:19]([NH2:20])=[O:39])=[C:13]3[NH:12][CH2:11]2)[CH2:34]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2

Procedure:
The desired product was prepared from 1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 465.9.
Reaction SMILES: O1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12](O)(=O)C>>[C:6]1([CH2:5][CH2:4][C:2](=[O:3])[CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: CC(=O)O
Reactant: O=C1CCC2CCCCC2O1
Product: CC(=O)CCC1=CCCCC1
Yield: 47.1 %

Procedure:
Using the same procedure as described under A) but starting with a solution consisting of octahydrocoumarine (22 g, 145 mmoles) into 58 g of acetic acid and a supported catalyst obtained according to procedure a), there were obtained (after bulb to bulb distillation at 42 mbar, oven=175°) 10.4 g of 4-(1-cyclohexen-1-yl)-2-butanone (purity: 71%; yield: 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C@H:19]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]1>CN(C=O)C>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][O:22]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Temperature: 160 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
3-Nitrophenol (2.0 g, 14.37 mmol) was taken up in 20 mL of anhydrous DMF along with anhydrous potassium carbonate (4.96 g, 35.93 mmol) and (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (2.55 mL, 18.68 mmol). The resulting reaction mixture was heated in the microwave reactor, with stirring, at 160° C. for 4 h. The crude reaction mixture was rinsed with water, filtered and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography using ethyl acetate: pentane to obtain the desired product as an amber-colored oil (52%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: C1=COCCC1
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCCC#N)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC2CCCCO2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 19 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4 -(3-nitrophenyl )pyridine-3-carboxylic acid in 0.5 ml of tetrahydrofuran were added 5 mg of p-toluenesulfonic acid, and then 0.138 ml of 3,4-dihydro-2H-pyran. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified using preparative TLC to obtain 16.4 mg of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23]>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CCC(Br)C(C)=O
Solvent: CC#N
Product: CCC(Oc1cc(N)c(Cl)cc1C(=O)NCCN(CC)CC)C(C)=O
Reaction time: 3 h
Yield: 20.3 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.5 g, 20 mmoles) (from Preparation No. 3) in acetonitrile (150 ml) was treated with 3-bromo-2-pentanone (3.3 g of 80%, 20 mmoles, contaminated with 15% of 1-bromo-2-pentanone) [obtained according to the procedure of E. T. Borrows, D. O. Holland and J. Kenyon, J. Chem. Soc. 1083, (1946)]. After 3 hours, the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and the solvent evaporated. The semisolid residue was triturated with ether to yield a solid which was recrystallized from etherpetroleum ether to yield 1.5 g of the title compound, mp. 75°-78°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.26 (s, 1H); 8.14 (bs, 1H); 6.1 (s, 1H); 4.5 (t, 1H); 4.4 (s, 2H); 3.69 (q, 2H); 2.64 (m, 6 H); 2.1 (s, 3H); 2.1-1.7 (m, 2H); 1.05 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Br:17]N1C(=O)CCC1=O>COCCOCCOC>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[Br:17])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)C(Br)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,9 g of ethyl p-cyanophenylacetate in 50 ml of diglyme is added to a slurry of 0.48 g of sodium hydride (50% oil dispersion) in 10 ml of diglyme. The reaction mixture is stirred at room temperature for 2 h, cooled to 0° and 1.75 g of N-bromosuccinimide is added portionwise. The solvent is evaporated under high vacuum and the residue is chromatographed on 50 g of silica with ether to yield ethyl-α-bromo-p-cyanophenylacetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=O)=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:47][C:48]1[C:56]2[C:55]([NH2:57])=[CH:54][CH:53]=[CH:52][C:51]=2[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][C:55]=2[NH:57][C:19]([C:16]2[N:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:11][C:12]3=[N:18][CH:17]=2)=[O:21])[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCOCC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.055 g, 0.186 mmol) was dissolved in dimethylformamide (0.6 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (53 mL, 0.17 mmol), 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example 35, Steps A-D; 0.042 g, 0.167 mmol), and diisopropylethylamine (0.058 mL, 0.334 mmol) were combined in a 1 dram vial. The mixture stirred at ambient temperature overnight. The crude mixture was purified using preparative thin layer chromatography (silica, 20×20 cm, 1 mm) developed in a chamber with 10% Methanol/dichloromethane to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide (6 mg). MS m/z 526.1 (M+, APCI+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[S:15][C:14]([S:16][CH3:17])=[C:13]([S:18]([C:21]2[CH:22]=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([O:34]C)=[CH:29][C:28]=3[CH2:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:12]=1)(=[NH:10])[NH2:9].