Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br.CC(C)=O>C(OCC)C>[Cl:1]/[C:2](/[C:12]([F:13])([F:14])[F:15])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([O:9][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=2[Cl:22])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of (±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (1.20 g), anhydrous potassium carbonate (2.0 g), 2-chloro-4-fluorobenzyl bromide (1.10 g), and dry acetone (30 ml) was stirred for a period of 2 hours at the ambient temperature (ca 25° C.) and kept at that temperature for a further 18 hours. After diluting the mixture with diethyl ether (300 ml) the resultant mixture was washed with dilute aqueous sodium carbonate solution and dried over anhydrous magnesium sulphate. The solvents were evaporated and the residual oil purified by preparative thick layer chromatography using silica gel plates and chloroform eluent, to give 2-chloro-4-fluorobenzyl(±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (1.31 g) as a colourless oil.
Reaction SMILES: C(OC([CH2:11][NH:12][CH:13]([CH:38]([CH3:40])[CH3:39])[C:14]([NH:16][CH:17]([C:30]1[NH:35][C:34](=[O:36])[CH:33]=[C:32]([CH3:37])[N:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15])=O)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:26]([C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([C:30]2[NH:35][C:34](=[O:36])[CH:33]=[C:32]([CH3:37])[N:31]=2)[NH:16][C:14](=[O:15])[CH:13]([NH:12][CH3:11])[CH:38]([CH3:40])[CH3:39])[CH:24]=[CH:23][C:22]=1[OH:25])([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1cc(=O)[nH]c(C(Cc2ccc(O)c(C(C)(C)C)c2)NC(=O)C(NCC(=O)OCc2ccccc2)C(C)C)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nc(C)cc(=O)[nH]1)C(C)C

Procedure:
A mixture of 2-(1-(2-(benzyloxycarbonylmethylamino)-3-methyl-butyrylamino)-2-(3-tert-butyl-4-hydroxyphenyl)ethyl)-6-methyl-4-pyrimidinone (0.71 g, 1.294 mmol), 20% palladium hydroxide/carbon (0.15 g) and methanol (20 ml) was stirred in a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving two diastereoisomers A and B of the titled compound, A (296 mg, 38%) being eluted first and then B (77 mg, 9.4%). (A)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-hydroxybenzaldehyde (60.0 g, 299 mmol), ethylene glycol (56 mL, 1.00 mol), and p-toluenesulfonic acid (1.14 g, 5.98 mmol) in toluene (450 mL) was refluxed with Dean-Stark head for overnight. Potassium carbonate (3 g) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-(1,3-dioxolan-2-yl)phenol (66.1 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:18])=[O:11]
Reactant: O=C(O)c1cccc(-c2ccccn2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(-c2ccccn2)c1

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-2-yl)benzoic acid (1.69 g, 8.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give 3-(pyridin-2-yl)benzoyl chloride. 1.66 g of crude product was obtained. To a solution of methyl 3-amino-2-hydroxybenzoate (0.84 g, 5 mmol) and pyridine (790 mg, 10 mmol) in toluene (50 mL) were added crude 3-(pyridin-2-yl)benzoyl chloride (1.6 g, 7.37 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(3-(pyridin-2-yl)benzamido)benzoate (1.48 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:13])[C:7]2([CH2:11][CH2:10][NH:9][CH2:8]2)[O:6][C:5](=[O:12])[CH2:4]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([C:36](O)=[O:37])[CH2:35][CH2:34]3)=[C:29]([F:39])[CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[CH3:2][C:3]1([CH3:13])[C:7]2([CH2:11][CH2:10][N:9]([C:36]([C:33]3([C:30]4[CH:31]=[CH:32][C:27]([N:24]5[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:26][CH2:25]5)=[CH:28][C:29]=4[F:39])[CH2:34][CH2:35]3)=[O:37])[CH2:8]2)[O:6][C:5](=[O:12])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)O)CC3)c(F)c2)CC1
Reactant: CC1(C)CC(=O)OC12CCNC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2-one hydrochloride (20.3 mg, 0.0000988 mol) and 1-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2-fluorophenyl}cyclopropanecarboxylic acid (36.0 mg, 0.0000988 mol) in N,N-dimethylformamide (0.30 mL, 0.0039 mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (48.1 mg, 0.000109 mol) followed by N,N-diisopropylethylamine (0.0206 mL, 0.000118 mol). After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried. The crude residue was used directly in the next step without further purification. LCMS (M+H) 516.3. (M+Na) 538.3.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)Nc3ccccc3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), aniline (46 uL, 47 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 43 mg (50% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.58 (m, 4 H), 1.61 (s, 9 H), 2.21-2.38 (m, 1 H), 3.29-3.35 (m, 2 H), 3.85-3.93 (m, 2 H), 4.45 (d, J=7.62 Hz, 2 H), 6.96-7.04 (m, 1 H), 7.04-7.11 (m, 2 H), 7.11-7.21 (m, 2 H), 7.84-7.89 (m, 1 H), 7.91-7.98 (m, 1 H), 8.06 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=428.0; Anal. Calcd for C23H29N3O3S+1.10 TFA+0.30 EtOAc+0.2H2O (583.03): C, 54.39; H, 5.69; N, 7.21. Found: C, 54.43; H, 5.68; N, 7.22.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH3:21])[CH:14]=[CH:13][C:12]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:21])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Yield: 94.3 %

