Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:15]=[C:14]([F:16])[C:13]([Br:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl.[N+]([O-])([O-])=O.[Na+].[I-:24].[K+]>O.CCOC(C)=O>[Br:17][C:13]1[C:14]([F:16])=[CH:15][C:7]([I:24])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [I-]
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)c(F)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (19.36 mL, 363 mmol) was added to a solution of 2-amino-5-bromo-4-fluorobenzoic acid (5.00 g, 21.37 mmol) in concentrated HCl (5.13 mL, 64.1 mmol) at 0° C. To this was added a solution of sodium nitrate (1.816 g, 21.37 mmol) in water (9 mL). The reaction was stirred for 40 minutes at 0° C. before potassium iodide (7.09 g, 42.7 mmol) in water (9.00 mL) was added dropwise. The solution was stirred at rt for 1 hour, at which point it had become a viscous oil. The mixture was poured into a mixture of ice water (250 mL) with EtOAc (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with 1N HCl, 1 N aqueous sodium sulfite, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 5-bromo-4-fluoro-2-iodobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.C[O-].[Na+].CO>CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 99.7 %

Procedure:
2-Chloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (12.3 g) was dissolved in methanol (150 mL). To the mixture was added 28% sodium methoxide-methanol solution (1 mL), and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (8.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cncc(Br)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150.0 mg, 0.36 mmol) in methanol (30 mL) was added sodium hydroxide (43 mg, 1.08 mmol) and water (1 mL) The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to PH 5 with HCl (3 N). The product were collected by filtration to afford 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (120.0 mg, 80%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH:19][C@@H:20]1[C:32]2[C:24](=[CH:25][C:26]3[O:30][CH2:29][O:28][C:27]=3[CH:31]=2)[C@@H:23]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([OH:41])=[C:35]([O:42][CH3:43])[CH:34]=2)[C@@H:22]2[C:44](=[O:47])[O:45][CH2:46][C@@H:21]12>ClCCl>[C:9](=[O:10])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:41][C:36]1[C:35]([O:42][CH3:43])=[CH:34][C:33]([C@H:23]2[C@@H:22]3[C:44](=[O:47])[O:45][CH2:46][C@H:21]3[C@H:20]([OH:19])[C:32]3[C:24]2=[CH:25][C:26]2[O:30][CH2:29][O:28][C:27]=2[CH:31]=3)=[CH:38][C:37]=1[O:39][CH3:40]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
0.55 mmol of triethylamine and 0.37 mmol of benzyl chloroformate are added in succession to a solution of 0.25 mmol of (5R,5aS,8aS,9S)-9-hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one in 10 ml of anhydrous dichloromethane at 0° C. and under argon. After stirring for 1 hour, the reaction mixture is washed with water. The organic phase is then dried, filtered and subsequently concentrated under reduced pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 60/40) enables the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[C:37]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:36]=[C:37]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2)c1
Yield: 88.3 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (84 mg, 0.19 mmol) in CH3CN (5 ml) was added 1-Bromomethyl-3,5-di-tert-butyl-benzene (80.0 mg, 0.28 mmol), and diisopropylethylamine (66 μl, 0.38 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (109 mg, 85%). Calcd for C41H54F3NO2 (M+H) 649.87, Found 650.5