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[S:15][C:14]([S:16][CH3:17])=[C:13]([S:18]([C:21]2[CH:22]=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([OH:34])=[CH:29][C:28]=3[CH2:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH:12]=1)(=[NH:9])[NH2:10]
Reactant: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)c(COCC(=O)O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2COCC(=O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of [3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid ((Example 192: step g) 0.077 g, 0.0148 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C. and treated with BBr3 (0.592 mL, 0.592 mmol) dropwise. The reaction stirred at 0° C. for 30 min. then was allowed to warm to room temperature and stir 27 h. The reaction mixture was cooled to 0° C. and quenched with MeOH. Some HBr evolution was seen. All solvents were evaporated in vacuo, and the residue was taken up in EtOAc (100 mL) and washed with water (1×75 mL) and brine (2×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Preparatory HPLC (5–50% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-hydroxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid trifloroacetate (0.039, 52%) as a white glassy solid. 1H NMR (MeOD): δ 8.344 (s, 1H), 8.090 (d, 1H, J=8.0 Hz), 7.877 (t, 1H, J=2.0 Hz), 7.721 (t, 1H, J=7.6 Hz), 7.572 (d, 1H, J=7.6 Hz), 6.778 (d, 1H, J=2.8 Hz), 6.735 (d, 1H, J=2.0 Hz), 2.710 (s, 3H), 2.028 (s, 2H), 1.935 (s, 3H), 1.254 (t, 2H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: N#Cc1cccc(B(O)O)c1
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: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 51.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.036 g (51%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](O)C2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 60 mg, 0.134 mmol) and (6-methylpyridin-3-yl)boronic acid (36.8 mg, 0.19 mmol) were dissolved in DME (0.5 mL). A solution of 2 M aq. NaHCO3 (0.2 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and then treated with Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol). The RM was stirred under argon at 90° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.09 min, UPLC-MS (Condition 7) m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.75 (m, 1H) 1.76-1.87 (m, 1H) 2.52 (s, 3H) 2.86 (d, J=11.73 Hz, 1H) 3.11-3.24 (m, 2H) 3.27-3.43 (m, 1H) 4.17 (br. s, br. s, 1H) 4.83 (br. s, br. s, 1H) 7.28-7.39 (m, 3H) 7.69 (dd, J=7.82, 1.96 Hz, 1H) 7.79-7.89 (m, 2H) 7.98 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:21][CH2:22][CH2:23][O:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(=O)c2ccccc2)c1OCCBr
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate (42.1 g, 155 mmol) in N,N-dimethylformamide (300 mL) was added 1,2-dibromoethane (135 mL, 1550 mmol) and cesium carbonate (76 g, 232 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 6.5 h. The volume of the reaction mixture was reduced by half in vacuo, and then partitioned between water (500 mL) and ethyl acetate (500 mL). The layers were separated, and the organic layer was washed with brine (200 mL), dried over anhydrous magnesium sulfate and concentrated. The crude precipitate was triturated with 50% diethyl ether/hexanes (200 mL). The solid was washed with 50% diethyl ether/hexanes (2×200 mL) and isolated to give 30.6 g (52% over 2 steps) of methyl 2-[(2-bromoethyl)oxy]-3-[(phenylcarbonyl)oxy]benzoate as an off-white powder: 1H NMR (400 MHz, CDCl3): 8.23-8.21 (m, 2H), 7.77 (dd, J=1.6, 7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.53 (t, J=6.0 Hz, 2H), 7.39 (dd, J=1.8, 8.0 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 4.31 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 3.52 (t, J=6.4 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:15][O:16][CH2:17]Cl>CN(C)C=O.C(OCC)C>[CH3:15][O:16][CH2:17][O:14][C:6]1[CH:5]=[C:4]([CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COCCl
Reactant: COC(=O)c1ccc(C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1cc(C)ccc1C(=O)OC
Reaction time: 0.25 h
Yield: 112.3 %

