Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: Fc1cc(Br)c2occc2c1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2cc(F)cc3ccoc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To the compound (210 mg, 0.977 mmol) of Step 1, 4-hydroxyphenylboronic acid (162 mg, 1.17 mmol), sodium carbonate (228 mg, 2.15 mmol), and Pd(dppf)Cl2 (catalytic amount), 1,4-dioxane (1.2 mL) and water (0.4 mL) were added, and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.CC(C)=O>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 165 h

Procedure:
A solution of ethyl DL-phenylglycinate (5.00 g., 28 mmole) and (+)-tartaric acid (4.18 g., 28 mmole, 1 equiv.) in ethanol (50 ml.) was made at 58°. The solution was cooled, acetone (4.1 ml., 55.6 mmole, 2 equiv.) was added and the mixture was stirred at 20° to 25° for 165 hours. The solid was filtered off, washed with ethanol (2 × 10 ml.) and dried at 26°/2 mm. for 41/2 hours to give ethyl D-phenylglycinate (+)-hemitartrate as a monoethanol solvate (9.338 g., 89%), [α]D -46.5° (c 2.5 H2O).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([O:23]C)=[O:22])[CH:16]=[CH:17][C:18]=1[OH:19]>CO.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isopropylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isopropylbenzyl chloride with methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 146.5°-148° C. in a methanol-water 2:1 mixture.
Reaction SMILES: S(Cl)(Cl)=O.O1CCN(CC2C=CC(C(Cl)=O)=CC=2)CC1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([N:58]=[C:59]=[S:60])=[O:57])=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>C1(C)C=CC=CC=1.C(O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:59]([NH:58][C:56](=[O:57])[C:53]2[CH:52]=[CH:51][C:50]([CH2:49][N:46]3[CH2:45][CH2:44][O:43][CH2:48][CH2:47]3)=[CH:55][CH:54]=2)=[S:60])=[CH:38][CH:37]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(CN2CCOCC2)cc1
Agent: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CN5CCOCC5)cc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C)C=O>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (934 mg, 0.0358 mol) in DMF (57 mL) was added dropwise under N2, a solution of 1H-pyrrolo[2,3-b]pyridine (3.00 g, 0.0254 mol) in DMF (20 mL). The mixture was stirred at r.t. for 45 min. then cooled to 0° C. and treated dropwise with [2-(trimethylsilyl)ethoxy]methyl chloride (6.32 mL, 0.0357 mol). The mixture was stirred at rt for 12 h. then poured into water (10 mL), stirred for 30 min. and extracted with Et20 (4×10 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product which was chromatographed over silica gel eluting with hexane→1:9 Et2O: hexane to afford 6 g desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([O:47]S(C)(=O)=O)[C:44]=1[O:45][CH3:46])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl.O1CCOCC1>ClCCl.ClCCl.CO.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([OH:47])[C:44]=1[O:45][CH3:46])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OS(C)(=O)=O)c4)C3)CC2)nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(O)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium carbonate (0.5 g). After 18 hours, add a 1 M aqueous sodium hydroxide solution (1 mL) and extract with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to give a residue. Combine the residue and dichloromethane (4 mL). Add a solution of hydrochloric acid in dioxane (0.12 mL, 4 M, 0.48 mmol). Warm to ambient temperature. After 1 hour, evaporate in vacuo to give a residue. Triturate with diethyl ether to give a solid. After 1 hour, collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH3:28][NH:29][O:30][CH3:31].Cl>ClCCl.O>[CH3:31][O:30][N:29]([CH3:28])[C:11]([CH2:10][CH2:9][C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])=[O:13]
Reactant: CNOC
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 34.6 %

Procedure:
3-Benzoylpropionic acid (3.56 g, 20.0 mmol) was dissolved in dichloromethane (50 mL), to the solution was added triethylamine (2.22 g, 22.0 mmol) and trimethylacetyl chloride (2.41 g, 20.0 mmol) at 0° C., and the mixture was stirred at room temperature for 60 hours. Subsequently, to the reaction mixture was successively added triethylamine (4.04 g, 40.0 mmol) and N,O-dimethylhydroxylamine (1.95 g, 20.0 mmol), and the mixture was further stirred at room temperature for 5 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform/methanol=50/1→40/1) to give 3-(N-methoxy-N-methylcarbamoyl)-propiophenone (1.53 g, 35%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:43]=[CH:44][C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:39][CH:40]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(Cn2cncn2)cc1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]([NH:22][C:23]([C:25]2[NH:29][C:28]3[S:30][C:31]([Cl:33])=[CH:32][C:27]=3[CH:26]=2)=[O:24])[C:13]1=[O:34])(O)=[O:9].CCN=C=NCCCN(C)C.CN(C=O)C>CN(C)C1C=CN=CC=1.C1COCC1.O>[Cl:33][C:31]1[S:30][C:28]2[NH:29][C:25]([C:23]([NH:22][CH:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]([CH2:11][C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[C:13]3=[O:34])=[O:24])=[CH:26][C:27]=2[CH:32]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1Cc2ccccc2N(CC(=O)N2CCC(O)CC2)C1=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
4-Dimethylaminopyridine (5 mg, 0.038 mmol) and 4-hydroxypiperidine (42 mg, 0.41 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 150 mg, 0.38 mmol) and EDCI (79 mg, 0.41 mmol) in THF (0.5 mL) under an inert atmosphere. DMF (0.5 mL) was added and the mixture stirred at ambient temperature for 18 h. After pouring into water (10 mL) the resultant solid was filtered off and washed with 1M HCl aq. and water. Chromatography on silica gel (eluent gradient of CH2Cl2 to MeOH:CH2Cl2 (1:9)) afforded the title compound (109 mg, 59%) as an off white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[C:25](=[O:40])[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][CH2:38]O)[N:28]=2.[O-]S([O-])(=S)=O.[Na+].[Na+].Cl.[C:49]1([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C1COCC1.CCOCC.ClCCCl.CS(C)=O>[F:23][C:24]1[C:25](=[O:40])[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:62]1[CH2:61][CH2:60][N:59]([C:49]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=[CH:51][CH:50]=3)[CH2:64][CH2:63]1)[N:28]=2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=c1[nH]c2nc(OCCCCO)ccc2cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CCOCC
Product: O=c1[nH]c2nc(OCCCCN3CCN(c4cccc5ccccc45)CC3)ccc2cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a suspension of Dess-Martin periodinane (0.79 g, 1.86 mmol, 1.2 eq) in CH2Cl2 (20 mL) was added a solution of 3-fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (0.39 g, 1.5 mmol) in THF (6 mL)/DMSO (2 mL). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with Et2O (100 mL) and quenched with aqueous NaHCO3 (20 mL) containing Na2S2O3 (1.66 g, 10.5 mmol, 7 eq). After extraction with Et2O (3×40 mL), the combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give the crude aldehyde as a pale yellow solid. To a solution of the aldehyde in 1,2-dichloroethane (20 mL) was added 1-naphthalen-1-yl-piperazine monohydrochloride (0.522 g, 2.1 mmol, 1.4 eq), Et3N (0.38 mL, 2.85 mmol, 1.9 eq) and NaBH(OAc)3 (0.445 g, 2.1 mmol, 1.4 eq). The mixture was stirred at room temperature for 1 h and quenched with water and saturated NaHCO3. After extraction with CH2Cl2 (3×50 mL), the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (3% MeOH/CH2Cl2) to give the title compound (430 mg, 62% in two steps). 1H NMR (400 MHz, δ ppm): 12.60 (br s, 1H), 8.10 (d, J=6.0 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.85 (m, 2H), 7.60 (d, J=6.0 Hz, 1H), 7.50 (m, 2H), 7.40 (d, J=6.0 Hz, 1H), 7.10 (d, J=6.0 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 4.35 (t, J=4.0 Hz, 2H), 3.00 (br s, 4H), 2.60 (br s, 4H), 2.40 (t, J=3.8 Hz, 2H), 1.80 (m, 2H), 1.60 (m, 2H); 19F NMR: −140 ppm; MS: 447 (M+H)+ (Exact Mass: 446.21).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:13][C@H:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:11][C@H:12]([OH:14])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc([C@H]2C[C@H](O)C2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc([C@H]2C[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of trans-3-(4-nitrophenyl)cyclobutanol (step 3, 1.0 g, 4.9 mmol) in methanol (20 mL) was added 10% Pd—C (50 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 2.5 h. The palladium catalyst was removed by filtration and washed with methanol (100 mL) and ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to afford 0.9 g (quant.) of the title compound as pale yellow solids: MS (EI) m/z 163 (M+); 1H-NMR (CDCl3) δ 7.03 (2H, d, J=8.3 Hz), 6.66 (2H, d, J=8.3 Hz), 4.56-4.47 (1H, m), 3.58-3.48 (3H, m), 2.48-2.31 (2H, m), 1.73 (1H, d, J=5.1 Hz).
