Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
Sodium hydride (60% in oil, 1.44 g, 36.00 mmol) was added to a 0° C. solution of 4-hydroxybenzaldehyde (4.40 g, 36.03 mmol) in DMF (16 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrimidine (4.12 g, 35.97 mmol) in DMF (8 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 6.20 g (86%) of the title compound. MS 201 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22].CI.[C:30](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:30])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22]
Reactant: CCOC(=O)c1cc2c(F)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A mixture of ethyl 4-fluoro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (455 mg), methyl iodide (0.103 mL), potassium carbonate (183 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.45 g, yield 96%) as pale-pink crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33](Br)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(C(OCCCN2CCNCC2)c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(C(OCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A solution containing 10.4 g of 1-[3-[bis(4-fluorophenyl)methoxy]propyl]piperazine, 4.6 ml of triethylamine and 8.1 g of benzhydryl bromide in 100 ml of anhydrous xylene is refluxed for 8 hours and then cooled down. The mixture is washedwith water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resiude is recrystallized from n-hexane to give the aimed product, m.p.: 78°-79° C.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([NH2:25])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g, 10.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine, followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 45 minutes and 1 mL of concentrated ammonium hydroxide then is added. After 10 minutes, the reaction mixture is diluted with 50 mL water and the resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1 mm) to afford 2.46 g (84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp 224°-226° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.79 (s, 4 H, Ar), 7.71 (br s, 1 H, CONH2), 7.32 (br s, 1 H, CONH2), 7.20-7.02 (m. 5H, Ar), 5.06-4.98 (m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d6, 250 MHz) δ: 169.6, 168.0, 137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal. Calculated for C17H14N2O3. Theoretical: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.37; H, 4.73; N, 9.43.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.0, 533.0 (M)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:11]=1[C:25]#[N:26].S(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:14]1[C:10]([CH3:9])=[C:11]([C:25]#[N:26])[N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C)c2C#N)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2C#N)cc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
N-Bromosuccinimide (12.0 g, 67.4 mmol) is added all at once to a suspension of 3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile (14.45 g, 55.6 mmol) in N,N-dimethylformamide (60 mL) at ambient temperature. The mixture is stirred at ambient temperature for 29 hours and is then cooled in an ice bath. Saturated aqueous sodium bisulphite solution (90 mL), water (90 mL) and ethyl acetate (250 mL) are then added. The phases are separated, and then the aqueous phase is extracted with ethyl acetate (2×70 mL). The combined organic phases are washed with 5% aqueous potassium bicarbonate solution (90 mL), water (3×90 mL), and then brine (3×90 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography over silica gel using toluene and heptane as eluants to obtain the expected compound in the form of a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:20]([OH:24])=[CH:19][CH:18]=[CH:17][C:16]=2[CH:15]=1.[H-].[Na+]>CN(C)C=O>[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[CH:15]=1
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc2c(OCc3ccc4ccccc4c3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
2-Bromomethylnaphthalene (4.60 g) is added to a mixture of 2-Amino-5-naphthol (3.34 g) and sodium hydride (1.00 g) in dimethylformamide (100 mL) at −40 deg. C. Let stir overnight at room temperature. Concentrate in vacuo. Redilute with ethylacetate and absorb onto silica gel. Chromatograph (ethyl acetate/hexane) to give 2-amino-5-(Naphthalen-2-ylmethoxy)-naphthalene (1.86 g, 30%). Without further characterization this amine and triethylamine (0.90 mL) were dissolved in dichloromethane (75 mL). Cooled in an acetone and dry ice bath. Triflic anhydride (1.05 mL) was added and the mixture had warmed to room temperature overnight. Partition between water and ethyl acetate. Separate and dry with magnesium sulfate. Concentrate at rotovap, and triturate with ethyl acetate to provide the title compound (0.825 g, 30%) as a pale yellow solid, m.p. 140-142° C. 1H NMR (DMSO-d6, 400 MHz): δ 5.47 (s, 2H), 7.12 (d, 1H), 7.40-7.56 (m, 5H), 7.67 (d, 1H), 7.75 (s, 1H), 7.91-7.98 (m, 3H), 8.09 (s, 1H), 8.30 (d, 1H). MS [EI, m/z]: 430 [M−H]+. Anal. Calcd. for C22H16F3NO3S: C, 61.25; H, 3.74; N, 3.25. Found: C, 61.05; H, 3.81; N, 3.12.
Reaction SMILES: C1([Li])C=CC=CC=1.Br[C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[C:11]([Br:19])[C:10]=1[O:20][CH2:21][O:22][CH3:23].CN([CH:27]=[O:28])C.O>C1CCCCC1.CCOCC.C1COCC1>[Br:19][C:11]1[C:10]([O:20][CH2:21][O:22][CH3:23])=[C:9]([CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=1)[CH:27]=[O:28]
Reactant: COCOc1cc(Br)c(OCOC)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: O
Product: COCOc1cc(Br)c(OCOC)c(C=O)c1
Yield: 70 %

