Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:31][CH2:30][CH2:29][CH2:28][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=1)=[O:15])=[O:7].[CH:35]1([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)[CH2:37][CH2:36]1>>[C:45]([N:42]1[CH2:41][CH2:40][CH:39]([N:38]([CH2:2][C:3]2[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=2)[C:6]([NH:8][C:9]2[S:10][C:11]3[CH2:31][CH2:30][CH2:29][CH2:28][C:12]=3[C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[O:15])=[O:7])[CH:35]2[CH2:37][CH2:36]2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CCl)c3)sc3c2CCCC3)cc1
Reactant: CC(=O)N1CCC(NC2CC2)CC1
Product: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CN(C4CC4)C4CCN(C(C)=O)CC4)c3)sc3c2CCCC3)cc1
Yield: 77.7 %

Procedure:
By using 5.34 g of 2-{[3-(chloromethyl)benzoyl]amino}-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 13.1 g of 1-[4-(cyclopropylamino)piperidin-1-yl]ethanone as starting materials, a reaction was performed under the conditions similar to Preparation Example 29, thereby obtaining 5.37 g of 2-[(3-{[(1-acetylpiperidin-4-yl)(cyclopropyl)amino]methyl}benzoyl)amino]-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II) chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0->10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: FC1C=C(C=CC=1F)C(O)=[O:6].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]3[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH2:19][CH2:20][C:12]3=[O:6])=[N:27][CH:26]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC3)nc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[(2,3-dihydro-1H-inden-5-yl)oxy]-3-pyridinylamine obtained in Reference Example 19 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.N[C@H:23](C1C=NC=C(Br)C=1)[C@](C1C=C(F)C=CC=1F)(O)C>>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])([CH3:23])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Reactant: C[C@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Product: C[C@@]1(c2cc(F)ccc2F)OC(=O)N[C@@H]1c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as ((4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2S)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.52-8.46 (m, 1H), 8.29 (s, 1H), 7.66 (s, 1H), 7.19 (ddd, J=9.2, 5.9, 3.2 Hz, 1H), 7.13-7.06 (m, 1H), 7.00 (ddd, J=10.6, 9.2, 4.6 Hz, 1H), 5.15 (d, J=1.8 Hz, 1H), 1.89 (s, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Cc1cc(Br)sc1C=O
Reactant: OB(O)c1ccccc1
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
Product: Cc1cc(-c2ccccc2)sc1C=O
Yield: 91.2 %

