Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1/[CH:29]=[CH:30]/[C:31](Cl)=[O:32]>C(Cl)Cl>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[CH:30][C:31]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1)=[O:32]
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Anhydrous pyridine (0.331 g, 4.2 mmol, 1.2 eq) and ethyl 4-aminobenzoate (0.577 g, 3.50 mmol) were added to a solution of (E)-3-(2-naphthyl)propenoyl chloride (prepared from its corresponding acid) (0.757 g, 3.50 mmo) in anhydrous DCM (15 ml) under Ar. After stirring overnight at room temperature, the white precipitate was filtered, washed with DCM (10 ml) and dried under vacuum to give the amide 42 (0.960 g, 2.78 mmol, 80%) as a white solid, mp 173-175° C. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (3H, t, J 7.2 Hz), 4.28 (2H, t, J 7.2 Hz), 6.97 (1H, d, J 15.4 Hz), 7.54-7.57 (2H, m), 7.7 (1H, d, J 15.4 Hz), 7.77 (1H, dd, J 1.6, 9.2 Hz), 7.84 (2H, d, J 8.8 Hz), 7.93-7.97 (5H, m), 8.15 (1H, s), 10.58 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 14.88, 61.09, 119.30, 122.91, 124.18, 124.99, 127.47, 127.83, 128.38, 129.09, 129.36, 130.05, 130.98, 132.82, 133.68, 134.26, 141.64, 144.33, 164.69, 166.01. νmax (solid)/(cm−1) 3357, 1702, 1660, 1619, 1607, 1591, 1521, 1403, 1282. MS (API-ES): m/z 346 [M+H]+ (100%), HRMS (API-ES) m/z found 346.1443 [M+H]+.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C[N:10]1[CH2:14][C@@H:13]([CH3:15])[C@@:12]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([C:16](=[O:30])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[CH2:11]1>[OH-].[Pd+2].[OH-].CO>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:16]([C@:12]2([CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:13]([CH3:15])[CH2:14][NH:10][CH2:11]2)=[O:30])[CH2:23][CH2:22]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3Cl)C[C@H]2C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CNC[C@H]2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methanol (10 ml) and 20% palladium hydroxide (50 mg) were added to 250 mg of tert-butyl 2-[(3R*,4S*)-1-[(2,6-dichlorophenyl)methyl]-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate obtained in Example 10h, followed by stirring at room temperature for two hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (180 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].FC(F)(F)C(O)=O.[F:30][C:31]([F:44])([F:43])[C:32]1[S:36][C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:34][N:33]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:19])([F:20])[F:18])=[C:9]([C:10]([N:40]2[CH2:39][CH2:38][N:37]([C:35]3[S:36][C:32]([C:31]([F:43])([F:30])[F:44])=[N:33][N:34]=3)[CH2:42][CH2:41]2)=[O:11])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1
Yield: 56 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid (Example A30) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as an off-white solid (yield 56%). MS (m/e): 569.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[CH:8]=1)=[O:5].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a suspension of ethyl 5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 122A, 58.3 g, 0.117 mol) in IMS (580 mL), was added 2M aqueous sodium hydroxide solution (176 mL, 0.352 mol) and the reaction stirred at room temperature for 5 hours. The reaction mixture was diluted with water (600 mL) and acidified to pH1 with hydrochloric acid solution (40 mL, 36%). The resulting solid was filtered and washed with water (50 mL) to give the title compound as a white solid (53.1 g, 97%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH3:26])=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-(5-benzylbenzofuran-2-yl)-3-fluorobenzaldehyde (0.559 g, 2 mmol) in THF at 0° C. was added methyl-magnesium bromide (1.4M solution in toluene/THF=3:1, 2.40 mL, 3 mmol) dropwise over 5 min. The mixture was allowed to stir for 20 min at 0° C., treated with NH4Cl, extracted with EtOAc, dried over MgSO4, and evaporated. The crude product was purified by flash chromatography (EtOAc/hexanes) to give 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanol. 1H NMR (300 MHz, CDCl3) δ ppm 7.98 (t, J=8.0 Hz, 1H), 7.38-7.46 (m, 2H), 7.10-7.34 (m, 9H), 4.77-5.04 (m, 1H), 4.08 (s, 2H), 1.85 (d, J=3.8 Hz, 1H), 1.46-1.60 (m, 3H). MS (ESI) m/z: Calculated; 346.1 Observed: 347.1 (M++1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:7]>O1CCOCC1.O>[S:21]1[C:17]([C:15]2[CH:16]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]1=2
