Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33](=[O:35])[NH:34][C:30]=3[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)COc1cc(F)ccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4COc4cc(F)ccc43)cc2[nH]1
Temperature: -26 °C
Yield: 27.1 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,8-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 326 mg, 1.0 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (250 mg, 0.961 mmol), Na2CO3 (2M in water, 1.20 mL, 2.40 mmol), dioxane (7 mL), and Pd(PPh3)4 (58 mg, 0.051 mmol). Purify the crude product on silica gel (12 g) eluting with 50% to 70% THF/hexanes to afford two lots of yellow solid weighing 180 mg and 151 mg. Dissolve the 180 mg lot in boiling MeOH (20 mL), concentrate to 10 mL and cool to −26° C. to precipitate 165 mg (46%) of the title compound as a white solid. Repeat the recrystallization on the 151 mg lot to afford 98 mg (27%) of the title compound as a white solid. HPLC (ISO80-10) t=2.38 min, 97%; MS [ES] 375 (M−H), 377 (M+H); 1H-NMR (DMSO-d6) δ 10.57 (s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, J=8.4, 7.0 Hz), 7.49 (dd, 1H, J=9.2, 2.6 Hz), 7.08 (td, 1H, J=12.5, 4.3 Hz), 7.01 (d, 1H, J=5.7 Hz), 6.97 (s, 1H), 6.79 (td, 1H, J=12.0, 4.2 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.61 (dd, 1H, J=10.6, 2.6 Hz), 6.52 (s, 1H), 5.78-4.78 (br d, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:11][CH2:12][CH3:13])[C:7](=[CH2:10])[CH2:8][OH:9])[CH3:4].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1.CN(C)C=O>[CH2:12]([O:11][CH:6]([O:5][CH2:3][CH3:4])[C:7](=[CH2:10])[CH2:8][O:9][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: ClCc1ccccc1
Reactant: C=C(CO)C(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=C(COCc1ccccc1)C(OCC)OCC
Reaction time: 2 h

Procedure:
3.0 g (62.4 mmol) of 50% sodium hydride dispersion in mineral oil are placed in 50 ml of tetrahydrofuran and 40 ml of dimethylformamide, a solution of 10.0 g (62.4 mmol) of 3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is slowly added dropwise at 0°, and the mixture is stirred at 0° for 2 hours. The mixture is diluted with 15 ml of tetrahydrofuran and 10 ml of dimethylformamide and stirred at room temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chloride in 10 ml of dimethylformamide are then added at 0°, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate, and the organic phases are washed with saturated sodium chloride solution. The organic phases are combined, dried over Na2SO4, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride, yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale yellowish liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([NH:26][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 97.5 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (10.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.61 g), K2CO3 (8.38 g) and CuO (371 mg) in DMF (60 ml) was stirred at 100° C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-Hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (15.95 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[NH2:10].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1CCN2C(=NCCC2)CC1.[CH2:34]([O:36][C:37]([C:39]1([CH:42]=O)[CH2:41][CH2:40]1)=[O:38])[CH3:35]>C(O)C>[CH2:34]([O:36][C:37]([C:39]1([C:42]2[N:1]=[C:2]3[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]3[N:10]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35]
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: COc1ccc[n+](N)c1N
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a stirred solution of diamino-3-methoxy-pyridinium salt of 4-nitrobenzoic acid (1 g, 7.14 mmol) in ethanol (10 mL) at 0° C., DBU (2.1 mL) was added followed by 1-formyl-cyclopropanecarboxylic acid ethyl ester (1.5 g, 10.71 mmol). After addition the reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated, the obtained residue was diluted with EtOAc (100 mL), washed with water (20 mL×2), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (using 0 to 15% EtOAc in CH2Cl2 as eluent) to afford the title compound (800 mg, 53%, white solid). 1H NMR (400 MHz, CDCl3): δ=8.18-8.16 (d, J=6.4 Hz; 1H), 6.89 (t, J=7.2 Hz, 1H), 6.76 (d, J=8 Hz; 1H), 4.20-4.14 (m, 2H), 4.03 (s, 3H), 1.73-1.70 (m, 2H), 1.59-1.56 (m, 2H), 1.20 (t, J=6.8 Hz; 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)SC=1)=[O:9].BrC1C=[C:30](C(O)=O)[S:31]C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:10]1[S:31][CH:30]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)cs1
Reactant: COc1cccc(CNC(=O)c2csc(-c3c[nH]c4ncccc34)c2)c1
Product: COc1cccc(CNC(=O)c2cc(-c3c[nH]c4ncccc34)cs2)c1

Procedure:
The above compound was made by the same procedure as N-(3-methoxybenzyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-3-carboxamide starting with the regioisomer, 4-bromothiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[N+:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[C-:11].[NH4+].[Cl-].C(Cl)Cl>COCCOCCOC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]1[N:6]=[CH:11][NH:10][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCOC(C#N)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CCOC(OCC)c1nc[nH]c1C(=O)OC
Temperature: 75 °C
Yield: 26 %