Procedure:
Add a solution of phenyllithium (7.80 mL of a 1.8 M solution in cyclohexane-Et2O (70:30), 14.04 mmol) over 15 seconds to a −78° C. solution of 1,3-dibromo-2,5-bis-methoxymethoxy-benzene (5.00 g, 14.04 mmol) in THF (100 mL). After stirring the reaction for 15 minutes, add DMF (2.17 mL, 28.08 mmol) and stir the reaction for 1 hour. Pour the reaction into H2O (150 mL) and extract with EtOAc (2×100 mL). Combine the organic extracts, wash with brine, dry (MgSO4), filter and concentrate. Purify the crude material using silica gel chromatography, eluting with Hex:EtOAc (80:20) to afford the subtitled product (3.00 g, 70%) as an oil. 1H NMR (CDCl3) δ 3.47 (s, 3H), 3.61 (s, 3H), 5.14 (s, 2H), 5.16 (s, 2H), 7.45 (d, J=3.0 Hz, 1H), 7.53 (d, J=3.1 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26](F)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(OCc5cccc(Cl)c5)c(Cl)c4)ncnc3cn2)cc1
Temperature: 71.5 °C
Reaction time: 91 h

Procedure:
A mixture of compound 201 (2.60 g, 6.27 mmol) and 4-methoxybenzylamine (8.24 mL, 62.7 mmol) in dry DMSO (15 mL) was stirred under a nitrogen atmosphere at 71-72° C. (bath temperature) for 91 h. It was partitioned in between ethyl acetate (500 mL) and water (300 mL). The ethyl acetate layer was separated and washed further with water (3×300 mL); dried (MgSO4) and evaporated to give a crude product of N4-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-N6-(4-methoxybenzyl)prido[3,4-d]pyrimidine-4,6-diamine (210). Chromatography on silica gel (ethyl acetate/petroleum ether=1:1) gave pure 210 (2.02 g, 61%) as a yellow/orange solid, mp 120-122° C.; 1H NMR δ [(CD3)2SO] 9.59 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.48-7.38 (m, 3H), 7.36-7.19 (m, 4H), 7.15 (br s, 1H), 6.91-6.85 (m, 2H), 5.25 (s, 1H), 4.48 (d, J=6.3 Hz, 2H, 3.71 (s, 3H). Anal. Calcd for C28H23Cl2N5O2: C, 63.16; H, 4.35; N, 13.15. Found C, 62.96; H, 4.63; N, 13.12.
Reaction SMILES: [CH3:1][C@:2]1([C:18]([O:20]C)=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[Li+:22].[OH-]>>[CH3:1][C@:2]1([C:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=1.[Li+:22]
Reactant: COC(=O)[C@@]1(C)CCCN1Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: C[C@]1(C(=O)[O-])CCCN1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound (D113) (42 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from (R)-methyl 2-methyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D80) (50 mg). (LiOH: 3 eq; Reaction time: 18 hrs; RT)
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@:11]([N:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])[CH3:18])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:19]([N:17]([CH3:18])[C@@:11]([CH3:16])([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:9][OH:8])=[O:33])=[O:20])=[CH:26][CH:25]=1
Reactant: CNC(=O)[C@@](C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@](C)(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 25.1 %

Procedure:
10% Pd—C (7.0 mg) was added to a methanol (2.6 mL) solution of (2S)-N-(benzyloxy)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N′,2-dimethylpropanediamide (21 mg) as obtained in Example 13-(1), and the mixture was stirred in a hydrogen atmosphere for 6 hours at room temperature. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=6/1) to obtain (2S)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′,2-dimethylpropanediamide (Compound 341, white solid) (4.2 mg, 27%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].C1COCC1.Br[CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31]>CN(C)C=O>[CH3:31][O:30][CH:29]([O:32][CH3:33])[CH2:28][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: COC(CBr)OC
Reactant: Oc1ccc2ncccc2c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(COc1ccc2ncccc2c1)OC
Reaction time: 6 h

Procedure:
To a cooled (0° C.) solution of quinolin-6-ol (5.81 g, 40 mmol) in N,N-dimethylformamide (30 mL) was slowly added a 1M solution of sodium hexamethyldisilazane in THF (40 mL, 40 mmol). The mixture was stirred for 15 min after which 2-bromo-1,1-dimethoxyethane (5.18 mL, 44 mmol) was added. The reaction mixture was then refluxed conditions for 6 h. The solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (100 mL) and washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes. (0-50%) to give the desired product. (9 g, 96%) LCMS: (M+H)+=233.9.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O(C)[Li].I[C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>CO>[CH2:30]1[O:31][C:25]2[CH:24]=[CH:23][CH:28]=[CH:27][C:26]=2[O:29]1
Reactant: Ic1ccc2c(c1)OCO2
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Li]OC
Solvent: CO
Product: c1ccc2c(c1)OCO2
Temperature: 60 °C