Procedure:
To a solution of 5-bromo-3-methyl-thiophene-2-carbaldehyde (1.00 g, 4.88 mmol) in ethylene glycol dimethyl ether (9 ml) was added phenylboronic acid (0.773 g, 6.34 mmol), 2M Na2CO3 solution (6.3 ml) and Pd(PPh3)4 [0.282 g, 0.24 mmol). The mixture was heated for 18 hours, cooled and the solvent removed at reduced pressure to leave a brown residue which was partitioned between water (15 ml) and dichloromethane (20 ml). The organic was separated, washed with water (2×5 ml), brine (10 ml), dried (MgSO4) and the solvent removed at reduced pressure to give a brown oil. Purification by flash column chromatography (6:1 petrol 40-60° C./ethyl acetate) gave the sub-title compound as a yellow oil (0.90 g, 91% yield): 1H NMR (400 MHz, CDCl3) δH 2.75 (3H, s), 7.25 (1H, s) 7.35-7.75 (5H, s), 10.05 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-1H-inden-1-one (1.0 g, 6.2 mmol), benzyl alcohol (0.65 g, 5.6 mol) and tributylphosphine (1.7 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azocarbonyl)dipiperidine (2.1 g, 8.4 mmol), and the mixture was stirred at room temperature for 16 hours. Insolubles were filtered off, and then the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound (1.3 g, yield 97%) as powders.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:10][N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=3[F:21])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A mixture of 3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) (0.48 g, 1.8 mmol), 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) and K2CO3 (498 mg, 3.6 mmol) in 14 ml CH3CN was stirred at 80° C. for 16 h. A second portion of 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) was added and the mixture was stirred for additional 7 h. Water was added, the mixture was extracted 3 times with ethyl acetate, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was crystallized from 10 ml 2-propanol and dried in vacuo to give 0.364 g of 3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(O)cc1
Product: O=C(Cc1ccc(O)cc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(4-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.38-8.42 (m, 1H), 7.95-8.02 (m, 2H), 7.72-7.75 (m, 1H), 7.60-7.67 (m, 4H), 7.17-7.19 (m, 2H), 6.73-6.75 (m, 2H), 3.57 (s, 2H); MS (ESI−) M/Z 404 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH3:14])[CH:9]=[CH:8][N:7]=1.[OH-].[Na+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:13]([CH3:14])[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])[CH:11]=1)([OH:27])[C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)O)c1)C(F)(F)F
Temperature: 55 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of {4-[2-(2,4-dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid methyl ester (127 mg) in methanol (2 mL) was added an aqueous solution of NaOH (1N, 0.58 mL) and the mixture was allowed to stir at 55° C. for 2 hours. The pH of the mixture was adjusted to pH 2 with aqueous 1N HCl solution and methanol was removed by evaporation. The aqueous solution was extracted twice with ethyl acetate and the organic layers were washed with brine, dried and evaporated. The residual oil was stirred in hexane (5 mL) over night and the suspension was filtered to give the title compound as a colorless powder (96 mg). MS (m/e): 424.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][CH2:25][OH:26].CCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]2[O:26][CH2:25][CH2:24][CH2:23][O:7]2)=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Br)cc(C)c1C=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C)c1C1OCCCO1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-2,6-dimethylbenzaldehyde (2.51 g, 12 mmol), 4-methyl-benzenesulfonic acid (0.20 g, 1.2 mmol), and propane-1,3-diol (1.2 mL, 16 mmol) in toluene (200 mL) was heated under nitrogen at 140° C. for 16 h, using a Dean-Stark trap to remove water. The reaction solution was then cooled to 25° C., diluted with EtOAc (200 mL), and sequentially washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow-brown oil. Hexane (200 mL) was added to the oil, and the resulting mixture was stirred vigorously for 10 min, resulting in the precipitation of a solid. This solid was collected by vacuum filtration, washed with hexanes (100 mL), and dried in vacuo to provide 2-(4-bromo-2,6-dimethylphenyl)-1,3-dioxane as a tan solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([Br:13])=[C:10]([Br:12])[N:11]=1.C1C[O:25][CH2:24][CH2:23]1>>[Br:12][C:10]1[N:11]=[C:7]([CH2:23][CH2:24][OH:25])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[Br:13]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(CCO)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 31 %

Procedure:
n-BuLi (4.30 mL of a 1.6 M solution in hexanes, 6.80 mmol) was added dropwise to a −78° C. solution of 2,4,5-tribromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (2.96 g, 6.80 mmol) in THF (55 mL). After 25 min, oxirane gas was bubbled through the solution for 25 mins. The reaction mixture was allowed to warm slowly to RT, stirred overnight, quenched by addition of sat'd NH4Cl and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (5-50% EtOAc/hex) to afford the title compound (0.83 g, 31%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.36 (s, 2H), 3.82 (t, J=6.09 Hz, 2H), 3.55 (dd, J=8.94, 7.65 Hz, 2H), 3.10 (br. s., 1H), 2.90 (t, J=6.09 Hz, 2H), 0.85-0.98 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 mL (210 mmol) of 2-bromopyridine in 500 mL of dry ether at −78° C. under Ar was added 85 mL of a 2.5 M solution of n-butyllithium in hexane in a slow stream. After stirring in the cold for 30 min, the solution was transferred over a 5 min period via two cannula into a 0° C. stirred solution of 100 mL (736 mmol) of diethyl oxalate in 1.0 L of dry ether under Ar. After stirring for 2 h in the cold, the reaction mixture was washed with 600 mL of sat. NaHCO3, water, and brine. The solution was dried over MgSO4 and the solvents concentrated at reduced pressure to give a red oil that was purified by SiO2 chromatography (10×15 cm) using 1:4 to 35:65 EtOAc-hexanes. The product-containing fractions were concentrated at reduced pressure to afford I-1-1 as a reddish oil: 1H NMR (CDCl3) δ1.42 (t, 3H), 4.45-4.55 (m, 2H), 7.55-7.6 (m, 1H), 7.9-7.95 (m, 1H), 8.11 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.C(=O)=O.CC(C)=O>>[Cl:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: OB(O)c1ccc(O)c(Cl)c1
Temperature: -78 °C
Yield: 26.7 %