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([NH:9][NH:10][C:11]([CH2:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1)=[O:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.[CH:45]([C:47]1[S:51][C:50]([NH:52][C:53](=[O:55])[CH3:54])=[CH:49][CH:48]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:53]([NH:52][C:50]1[S:51][C:47]([CH:45]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][C:11]([NH:10][NH:9][C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])=[O:12])=[CH:39][CH:38]=2)=[CH:48][CH:49]=1)(=[O:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(C=O)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C=Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
{4-[2-(tert-Butoxycarbonyl)hydrazinocarbonylmethyl]benzyl}(triphenyl)phosphonium chloride (2.97 g, 5.29 mmol) was suspended in anhydrous tetrahydrofuran (8 ml), and cooled to −78° C. n-Butyllithium (1.6M-hexane solution, 3.3 ml, 5.3 mmol) was added dropwise, and the mixture was stirred at −78° C. for 15 mins and at 0° C. for 2 hrs. A solution of N-(5-formylthiophen-2-yl)acetamide (280 mg, 1.65 mmol) in anhydrous tetrahydrofuran (2 ml) was added dropwise, and the mixture was warmed to room temperature. After stirring at room temperature overnight, saturated aqueous ammonium chloride solution was added. The mixture was extracted with dichloromethane and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3→80:20) to give tert-butyl 2-({4-[2-(5-acetylaminothiophen-2-yl)vinyl]phenyl}acetyl)hydrazinecarboxylate (192 mg, yield 28%, E/Z mixture) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[C:24](Cl)(=O)[CH2:25][CH:26]([CH3:28])[CH3:27].C(=O)=O>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:24]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:1][C:2]=2[CH:10]=1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)Cc1nc2cc(Cl)ccc2c(=O)o1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with an overhead stirrer, thermometer, dropping funnel, cooling bath and condenser was charged with 406.41 g of 2-amino-4-chlorobenzoic acid (1 eq.), 270 g (1.35 eq.) of sodium bicarbonate, Na2SO4 (as a dehydrating agent) and 1,000 mL of THF. After commencing agitation, 354.7 g (1.2 eq.) of isovaleryl chloride was added dropwise. The reaction was exothermic and generated a gas (CO2). Temperature was maintained around 20–30° C. and completion of the reaction monitored by TLC (EtOAc/hexanes 1:1). The reaction mixture was then filtered and washed with THF (1,000 mL) the majority of which was then stripped off under vacuum. Acetic anhydride (1,450 mL) was then added to the reaction vessel and the temperature raised to 90–100° C. Completion of the reaction monitored by TLC (EtOAc/hexanes 1:1). The acetic anhydride was removed under vacuum at 80–100° C., followed by cooling to 60° C. The reaction vessel was then charged with heptane (1,000 mL) and cooled to 0° C. with stirring. The resulting precipitate was isolated by filtration and then washed with heptane (300 mL) and dried in a vacuum oven at 30° C. overnight to afford the title product (507 g, 90% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.C(O)C.C(=O)(O)[O-].[Na+].[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>ClCCl.O.C(Cl)Cl.CO.C1(C)C=CC=CC=1>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10](=[O:12])[NH:9][CH:8]=[CH:7]3)=[CH:23][CH:22]=1
Reactant: O=c1[nH]ccc2cccc(Br)c12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1[nH]ccc2cccc(-c3ccncc3)c12
Temperature: 130 °C
Yield: 46.9 %