Procedure:
A solution of 6.25 g (49.00 mmoles) of 4-chloroaniline in 10 ml of methylene chloride was added to a solution of 9.85 g (49.95 mmoles) of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide the title compound (87% yield) with a melting point of 174-176° C.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:6][CH2:7][C:8]([NH:10]/[C:12](=[CH:16]\[CH3:17])/[C:13]([OH:15])=[O:14])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=O)C(=O)O
Reactant: NC(=O)CCC1CCCC1
Product: C/C=C(\NC(=O)CCC1CCCC1)C(=O)O

Procedure:
A solution of 1.41 g (10 mmole) of 3-cyclopentylpropionamide and 1.53 g (15 mmole) of 2-ketobutyric acid was stirred and refluxed under a small Dean-Stark trap. After 8 hrs the solution was cooled, resulting in heavy crystallization. The solid was collected on a filter and washed with toluene and CH2Cl2. Yeld of white crystals=1.44 g, mp 180.5°-182° (prelim. softening). The material was recrystallized from methyl ethyl ketone. Yield of white needles=0.63 g (28%), mp 184°-185° (slight prelim. softening). Tlc (4:1 toluene-AcOH) now showed a single spot, and NMR indicated essentially pure Z-isomer.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6](N1CCOCC1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([O:22][C:23]([C:25]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:32]2[N:28]([CH:29]=[CH:30][CH:31]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:6]([C:29]1[N:28]2[C:32](=[CH:31][CH:30]=1)[C:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:26][CH2:27]2)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)N1CCOCC1
Reactant: CCOC(=O)C1(C(=O)OCC)CCn2cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.2 %

Procedure:
A mixture of POCl3 (166 mg, 1.08 mmole) and N-benzoylmorpholine (96 mg, 0.5 mmole) was maintain for 6 hours at 25° C. A solution of diethyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (126 mg, 05 mmole) in dichloroethane (2 ml) was added. Then, the mixture was maintained at 50° C. for 3 days. The reacted mixture was poured with 2.5 ml of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 10 hours, and refluxed for 2 hours. The organic layer was separated, and the aqueous layer was washed with 1,2-dichloroethane. The organic layer was dried using sodium carbonate, and the solvent was removed. Finally, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:9) as an eluting solvent and 178 mg of the product diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (84%) was obtained. The IR and NMR spectral properties were identical to those of an authentic sample.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[NH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([N:7]2[C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)c1cc(C(F)(F)F)n[nH]1
Product: CN(C)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1

Procedure:
5-Dimethylamino-3-trifluoromethylpyrazole (2.9 mmol) was reacted with 4-nitrofluorobenzene (2.9 mmol), as described in Method L, to give 1-(4′-nitrophenyl)-5-dimethylamino-3-trifluoromethylpyrazole which was purified by chromatography over silica gel (hexanes/EtOAc, 8:2) (0.423 g, 46%). The nitrophenylpyrazole (1.35 mmol) was reduced by phase transfer hydrogenation, described generally in Method L, to give 1(4′-aminophenyl)-5-dimethylamino-3-trifluoromethylpyrazole as an off-white solid (0.321 g, 84%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[O:8])[CH2:33][CH2:32]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)NCc3ccccn3)CC2)cc1
Yield: 60 %