Procedure:
A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g, 24.1 mmol) and purged with N2(g). Anhydrous THF (100 mL) added with stirring and the vessel cooled to −78° C. (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at −78° C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At about 0° C. 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in ethyl acetate (50 mL). Distilled H2O (50 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic portions were combined and washed with sat. Na2CO3 (aq). The aqueous layer was separated and treated with 2M HCl (aq) until the pH was about 4. This was then extracted with ethyl acetate (50 mL×2). The organic portions were then dried over MgSO4 and solvent removed. The resultant brown residues were taken up in a minimum of ethyl acetate (2-3 mL) and added to dropwise to hexane (50 mL) with stirring. The brown ppt was filtered to give the title compound as a brown solid (1.11 g, 27%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O.CC(C)=O>[CH2:10]([O:17][C:18]([N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[NH2:9])[CH2:3][CH2:2]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of piperidine-4-carboxamide (5 g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol) in a mixture of water (30 mL) and acetone (40 mL), NaOH 1N (39 mL, 39 mmol) was added dropwise, while maintaining the pH between 6 and 8. The mixture was stirred at r.t. for 3 h; then acetone was evaporated and the resulting precipitate filtered and dried at 70° C. under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76%).
Reaction SMILES: C1([O:7][C:8]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:11]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[CH3:15][N:14]1[C:10]2[C:8](=[O:7])[NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:11]=2[C:12]([CH3:16])=[N:13]1
Reactant: Cc1nn(C)c(C(=O)Oc2ccccc2)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2c1Nc1ccccc1NC2=O
Yield: 70.8 %

Procedure:
2.4 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid phenyl ester are hydrogenated in 150 ml of toluene and 5 ml of glacial acetic acid using 0.75 g of 10% strength palladium-on-charcoal at room temperature for 2.1 hours in a circulatory hydrogenation apparatus. The solution is filtered and concentrated in vacuo; the residue is chromatographed over a silica gel column using 1:1 petroleum ether (50°/70° C.)/ethyl acetate to yield 1.1 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 189° to 190° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([O:36][CH3:37])[CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH3:37][O:36][CH:4]([CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:38])=[O:2]
Reactant: COC(=O)C(Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1)C(=O)O
Reaction time: 1 h

Procedure:
0.43 g (0.82 mmol) of the above prepared [rac]-2-methoxy-3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-2-yl)-propionic acid methyl ester was dissolved in 15 ml of THF/MeOH (2:1); to the stirred solution was then added 1.64 ml of LiOH-solution (1 molar in water). After one hour, the reaction mixture was poured onto crashed ice/HCl and extracted twice with CH2Cl2; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography [SiO2, CH2Cl2/MeOH (0 to 5% MeOH)] to give 0.42 g of pure title compound as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:46]3[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=3)=[CH:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC(C)C)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cnc2c(c1)cc(C(=CC(C)C)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 72.5 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[3-methyl-1-(toluene-4-sulfonyloxy)-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.2 g, 2.1 mmol), 4-(methanesulfonyl)phenylboronic acid (1.0 g, 5.2 mmol), dichlorobis(triphenylphosphine)palladium (II) (150 mg, 0.21 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 5.2 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (820 mg, 73%) as a light yellow solid: LC/MS m/e calcd for C27H26N2O6S2 [M+H]+ 539.65, observed 539.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.6 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 2.68 (m, 1H), 3.08 (s, 3H), 3.99 (s, 3H), 6.27 (d, J=10.2 Hz, 1H), 6.67 (s, 1H), 7.28 (m, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.78 (m, 2H), 8.55 (d, J=2.0 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H).