Reaction SMILES: C([O-])C.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:17]3[NH:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[CH:8][CH:7]=1.ClCCl.CO>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:17]3[C:14](=[O:13])[NH:15][N:16]=2)=[CH:8][CH:7]=1
Reactant: Brc1ccc(-c2nnc(-c3ccc[nH]3)o2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(Br)cc2)n2cccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 0.469 g sodium ethanolate (6.89 mmol) dissolved in 20 ml ethanol was added 1.0 g 2-(4-bromophenyl)-5-(1H-pyrrol-2-yl)-1,3,4-oxadiazole (3.45 mmol) at room temperature under nitrogen and the mixture was stirred at room temperature for 5 minutes. The reaction was heated at 160° C. for 2 hours in a microwave (Biotage Initiator 2.5). The reaction was monitored by TLC dichloromethane/methanol=9/1. Additional equivalents of sodium ethanolate were added and additional heating was carried out until completion of the reaction according to TLC. The reaction mixture was concentrated under reduced pressure and adsorbed on silica gel. The product was purified by silica gel chromatography (gradient: cyclohexane/ethylacetate=0-100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.85-7.78 (m, 2H), 7.76-7.69 (m, 2H), 7.39 (dd, J=1.3, 2.9, 1H), 7.16 (dd, J=1.4, 3.8, 1H), 6.77 (dd, J=2.9, 3.8, 1H). 13C NMR (400 MHz, DMSO-d6) δ 154.22, 136.46, 131.98, 130.90, 129.52, 124.07, 124.00, 118.80, 114.42, 111.01.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([I:1])=[CH:17][N:18]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1ccc2nccn2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2ncc(I)n2c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
10.7 g N-iodosuccinimide was added in divided portions to 100 mL solution of 9 g 6-bromoimidazo[1,2-a]pyridine in N,N-dimethylformamide, and the mixture was stirred for 2 hours. An aqueous sodium thiosulfate solution was added thereto and stirred for 1 hour, water was added thereto, and the formed crystals were collected by filtration. The product was recrystallized from tetrahydrofuran/ethanol to give 13.5 g of the title compound (colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:15][C:16](=[O:17])[CH3:18])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
A mixture containing 45 g of ethyl 4-chlorobenzoate in 235 ml of anhydrous THF and 19.50 g of NaH (60% in mineral oil) in 235 ml of anhydrous THF is placed under nitrogen. 36 ml of acetone and 750 ml of additional anhydrous THF are added dropwise at 0° C., and it is heated under reflux for 3 hours. The mixture is acidified to pH=5 by addition of 2N HCl then it is extracted with ether and washed with water and then with saturated NaHCO3 solution; it is dried over MgSO4 and concentrated. The raw product is dissolved in a minimum of toluene, the insoluble matter is filtered then it is purified by chromatography on silica, eluting with cyclohexane/AcOEt mixture (95/5; v/v). 47.9 g of the expected compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:14]2[C:13](=[O:15])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)nc1
Agent: [K]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 160 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-chloromethylpyridine (8.1 g, 0.05 mol) and potassium phthalimide (10.2 g, 0.055 mol) were mixed together at ambient temperature (20° C.) and the resulting mixture was then heated with stirring at 160° C. for 12 hours. The reaction mixture was then cooled to ambient temperature (20° C.) and dichloromethane was added until most of the solid residue had dissolved. The dichloromethane extract was then washed with water (2×150 ml) and brine (1×200 ml), dried using magnesium sulphate, and evaporated under reduced pressure to give a light-brown solid. The title product, N-(6-chloro-3-pyridylmethyl) phthalimide, was isolated from this solid by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v ether/ dichloromethane as eluent, as a buff solid (10.70 g, 78.5%), mp 140° to 142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](Br)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:5]3[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=3[CH:16]=2)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5,7-dibromo-benzothiazol-2-yl)-3-ethyl-urea (1.60 g, 0.40 mmol) in DMF-H2O (2:1, 48 mL) was added pyridine-3-boronic acid (0.51 g, 0.42 mmol) and K3PO4 (0.90 g, 0.42 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for 30 min followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.35 g, 0.042 mmol). The reaction mixture was then again degassed for 30 min and heated at 120° C. for 1 h under nitrogen atmosphere. DMF was distilled off, water was added into reaction mixture and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified over silica (230-400 M) using ethyl acetate/hexane (gradient) to provide the desired compounds.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]([C:36]3[CH2:37][CH2:38][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1c(C2CCOCC2)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C2CCOCC2)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-ethyl 5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.