Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([F:16])[F:15]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in 25 mL DMF was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and 2.5 mL water. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 2.98 g (48%) of 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](OC)=[O:20])=[CH:14][C:13]=1[C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][C:13]=1[C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2cnn(C)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cn1cc(-c2cc(CCO)ccc2F)cn1
Reaction time: 0.25 h

Procedure:
A solution of diisobutylaluminium hydride in dichloromethane (1M, 35 mL) was added dropwise to a stirred solution of methyl 2-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate [Example 13, Step ii)] (3.36 g) in dichloromethane (15 mL) keeping temp of reaction mixture at gentle reflux. The mixture was stirred for 15 min. and carefully quenched by dropwise addition of MeOH (3 mL). The mixture was poured onto 2M HCl (100 mL) and extracted with a mixture DCM/MeOH (9:1, 5×50 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford 2-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethanol (2.2 g) that was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.78 (s, 1H), 7.39 (d, J=7.3 Hz, 1H), 7.09-7.02 (m, 2H), 3.97 (s, 3H), 3.88 (t, J=6.5 Hz, 2H), 2.87 (t, J=6.4 Hz, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[CH:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=3)[C:5]#[N:6])[CH:14]=2)[CH2:20][CH:21]1[CH3:24]
Reactant: N#Cc1cc(F)cc(CO)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3cc(F)cc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2-dimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:13][CH3:14])[CH3:2].[O:15]=[C:16]1[CH2:21][O:20][C:19]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)[CH:24]=[N:25][C:18]=2[NH:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:18]2[NH:17][C:16](=[O:15])[CH2:21][O:20][C:19]=2[CH:22]=1)[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CCc1c(CNC)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (3-ethylbenzofuran-2-yl)-N-methylmethanamine (115 mg, 0.6 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (140 mg, 0.54 mmol), 1-hydroxybenzotriazole (84 mg, 0.6 mmol), diisopropylethylamine (282 uL, 1.62 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (120 mg, 0.6 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a white solid (113 mg, 52%): 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.19 (s, 1H), 7.88 (d, J=6.4 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.51-7.49 (m, 2H), 7.29-7.25 (m, 3H), 4.99-4.79 (rotamers, 2s, 2H), 4.68 (s, 2H), 3.39 (s, 3H), 2.79-2.73 (m, 2H), 1.23-1.20 (m, 3H); MS (ESI) m/e 392 (C22H21N3O4+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH2:20]([O:27][CH2:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C@H:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[O:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[CH2:20]([O:27][CH2:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C@H:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([OH:34])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
22.2 ml of a 1.6M n-butyllithium solution in hexane are added to a solution of 5.1 ml of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under argon, while stirring. After 30 min, a solution, cooled to -78° C., of 2.5 ml of ethyl propiolate in 20 ml of tetrahydrofuran is added dropwise via a cannula. The yellow reaction solution is stirred at -78° C. for a further 1 h and 5.0 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexanal (Example 390) in 30 ml of tetrahydrofuran are then added dropwise. After the mixture has been stirred for 4.5 h, the reaction is quenched by addition of saturated aqueous ammonium chloride solution and the reaction mixture is allowed to warm to room temperature and is worked up in the customary manner. The crude product is purified by FC over silica gel (eluting agent C). The title compound is obtained as a mixture of the 4(S) and 4(R) diastereomers in a ratio of about (5.4:1): Rf (C)=0.28; FAB-MS: (M+H)+ =448.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][N:12]=1>O1CCOCC1.CC(OC)(C)C>[CH2:1]([O:7][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: C=CCCCCOc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
1.50 g (15 mmol) of 5-hexen-1-ol dissolved in 30 ml of dioxane were mixed with 600 mg (60%, 15 mmol) of sodium hydride and stirred at room temperature for 30 minutes. Addition of 1.7 g (7.5 mmol) of 2-chloro-4,5-diphenylpyrimidine was followed by stirring at room temperature for 6 hours. Taking up in MTBE and washing with saturated NaCl solution were followed by drying over sodium sulfate and evaporation. The residue was purified on silica gel with heptane/ethyl acetate (15:1). 1.93 g (77%) of the desired product were obtained.
Reaction SMILES: [CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([O:7]CC(C1C=CC=CC=1)=O)=[O:6]>C(O)(=O)C.[Zn]>[CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of benzyl 2(S)-[N-methyl-N-(2-phenacyloxycarbonylethyl)aminocarbonyloxy]-3-phenylpropionate (1.0 g) in acetic acid (10 ml) was added zinc dust (1.0 g) portionwise at ambient temperature. After being stirred for 2 hours, zinc dust (0.2 g) was added thereto. The reaction mixture was stirred overnight at the same temperature and filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and 0.5N hydrochloric acid (30 ml). The organic layer was extracted with 1N sodium hydroxide solution (20 ml×3). The combined aqueous extract was acidified to pH 2 with 1N hydrochloric acid and extracted with chloroform (50 ml×3). The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)aminocarbonyloxy]-3-phenylpropionate (543 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1cccc(F)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 30 mg. 1H NMR (CD3OD, TFA salt) δ (ppm):7.56 (s, 1H), 7.50 (m, 2H), 7.40 (d, 1H), 7.22 (s, 2H), 7.15 (m, 1H), 7.05 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][CH:32]=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:35]2[C:36]([CH3:38])([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Reactant: CC1(C)CCCC=C1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1ccc(C2=CCCCC2(C)C)cc1
Yield: 69 %