Procedure:
To a suspension of sodium hydride (1.62 g, 0.0675 mol) in 90 mL of dimethylformamide was added dropwise a solution of methyl 4-methylsalicylate (10.2 g, 0.0614 mol) in 20 mL of diethyl ether. After stirring for 15 minutes, a solution of chloromethyl methyl ether (5.6 mL, 0.0737 mol) in 10 mL of diethyl ether was added. The reaction mixture was stirred at room temperature for 18 hours and then it was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted an additional three times with diethyl ether. The combined organic extracts were washed with brine, dried with magnesium sulfate, and concentrated in vacuo to give 14.5 g of an oil. The product was purified by flash chromatography on silica gel eluting with 10%-15% ethyl acetate in hexane to give 9.41 g (73%) of product as an oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])[CH2:3][CH:4]=[CH2:5].[C:16](=O)(O)[O-].[Na+].CI>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCC(O)c1cc(C(=O)O)ccc1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC(O)c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Into a 100-mL round-bottom flask, was added a solution of 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoic acid (compound 4.2, 1.4 g, 6.79 mmol) in N,N-dimethylformamide (20 mL). Sodium bicarbonate (1.14 g, 13.6 mmol) and methyl iodide (0.847 mL, 13.6 mmol) were added and the resulting mixture was stirred overnight at 25° C. The reaction was quenched with saturated aqueous Na2S2O3 (50 mL) and diluted with EtOAc (150 mL). The organic layer was washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as the eluent to yield the title compound as a light yellow oil (800 mg, 53%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[C:21]([OH:22])=[CH:20][C:19]([CH:23]([CH3:25])[CH3:24])=[CH:18][C:16]=2[OH:17])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[NH:9]1[CH2:10][CH:11]=[C:12]([C:15]2[C:16]([OH:17])=[CH:18][C:19]([CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=2[OH:22])[CH2:13][CH2:14]1
Reactant: CC(C)c1cc(O)c(C2=CCN(Cc3ccccc3)CC2)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(O)c(C2=CCNCC2)c(O)c1
Yield: 54.4 %

Procedure:
The product of Example XI (30.1 g) was suspended in 150 ml methanol and hydrogenated using 4 g of 5% Pd on carbon. After uptake of 1 mole hydrogen, the catalyst was filtered, the solution concentrated and the residue crystallized from isopropyl alcohol to give 12.27 g (52.5%) of product, m.p. 269°-271°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([C:5](=[O:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: COc1ccccc1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride, (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5°-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5°-10° C. of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0°-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92°-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5](Cl)=[O:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:6]
Reactant: COC(F)(F)C(F)(F)C(=O)Cl
Reactant: OCC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(F)(F)C(F)(F)C(=O)OCC(F)(F)F
Reaction time: 8 h

Procedure:
Trifluoroethyl 3-methoxytetrafluoropropionate was prepared by reaction of 97.3 g (0.50 mol) of 3-methoxytetrafluoropropionyl chloride, 55.0 g (0.55 mol) of trifluoroethanol, and 39.5 g (0.50 mol) of pyridine in 100 mL methylene chloride. Reaction was extremely slow until the pyridine was added. After having stirred overnight, the reaction mixture was filtered, solids were rinsed with methylene chloride, and filtrates were distilled to give 119.4 g of ester, bp 44°-49° (20 mm, 2.7 kPa). The cloudy product was treated with 2 g of P2O5 and filtered to afford 109.3 g (93%) of the desired ester, pure by GC. IR (CCl4): 2855, 2975, and 3010 (sat'd CH), 1790 (C=O), and 1300-1100 cm-1 (CF, C--O).
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C1COCC1>[C:10]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][NH2:30])[CH2:21][CH2:22]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C#N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
To a solution of (2-cyano-phenyl)-piperazine (2.4 g, 12.78 mmol) in THF and H2O (25 mL, 1:1) was added K2CO3 (3.9 g, 28.12 mmol). The solution was allowed to stir for about 10 minutes at r.t. Boc-anhydride (3.1 g, 14.06 mmol) was then added and reaction was allowed to stir for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 3.2 g of 1-Boc-4-(2-cyano-phenyl)-piperazine (88%). To a solution of sodium borohydride (2.1 g, 56.03 mmol) in THF (25 mL) at 0° C. was added TFA (4.3 mL, 56.03 mmol) dropwise. 1-Boc-4-(2-cyano-phenyl)-piperazine (3.2 g, 11.21 mmol) was then added slowly at r.t. The reaction was allowed to stir for about 12 hours at r.t. The reaction was quenched with H2O, diluted five-fold with EtOAc and washed with brine. The organic phase was concentrated to dryness yielding about 1.0 g of 1-Boc-4-(2-aminomethyl-phenyl)-piperazine (30%). MS (ESI+) 292.1 (M+1)