Procedure:
280 mgs (1.10 mmol) of bis(pinacolato)diboron under anaerobic conditions in dry methanol (3 ml) in a reaction tube was treated with 2 ml of a 1 M LiOMe solution in methanol. After stirring, 25 mg of CoCl2(dppf)was added followed by 251 mg (1.01 mmol) of 1-iodo-3,4-methylenedioxybenzene. The reaction was warmed to 60° C. and stirred. On gc analysis after 16 hr reaction time, it was found that the required arylboronic acid ester had formed together with 3,4-methylenedioxybenzene.
Reaction SMILES: [CH2:1]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)(=O)=O.O>CN(C=O)C.ClC(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:8][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:19][CH2:18]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(N)(=O)=O
Reactant: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of n-butylsulphonamide (500 mg) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (150 mg, 60% dispersion in mineral oil) in DMF (10 ml) and the mixture was stirred for 10 minutes. 4-Methanesulphonyloxymethyl-N-benzyloxycarbonylpiperidine (1.09 g) was added and the mixture heated at 80° C. for 16 hours. The mixture was cooled, poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography, eluting with methanol/dichloromethane (1:99) to give a colourless semi-solid. This mixture was dissolved in warm tetrachloromethane (6 ml) and cooled to give 4-n-butylsulphonylaminomethyl-N-benzyloxycarbonylpiperidine (230 mg) as colourless prisms, mp 83°-85° C. NMR (d6DMSO): δ0.9(3H,t); 0.9-1.1(2H,m); 1.3-1.5(2H,m); 1.5-1.8(5H,m); 2.7-2.9(4H,m); 2.95(2H,m); 4.0(2H,d); 5.1(2H,s); 7.0(1H t); 7.3(5H m). m/e 369(M+H)+ ; 391(M+Na)+ ; calculated for C18H28N2SO4 : C, 58.7; H, 7.7; N, 7.6; found: C, 58.5; H, 7.8; N, 7.6%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34]>CC(=O)OCC>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:34])([F:35])[F:36])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.84 g of NaH were suspended using 60 ml of DME(anhydrous) and 4.5 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester added at a temperature between 10° C. and 25° C. The mixture was stirred at ambient temperature for 30 minutes followed by addition of a solution of 4.2 g of 3-hydroxy-2-(2,2,2-trifluoro-ethyl)-5-trifluoromethyl-2,3-dihydro-isoindol-1-one in 20 ml DME(anhydrous). The reaction mixture was refluxed for 1 h, then cooled to ambient temperature. 100 ml of EA were then added and the mixture washed twice using 200 ml of a semisaturated aqueous NaHCO3-solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. Chromatography was performed on Merck Lichrospher RP18, 10 μm, 50*250 mm. Conditions as follows:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH3:21])=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:32][NH:33][OH:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:33]([OH:34])[CH3:32])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH3:21])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12
Temperature: 4 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(methoxymethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 332 mg 0.9467 mmol) in anhydrous DMF (8.0 mL) was added CDMT (200 mg 1.136 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.13 mL 1.136 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2.0 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (395 mg 4.734 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by recrystallisation in hot IPA (20 ml) with cooling at 4° C. overnight to give 194 mg (60%) of 1-(4-fluorobenzyl)-N-hydroxy-3-(methoxymethyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a white solid. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, APCI, +mode): RT—1.028 min, m/e=344.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ =3.26 (s, 3H), 3.34 (s, 3H), 4.57 (s, 2H), 5.54 (s, 2H), 7.14 (t, 2H), 7.36 (m, 2H), 7.87 (s, 1H), 8.02 (s, 1H), 8.92 (s, 1H). Found: C, 62.72; H, 5.20; N, 12.17%. C18H18FN3O3, requires C, 62.97; H, 5.28; N, 12.24%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:17])[CH2:27]2)=[N:23][CH:24]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1C
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: Cc1ccc(-c2ccccc2C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)cc1C

Procedure:
prepared by reaction of 3′,4′-dimethyl-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Li])CCC.IC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:21])=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: CCCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-2-n-hexyl-1,2-dihydropyridine (4.84 g, 16.14 mmol) in 180 ml of THF at −42° C. was added n-butyllithium (19.4 mL, 19.37 mmol) dropwise via syringe. After the mixture had stirred at −42° C. for 1 h, iodomethane (3.0 mL, 48.42 mmol) was added and stirring was continued at −42° C. for 1 h and then at room temperature for 1 h. Water (50 mL) and ether (100 mL) were added, the layers were separated, the aqueous phase was extracted with ether (2×15 mL), and the combined organic extracts were washed with brine. The organic phase was dried over K2CO3 filtered through silica gel/Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography with 5% EtOAc in hexanes afforded 4.89 g (73.4%) of the product as an orange oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ5.65-5.58 (d, 1 H), 5.32 (br s, 1 H), 4.84-4.72 (q, 1 H), 2.13 (s, 3 H), 1.75-1.21 (m, 19 H), 0.91-0.85 (t, 3 H).