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (3.20 g, 7.28 mmol) and 6,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (1.71 g, 6.62 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane afforded the title compound (1.18 g) as a clear oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[O:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])(C)(C)C.C>C(OCC)(=O)C>[CH3:17][C:11]1[O:10][C:9]([S:6](=[O:8])(=[O:7])[NH2:5])=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=1
Reactant: Cc1cc(C(=O)O)c(S(=O)(=O)NC(C)(C)C)o1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)c(S(N)(=O)=O)o1
Yield: 92.6 %

Procedure:
Boiling stones and 42 gm (0.12 mol) of 2-(N-tert. butyl)sulfamoyl-5-methyl-furan-3-carboxylic acid were heated in a round bottom flask for 2 hours at 150° C. The cooled reaction mixture was taken up in 1 liter of ethyl acetate. After refluxing the solution was treated with activated charcoal, filtered and evaporated. 22.8 gm (69% of theory) of crystalline 5-methyl-2-sulfamoyl-furan-3-carboxylic acid were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19]C)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Na+].Cl>CO.[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)[C@@H](NC(=O)Cc1cc(F)cc(F)c1)C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reaction time: 2 h

Procedure:
A solution of methyl N-[(3,5-difluorophenyl)acetyl]-L-valinate (107a) in methanol (10 mL) was treated with 1N sodium hydroxide solution (2 mL) and stirred for 2 h. At the end of this period the reaction mixture was acidified with 1N hydrochloric acid solution, diluted with saturated sodium chloride and extracted with dichloromethane (100 mL). After drying over anhydrous magnesium sulfate and concentration under reduced pressure the organic layer afforded the title compound (210 mg). 1H NMR (300 MHz, CDCl3)) δ 0.87 (m, 3H), 2.05 (m, 1H), 3.58 (m, 2H), 4.15 (t, 1H, J=8 Hz), 7.07 (m, 3H), 8.30 (m, 1H), 12.61 (s, 1H). MS APCI, m/z=226(M+1) LC/MS: 1.84 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(C)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.0 g, 12.0 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (23.45 g, 72 mmol) and methyl iodide (17.03 g, 120 mmol) at 0° C. After stirring at room temperature for 3 hours the reaction mixture was cooled to 0° C. and acidified to pH 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane/AcOH=1:1:1) to give the product (1.24 g, 39.1%). 1HNMR (400 MHz, DMSO-d6) δ9.12 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 5.44 (dd, J=9.23, 2.49 Hz, 1H), 3.93-4.08 (m, 2H), 3.73 (s, 3H), 3.08 (dd, J=15.24, 2.64 Hz, 1H), 2.10-2.31 (m, 4H), 1.05-1.19 (m, 3H).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>ClCCl>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[N:9][C@H:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1])[CH3:16]
Reactant: CCOC(=O)C=O
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Treat a solution of neat (S)-α-methylbenzylamine (7.5 mL, 59 mmol) in dichloromethane (300 mL) at 0° C. with ethyl glyoxalate solution (50% in toluene, 11.5 mL). Add 4Å molecular sieves (20 g) to the above solution. Stir the reaction mixture at 0° C. for 2 h. Filter the solids off, concentrate and purify (silica gel chromatography, eluting with 20:80 to 70:30 ethyl acetate:hexanes) to give the title compound (11.1 g, 97%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=2.C(OC1C=C2C(=CC=1)NC(C)=C2/C=[CH:31]/[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33])C>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1/[CH:11]=[CH:31]/[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33])=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=2
Reactant: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Reactant: CCCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: CCCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 69 %