Reactant: COC(=O)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 65 °C
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (2.25 g, 53.5 mmol) was added to a suspension of methyl-7-benzo[b]thiophen-2-yl-1H-indazole-5-methanoate (3.37 g, 10.71 mmol) in a mixture of 1,4-dioxane (65 mL) and water (9 mL). The mixture was heated to about 65° C. for about 18 hours then cooled to about 40° C. and filtered. The filtrate was acidified with aqueous hydrochloric acid (1N, 54 mL) and the resulting precipitate was collected by filtration and dried under reduced pressure to give 7-benzo[b]thiophen-2-yl-1H-indazole-5-carboxylic acid (3.16 g, 100%); 1H NMR (DMSO-d6, 400 MHz) δ 13.56 (bs, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.14 (d, 1H), 8.04 (d, 1H), 7.94 (d, 1H), 7.45 (d, 2H); RP-HPLC (Table 1, Method e) Rt=1.06, m/z: (M−H)− 292.8.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[C:7]([Cl:6])[N:16]=3)=[CH:32][CH:33]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium acetate (0.65 g), 2,4-dichloroquinazoline (0.52 g) and 4'-aminomethyl[1,1'-biphenyl]-2-carboxylic acid methyl ester (0.73 g) were suspended in 25 mL of tetrahydrofuran. The reaction was stirred at room temperature for approximately 18 hours at which time the solvents were evaporated. The residue was loaded onto a silica gel column and the desired product was eluted with ethyl acetate/hexane (1:1). The yield was 0.75 g (71%) (m.p.=75°-90° C.): 1H NMR (DMSO-d6, 300 MHz) δ9.30 (t, J=6 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.60 (m, 3H), 7.45 (m, 4H), 7.25 (d, J=8.1 Hz, 2H), 4.80 (d, J=5.8 Hz, 2H), 3.58 (s, 3H); positive FAB MS m/e 404(MH). Anal. calcd for C23H18ClN3O2 : C, 68.40; H, 4.49; N, 10.40. Found: C, 68.09; H, 4.57; N, 10.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[OH-].[K+].I[CH3:15]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH3:11]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 5-fluoro-3-methyl-indole (CAS: 392-13-2, 2.5 g) in DMF (20 ml) was added potassium hydroxide (1.41 g). The suspension was stirred at rt for 1 h and iodomethane (2.85 g) was added dropwise at 0-5° C. The reaction mixture was stirred at rt for 18 h and concentrated under high vacuum. The residue was quenched with water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (2.15 g) as a colorless liquid. MS (EI): 163.1 (M)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1OCc1ccccc1
Yield: 79.07 %

Procedure:
To a suspension of 78 (3.1 g, 13.6 mmol) in dry toluene (150 ml)was added SOCl2 (12.9 g, 109.1 mmol). The mixture was reflux for 8 h and evaporated to give 83 as yellow liquid to use directly in the next step. (2.55 g, 10.3 mmol). Yield: 79.07%.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:16][S:17]([O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23](Br)[C:22]=1[CH:30]=[O:31])(=[O:19])=[O:18]>CN(C=O)C.C(OCC)(=O)C.[Cu]>[CH3:16][S:17]([O:20][C:21]1[C:22]([CH:30]=[O:31])=[C:23]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[C:9]=2[O:10][CH3:11])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])(=[O:19])=[O:18]
Reactant: COc1ccc(Br)c(C=O)c1OS(C)(=O)=O
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C=O)cc(OC)c(OC)c2OC)c(C=O)c1OS(C)(=O)=O
Temperature: 165 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a suspension of copper bronze (0.646 g, 10 mmol) in anhydrous DMF (2 mL) was added a solution of 2-bromo-3,4,5-trimethoxybenzaldehyde (0.80 g, 2.91 mmol) and 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate (0.30 g, 0.97 mmol) in anhydrous DMF (1 mL) and the suspension was stirred at 165° C. for 3 hours. TLC indicated the presence of unreacted 3-bromo-2-formyl-6-methoxyphenyl methanesulfonate and a further portion of 2-bromo-3,4,5-trimethoxybenzaldehyde (100 mg) was added. After a further 1 hour at 165° C. the reaction was complete and the reaction mixture was cooled and diluted with ethyl acetate (20 mL). The resulting suspension was filtered through Celite® (3 g) and the filtrate concentrated in vacuo. The residue was chromatographed over silica gel (70 g), eluting with hexane-ethyl acetate (gradient 2:1 to 1:1), followed by crystallisation (ethyl acetate) yielded 2,6′-diformyl-4,2′,3′,4′-tetramethoxybiphenyl-3-yl methanesulfonate (180 mg, 44%); m.p. 130-131° C.; Elemental Analysis Found: C, 53.7; H, 4.8; S, 7.8 (C19H20O9S requires C, 53.77; H, 4.75; S, 7.56%); NMR Spectrum δH (300 MHz, CDCl3) 10.18 (1H, s, 2-CHO), 9.63 (1H, s, 6′-CHO), 7.36 (1H, s, 5′-H), 7.26 (1H, d, J 8.4 Hz, 6-H), 7.15 (1H, d, J 8.4 Hz, 5-H), 4.03 (3H, s, OCH3), 3.98 (3H, s, OCH3), 3.57 (3H, s, OCH3), 3.43 (3H, s, SCH3); NMR Spectrum δC (100 MHz, CDCl3) 50.2, 56.5, 56.9, 61.2, 61.5, 106.2, 116.8, 127.5, 130.0, 130.7, 131.0, 132.1, 139.8, 147.6, 151.1, 152.6, 154.0, 189.3, 190.5; νmax/cm−1 (thin film) 2934, 2843, 1701, 1682, 1588, 1561, 1480, 1371, 1336, 1285, 1169, 1111, 1072; m/z (ES) 447 (MNa+, 100%), 379 (5); Rf (hexane-ethyl acetate 1:2) 0.20.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:15](=[O:18])[CH:16]=[CH2:17]