Procedure:
A reaction tube was charged with 8-bromoisoquinolin-1(2H)-one (1 g, 4.46 mmol) and a mixture of 3 mL of ethanol and 3 mL of toluene under argon. To this, an aqueous sodium bicarbonate solution (2 M, 710 mg, 3.35 mL, 6.69 mmol) was added and then pyridin-4-ylboronic acid (549 mg, 4.46 mmol). Then, tetrakis(triphenyl-phosphine)palladium (516 mg, 4.46 mmol) was added. The reaction mixture was heated in a Biotage microwave at 130° C. for 30 min. The reaction was monitored by TLC (DCM/methanol=9:1). After completion of the reaction, the reaction mixture was mixed with water and dichloromethane. The solid was sucked off. The organic phase was washed with an aqueous NaHCO3 solution, brine, dried (MgSO4) and evaporated. The residue was taken up with EA and the precipitate was sucked off. The crude product was purified by chromatography (Campanion normal phase, gradient elution, using 3-10% DCM in methanol) to yield 465 mg (46.9%) of the title compound.
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)cnc2c1C
Product: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)cnc2c1C
Temperature: 110 °C
Yield: 88 %

Procedure:
To ethyl 2-hydroxy-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (1.05 g, 3.50 mmol, 1 eq.) was added POCl3 (11 ml) at RT and the reaction mixture was heated to reflux at 110° C. for 3 h. Afterwards excess POCl3 was distilled off and the residue was diluted with EtOAc (50 ml). The mixture was washed with a sat. solution of NaHCO3 (50 ml), water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated to provide ethyl 2-chloro-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.98 g, 3.08 mmol, 88%), which was used in subsequent reactions without further purification.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[NH:11][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[NH:11][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][CH:8]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
(S)-tert-Butyl 2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (537 mg, 1.61 mmol) was dissolved into MeOH (20 mL) and then potassium carbonate (22 mg, 0.16 mmol) was added and the reaction was stirred at rt for 3 h. The reaction was concentrated, dissolved into dichchloromethane, loaded onto a SiO2 column and purified by BIOTAGE® Horizon (30-50% EtOAc/hexanes) to yield (S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (346 mg, 1.32 mmol, 82% yield) as an off-white solid. LC-MS retention time 0.878 min; m/z 260.35 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.17 (m, 1H), 4.92-4.87 (m, 1H), 3.43-3.30 (m, 2H), 3.05 (s, 1H), 3.03-2.85 (m, 1H), 2.20-1.88 (m, 3H), 1.60-1.45 (m, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55][NH:56][CH3:57])=[CH:47]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[N:56]([CH2:55][C:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[NH:46][CH:47]=1)[CH3:57])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)N(C)Cc4c[nH]c5ccccc45)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) are reacted with (1H-Indol-3-ylmethyl)-methyl-amine [36284-95-4] to afford the title compound as a colourless oil. Rf=0.20 (EtOAc-heptane 2:1); Rt=5.23.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[CH:15][C:14](N)=[N:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)O.[Br-:31].[Na+].Br>O.C(#N)C>[Br:31][C:14]1[CH:15]=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)[N:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: [Br-]
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Agent: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CSc1ccc(-c2cc(Br)nn2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of sodium nitrite (0.26 g) in water (0.3 ml) was added to an ice-salt cooled mixture of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3-pyrazolamine (1 g), acetonitrile (1 ml), sulfuric acid (0.6 ml) and water (1.6 ml). The mixture was stirred at 0° C. for 30 minutes. The resulting mixture was added portionwise to a mixture of cuprous bromide (645 mg), sodium bromide (582 mg), hydrobromic acid (1.7 ml) and water (3 ml) at 80° C. The mixture was stirred at 80° C. for 30 minutes and extracted with toluene. The extract was washed with water, dried, and evaporated in vacuo. The obtained residue was purified by column chromatography on silica gel (10 g) to give crystals of 3-bromo-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (0.35 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:42][C:43]1[O:44][C:45](=[O:49])[O:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:48][C:47]1[O:46][C:45](=[O:49])[O:44][C:43]=1[CH2:42][O:37][C:36](=[O:38])[CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Yield: 32.3 %

Procedure:
A solution of 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (450 mg, 0.82 mmol), 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (146 mg, 0.99 mmol) and potassium carbonate (170 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (175 mg, yield 32%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([OH:7])=O.Cl.[CH3:17][N:18](C)[CH2:19][CH2:20][CH2:21]N=C=NCC.ON1C2C=CC=CC=2N=N1.CNCCC.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]=1[F:11])[C:5]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:7]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(Br)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(Br)c(F)c(S(C)(=O)=O)c1

Procedure:
Mix 3-bromo-4-fluoro-5-methanesulfonylbenzoic acid (1.6 g, 5.04 mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (968 mg, 5.04 mmol) and 1-hydroxybenzotriazole (680 mg, 5.04 mmol) in DMF (20 mL) at room temperature for 20 min. Add methyl-propylamine (368 mg, 5.04 mmol) and triethylamine (520 mg, 15.1 mmol) and stir at room temperature for 1 h. Dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride, concentrate and purify (silica gel chromatography, eluting with 10:90 to 50:50 ethyl acetate:hexanes) to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:26]1[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Agent: Cl
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride hydrochloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 426(M+1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:17]=[N+:18]([CH3:20])[CH3:19].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(C)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:40][S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])=[O:27])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1cccc(F)c1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)c2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 3-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.86 (1H, br.s), 8.51 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.6 Hz), 8.14–8.08 (1H, m), 7.98–7.91 (1H, m), 7.89–7.81 (1H, m), 7.73 (2H, d, J=8.3 Hz), 7.61–7.50 (1H, m), 7.42 (2H, d, J=8.3 Hz), 7.40–7.30 (1H, m), 7.21–7.08 (4H, m), 5.37–5.24 (1H, m), 1.57 (3H, d, J=6.8 Hz); MS (ESI) m/z 572 (M+H)+, 570 (M−H)−.