Procedure:
A stirred mixture of 6-bromo-N-(2-pyridylmethyl)hexanamide (0.60 g, 2.1 mmol), 1-[2-(4-methoxyphenyl)phenyl]piperazine (0.68 g, 2.5 mmol) and K2CO3 (3.5 mmol) in acetonitrile was refluxed overnight. After cooling, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2×30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/MeOH, 19:1, as eluent) to afford pure compound in 60% yield. 1H NMR (CDCl3): δ 1.35-1.42 (m, 2H), 1.53-1.63 (m, 2H), 1.68-1.78 (m, 2H), 2.28 (t, 2H, J=7.4 Hz), 2.42 (app. t, 2H), 2.65 (br s, 4H), 3.09 (br s, 4H), 3.81 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 6.94 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.09-7.16 (m, 2H), 7.22-7.30 (m, 3H), 7.46 (d, 2H, J=8.8 Hz), 8.58 (m, 1H). GC-MS m/z 473 (M+1, 1), 472 (M+, 5), 379 (20), 282 (50), 226 (100), 210 (35).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:18]#[C:19]Br>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)=[CH:6][C:7]=1[F:12]
Reactant: NC(CO)c1ccc(Br)c(F)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: NC1=NC(c2ccc(Br)c(F)c2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a stirred, cooled (0° C.) solution of (RS)-2-amino-2-(4-bromo-3-fluoro-phenyl)-ethanol (3.26 g) and sodium acetate (2.22 g) in methanol (25 ml) was added dropwise a solution of cyanogen bromide (1.52 g) in methanol (10 ml) over 10 min. The mixture was then allowed to warm to at r.t. and stirring continued for 16 h. The mixture was concentrated in vacuo and the residue was resuspended in water and made basic by addition of 1 M aq sodium hydroxide solution. The mixture was then extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was triturated in dichloromethane and the resultign crystals washed with ether to give (RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (1.09 g, 30%) as a white solid. MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: COc1cccc2c(O)ccc(C=O)c12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(OCCBr)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water. (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3×90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2-bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:3]1[CH2:2][S:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])[CH3:17]
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCSc2ccccc21
Product: CN(C)C=C1CSc2ccccc2C1=O

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-4-thia-1(2H)-naphthalenone starting material was prepared from thiochroman-4-one (4.93 g, 26.8 mmol) and N,N-dimethylformamide diethyl acetal (23 ml, 133.8 mmol) to give the desired product as golden yellow crystals (5.15 g) m.p. 96-97°. MS (ES+) 220 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:14](O)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:50]1([C:56]2[N:57]=[C:58]([CH:61]3[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63][NH:62]3)[NH:59][CH:60]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18](=[O:19])[NH:17][CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=3)[C:14](=[O:15])[N:62]3[CH:61]([C:58]4[NH:59][CH:60]=[C:56]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[N:57]=4)[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63]3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Reactant: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2Cc3ccccc3CC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
3-(4-tert-Butoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (1.93 g, 4.2 mmol) was dissolved in dichloromethane (100 mL), cooled to 0° C., then N-methyl-morpholine (0.42 g, 4.2 mmol) was added neat followed by isobutyl chloroformate (0.52 mL, 4 mmol). After 1.25 hour 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline (1.10 g, 4 mmol) was added neat and the reaction was allowed to warm to room temperature. After 16 hours the reaction was extracted with water, then saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2.53 g (88%) of brown foam desired product {1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester, which was used without further purification. (LC/MS; Measured MW (MH+): 717)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=[O:24])[CH:13]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][CH:27]=2)[CH:13]=1
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(C=O)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(CO)c2)n1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of 3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzaldehyde [150 mg, 0.39 mmol, Example 35(v)], in DCM (4 mL) and MeOH (1 mL) is treated with sodium borohydride (74 mg, 1.95 mmol) at 0° C. After 1 hour at 20° C., the mixture is concentrated, and extracted twice with EtOAc (10 mL). The combined extracts are dried over magnesium sulfate and filtered through a plug of silica to afford (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol [110 mg, 73%, Example 9(d)]. LCMS: RT=2.79 minutes, MS: 388 (M+H). IC50=2.4 nM
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NCCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-1-butanol using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=7 Hz), 8.53 (1H, s), 8.17 (1H, s), 7.38 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.42 (1H, t, J=5 Hz), 4.36 (2H, t, J=5 Hz), 4.13 (2H, s), 3.47 (2H, t, J=7 Hz), 3.21-3.42 (6H, m), 2.00 (2H, t, J=6 Hz), 1.41-1.82 (8H, m); ES+ MS: 511 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:16]([CH3:18])[CH3:17])[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.ClCCl>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)=[CH:15][CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=1)(=[O:26])=[O:27]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC(C)C)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Yield: 94.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (800 mg, 1.48 mmol) in ethanol (4 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at 100° C. for 1 h. The mixture was acidified to pH 4-5 with a 2N aqueous hydrochloric acid solution, diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (540 mg, 95%) as a light yellow solid which was used without further purification: LC/MS m/e calcd for C20H20N2O4S [M+H]+ 385.46, observed 385.3.