Reactant: COCCNc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N(CCOC)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 3, react N-(2-methoxyethyl)-4-nitrobenzenamine with propenoyl chloride to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][O:11][NH:12][CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[CH3:10][O:11][N:12]([CH3:13])[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 2-(thiophen-3-yl)acetic acid (2.0 g, 14.1 mmol), O,N-dimethyl-hydroxylamine(1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol), HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50 mL) was stirred at room temperature under nitrogen for two hours. The reaction mixture was diluted with CH2Cl2, and the organic layer was washed with aqueous HCl solution (0.5 mol/L1, 30 mL×2), saturated NaHCO3 (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([N:15]4[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][CH:17]=[N:16]4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[CH:20]([C:19]1[N:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)[N:16]=[CH:17][N:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)c1ncnn1-c1nc2c(s1)CCOc1ccc(-c3cn[nH]c3)cc1-2

Procedure:
Following the procedure for 484, Step 4, 9-bromo-2-(5-isopropyl-[1,2,4]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to afford 489 as a white solid. LCMS (Method C): RT=10.17 min, [M+H]+=379. 1H NMR (DMSO-d6): 12.95 (1 H, bs), 8.42 (1 H, d, J=2.3 Hz), 8.18 (1 H, s), 8.07 (1 H, bs), 7.81 (1 H, bs), 7.51 (1 H, dd, J=8.3, 2.3 Hz), 7.06 (1 H, d, J=8.3 Hz), 4.36 (2 H, t, J=5.0 Hz), 4.12-4.04 (1 H, m), 3.38 (2 H, t, J=5.0 Hz), 1.47 (3 H, s), 1.46 (3 H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[CH2:17](B(O)O)[CH3:18].C(Cl)Cl.[F-].[Cs+]>CN(C=O)C.O1CCOCC1>[CH2:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH3:18]
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Reactant: CCB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cccc2c1CCOC2C1=NCCN1
Temperature: 150 °C

Procedure:
To a mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (100 mg), ethylboronic acid (56.2 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with CH2Cl2 (1:1) (13 mg) and CsF (108 mg) was added dioxane (4 ml) and DMF (1 ml). The mixture was degassed with N2 and heated in a microwave oven for 30 min at 100° C. and 30 min at 150° C. The title compound was purified by separation methods J and G. (Yield 6.1 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][C:18]=1[CH3:34])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C.[ClH:36]>C(Cl)Cl.[Zn+2].[Br-].[Br-]>[ClH:36].[ClH:36].[CH3:33][O:32][CH2:31][CH2:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][NH2:7])=[C:18]([CH3:34])[CH:19]=1
Reactant: COCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2cccnc2)c(C)c1
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COCCCc1ccccc1-c1ccc(C(CN)Cc2cccnc2)c(C)c1

Procedure:
To a solution of tert-butyl{2-[2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]-3-pyridin-3-ylpropyl}carbamate from step 3 (1 eq.) in CH2Cl2 (0.1M) was added ZnBr2 (10 eq.). The mixture was sonicated for 30 min, filtered on a plug of silica gel. The latter was washed with CH2Cl2/MeOH (NH3 2M) 10% and the combined fractions were concentrated. The residue was purified by reverse phase HPLC (C18 column; gradient 40 to 90% of CH3CN/H2O/TFA 0.1%). Fractions containing the desired material were combined, concentrated, neutralized with NaOH (1N) and extracted with CH2Cl2. The combined extract was dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH2Cl2, acidified with HCl (4N in dioxane; 4 eq.) and the resulting suspension was triturated with addition of Et2O to afford after filtration the title compounds as a light yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 8.71 (d, 1H), 8.67 (s, 1H), 8.27 (br s, 3H), 7.98 (d, 1H), 7.56 (brt, 1H), 7.47 (d, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.28-7.22 (m, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 7.02 (s, 1H), 3.74-3.64 (m, 1H), 3.45 (brdd, 1H), 3.21-3.17 (m, 4H), 3.13 (s, 3H), 3.04 (dd, 1H), 2.61-2.50 (m, 2H), 2.08 (s, 3H), 1.65-1.55 (m, 2H).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(OC)=[O:2].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:1](=[O:2])[NH:21][CH2:20][C:13]=2[CH:14]=1