Procedure:
2-Methyl-5-propoxyindole-3-carboxaldehyde 409b (200 mg, 0.920 mmol) was reacted in a similar manner to that for 402a to yield a bright yellow powder (204 mg, 69%): mp 228-229° C. TLC Rf 0.40 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.81-8.80 (m, 2H), 8.08-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=2.22 Hz), 7.34-7.31 (d, 1H, J=15.24 Hz), 7.30-7.29 (d, 1H, J=8.64 Hz), 6.85-6.83 (dd, 1H, J1=8.64 Hz, J2=2.28 Hz), 4.04-4.02 (t, 2H, 6.54 Hz), 2.56 (s, 3H), 1.80-1.74 (sex, 2H, J=6.66 Hz), 1.03-1.01 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.2, 154.6, 150.6, 145.75, 145.18, 139.6, 131.0, 126.6, 121.4, 112.90, 112.25, 111.4, 109.3, 104.4, 69.6, 22.3, 12.2, 10.6. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.00; H, 6.23; N, 8.69.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29](I)=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]2[CH:28]=[C:25]([C:26]#[N:27])[C:24]([Br:23])=[CH:31][C:30]=2[O:32][CH3:33])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(Br)c(C#N)cc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(C#N)c(Br)cc1OC
Temperature: 110 °C
Yield: 92.3 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (625 mg, 1.994 mmol, made via Method 42, Steps 1-2), 2-bromo-5-iodo-4-methoxybenzonitrile (809 mg, 2.393 mmol), Xantphos (57.7 mg, 0.100 mmol), Pd2(dba)3 (45.7 mg, 0.050 mmol), and cesium carbonate (1624 mg, 4.99 mmol) were added. A reflux condenser was attached, and the flask was heated to 110° C. overnight. The mixture was cooled, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The residue was taken up in 2-PrOH, and the mixture was heated to boiling briefly then sonicated for 30 s. When the mixture had returned to room temperature, it was filtered; and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-cyano-2-methoxyphenyl)amino)phenyl)acrylate (963 mg, 1.840 mmol, 92% yield) as a bright-yellow solid. m/z (ESI) 545.0 (M+Na)+.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8]>ClCCl>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C1=Cc2ccc(O)cc21

Procedure:
1000 ml of a 1-molar solution of boron tribromide in dichloromethane are poured over 19.5 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and the whole is heated at reflux for 6 hours. The whole is concentrated to dryness by evaporation and extracted by shaking with a mixture of 2000 ml of dichloromethane and 1000 ml of water and the organic phase is separated off, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. 5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of white crystals having a melting point of 108°-109° (from ether/hexane).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])=[CH:4][C:3]=1[CH3:30].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([CH3:51])[C:49]=1[F:50])[CH2:45]Br>C1COCC1>[F:50][C:49]1[C:48]([CH3:51])=[CH:47][C:44]([CH2:45][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]2[CH:28]=[CH:29][C:2]([F:1])=[C:3]([CH3:30])[CH:4]=2)[C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])=[CH:43][C:42]=1[CH3:41]
Reactant: Cc1cc(COCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Reactant: Cc1cc(CBr)cc(C)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a cooled (−78° C.) solution of (R)-3-(6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one (0.220 g, 0.532 mmol) in 5 mL of THF, was added LiHMDS (0.80 mL, 0.80 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (0.346 g, 1.596 mmol) in 3 mL of THF was added. After stirring at −78° C. for 1 h the reaction mixture was warmed to room temperature for 2 h, and then quenched with 20 mL of NH4Cl solution and extracted with dichloromethane (20 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.106 g, 36% yield). GC-MS: tR=15.6 min; m/z 549 (M+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[N:9]([C:10]=1[CH2:11][CH3:12])[CH:8]=[CH:7][S:6]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[CH2:11]([C:10]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[CH2:2][N:24]1[CH:23]=[CH:22][N:21]=[C:20]1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[N:15]=1)[CH3:12]
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCc1c(CCl)nc2sccn12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCc1c(Cn2ccnc2-c2cccc(F)n2)nc2sccn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 16.3 %

Procedure:
A mixture of 6-chloromethyl-5-ethyl-imidazo[2,1-b]thiazole (120 mg, 0.6 mmol), 2-fluoro-6-(1H-imidazol-2-yl)pyridine (82 mg, 0.6 mmol) and potassium carbonate (278 mg, 2.4 mmol) in DMF (6 mL) is stirred at room temperature for 48 h. Brine (15 mL) and methylene chloride (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with methylene chloride (2×20 mL). The combined organic layers are washed with brine (3×15 mL) and dried. The solvent is removed in vacuo. The residue is purified by preparative TLC to give 32 mg of 5-ethyl-6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-imidazo[2,1-b]thiazole as an oil. 1H NMR (CDCl3): 8.10, dd (1H); 7.82, dd (1H); 7.35, d (1H); 7.26, d (1H); 7.12, d (1H); 6.83, dd (1H); 6.80, d (1H); 5.92, s (2H); 2.90, q (2H); 1.07, t (3H).