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN)C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC1Cc2ccc(OC)cc2CNC1=O
Yield: 76 %

Procedure:
A solution of methyl (±)-3-carbomethoxy-4-[2-(aminomethyl)-4-methoxyphenyl]butanoate (10 g, 24 mmol) and triethylamine (17 mL, 120 mmol) in toluene (100 mL) was heated at reflux for 18 hr. The reaction was then concentrated and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated to afford the title compound (4.8 g, 76%) as tan solid: MS (ES) m/e 264.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.P.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([CH3:20])=[O:19]>C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:17][C:18](=[O:19])[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Product: COc1ccc(CC(C)=O)cc1
Yield: 84 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (143.2 mg, 1.0 mmol), palladium cinnamyl chloride (7.9 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (24.5 mg, 0.060 mmol), Cs2CO3 (651.0 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 12 h. 1-(4′-Methoxyphenyl)-2-propanone (137.9 mg) was obtained with a yield of 84% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.15-7.07 (m, 2H, ArH), 6.92-6.82 (m, 2H, ArH), 3.79 (s, 3H, OCH3), 3.63 (s, 2H, CH2), 2.13 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 206.8, 158.5, 130.3, 126.1, 114.0, 55.1, 50.0, 29.0; IR (neat) v (cm−1) 3002, 2957, 2935, 2911, 2837, 1713, 1612, 1584, 1514, 1464, 1442, 1423, 1356, 1301, 1249, 1179, 1158, 1109, 1034; MS (70 eV, EI) m/z (%): 165 (M++1, 2.58), 164 (M+, 23.60), 121 (100).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:14]=[CH2:15])[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+].CO>O1CCCC1.O>[CH3:12][C:9]1([CH3:13])[O:10][CH2:11][C:6]([CH:14]=[CH2:15])([C:4]([OH:5])=[O:3])[CH2:7][O:8]1
Reactant: C=CC1(C(=O)OCC)COC(C)(C)OC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC1(C(=O)O)COC(C)(C)OC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester (150 mg, 0.7 mmol) in tetrahydrofuran (3 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (59 mg, 1.4 mmol) in water (1 mL) was added and the reaction mixture was stirred at 5° C. for 30 minutes and then at room temperature for 5 hours. Methanol (0.5 mL) was added to give a clear solution and the reaction mixture was stirred at room temperature for 22 hours. The solvent was evaporated. Water (2 mL) was added to the residue and the solution was acidified to pH 2 with 2 M hydrochloric acid. Brine was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine. The organic extract was separated, washed with water (×5), and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (117 mg, 90%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 3H), 1.49 (s, 3H), 3.91 (d, J=12.0 Hz, 2H), 4.32 (d, J=12.0 Hz, 2H), 5.30 (d, J=17.8 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 5.76 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 185.1 [M−H], Tr=1.26 min.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>O.C(OCC)(=O)C>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=1)=[O:24]
Reactant: CC(C)NO
Reactant: CSc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(NC(=O)N(O)C(C)C)cc1
Yield: 55 %

Procedure:
N-Isopropylhydroxylamine hydrochloride (1.35 g, 12.1 mnmol) was dissolved in water (2 mL) then combined with diethyl ether (25 mL) followed by the addition of a solution of sodium hydroxide (0.48 g, 12.1 mmol) in water (2 mL). The reaction mixture was allowed to stir for several minutes then 4-(methylthio)phenyl isocyanate (2.0 g, 12.1 mmol) was added via pipette. A white precipitate formed. The reaction mixture was allowed to stir at ambient temperature overnight. The solid was isolated by filtration then dissolved in hot ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate then concentrated under vacuum. The precipitate was collected and dried to afford 1.60 g of the desired product as a crystalline solid, m.p. 150.0°-150.3° C. Analysis: Calculated for C11H16N2O2S: %C, 54.98; %H, 6.71; %N, 11.66; Found: %C, 54.96; %H, 6.53; %N, 11.61.