Procedure:
A mixture of diethoxyacetonitrile (38.72 mmol, 1 equiv.) and methyl isocyanoacetate (99.1 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (20 ml) was added to a suspension of 30-35% KH (54.2 mmol, 1.4 equiv.) in dry bis(2-methoxyethyl)ether (30 ml). The resulting mixture was heated overnight at 70-80° C. The reaction mixture was then cooled to 25° C., and sat. NH4Cl solution (20 ml) was added. DCM (100 ml) was added, and the phases were separated. The aqueous phase was extracted with DCM (2×75 ml) and the combined organic phases were dried over Na2SO4 and filtered, and the solvent was removed in vacuo. Cold ether (10 ml) was added to the brown oil so obtained, and the resulting solid was filtered out and washed with ether. The desired product was thus obtained in the form of a yellow solid. Yield: 26%
Reaction SMILES: [O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>CN1CCCC1=O.C(Cl)Cl>[O:1]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([NH:25][C:38](=[O:41])[CH:39]=[CH2:40])[CH:26]=[CH:27][CH:28]=4)[O:21][C:14]=23)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13.9 %

Procedure:
To a 20-mL glass vial was added 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (30.00 mg; 0.08 mmol), N,N-diethylethanamine (0.02 ml; 0.15 mmol) suspended in 1-methylpyrrolidin-2-one (0.35 ml) and DCM (2.00 ml). The resulting mixture was cooled to 0° C. and stirred for 5 minutes. Acryloyl chloride (0.02 ml; 0.23 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at room temperature overnight. The mixture was concentrated. The crude mixture was purified using Biotage column chromatography (0-40% MeOH/EtOAc) to afford the title compound as a white solid (5.00 mg, 15%). HPLC (method F): 100%, RT=4.538 min. 1H NMR (DMSO-d6) δ [ppm] 10.29 (s, 1H), 8.31 (d, 1H), 8.22 (s, 1H), 7.74 (d, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.43 (t, 1H), 7.35 (t, 2H), 7.31 (d, 2H), 7.09 (d, 3H), 7.02 (d, 2H), 6.66 (d, 1H), 6.41-6.36 (dd, 1H), 6.25 (d, 1H), 5.73 (d, 1H). MS: m/z=449 [M+H]+, RT=4.08 min.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25]1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:23][N:24]1[C:28]([NH:29][C:12]([C:11]2[C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)=[O:14])=[CH:27][CH:26]=[N:25]1
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Reactant: Cn1nccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(OC)ccc(C(=O)Nc3ccnn3C)c2s1
Yield: 30 %

Procedure:
Starting from 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.2 g), oxalyl chloride (0.15 ml), dichloromethane (20 ml) and dimethylformamide (1 drop), followed by 2-methyl-2H-pyrazol-3-ylamine (0.17 g), triethylamine (0.24 ml) and dichloromethane (40 ml). Purification by flash chromatography (eluent 10% methanol/dichloromethane) yielded the title compound as a yellow solid (0.08 g). TLC Rf 0.52 (10% methanol in dichloromethane), Mpt 185-186° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[OH:27])[CH:22]=[O:23].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[O:27][CH:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:31]=1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Yield: 64.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (2.62 mmol) of 3-chloro-4-hydroxy-5-methoxybenzaldehyde was alkylated with 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate to afford 0.570 g (64%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]3[N:21]=[CH:22][S:23][CH:24]=3)[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: O=C(Nc1cccc(Br)c1)[C@H](Cc1ccccc1)NCc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(-c2cccc(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a 5 mL flask was added (S)—N-(3-bromophenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 39.B (50 mg, 0.12 mmol), 2-methylpyridin-4-yl boronic acid (21 mg, 0.16 mmol, available from Combi-Phos), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol), DMF (0.5 mL) and saturated aqueous K2CO3 (0.5 mL). The reaction mixture was stirred at 100° C. for 2 hours. The mixture was diluted with methanol (3 mL), filtered and purified directly on reverse phase preparative HPLC to afford (2S)—N-(3-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 39 (27.2 mg, 53% yield) as a white solid. LCMS ESI (pos.) m/e: 429.1. (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.12 (d, J=1.96 Hz, 1H), 8.74 (d, J=6.36 Hz, 1H), 8.19 (s, 1H), 8.12 (dd, J=6.36, 1.96 Hz, 1H), 8.11 (t, J=1.71 Hz, 1H), 7.82 (d, J=1.96 Hz, 1H), 7.68-7.75 (m, 1H), 7.58 (t, J=7.83 Hz, 1H), 7.52-7.56 (m, 1H), 7.23-7.37 (m, 5H), 4.53 (d, J=4.65 Hz, 2H), 4.35 (dd, J=9.29, 5.87 Hz, 1H), 3.46 (dd, J=13.45, 5.87 Hz, 1H), 3.28 (dd, J=13.45, 9.29 Hz, 1H), 2.88 (s, 3H).
Reaction SMILES: [C:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])(=O)[CH3:2].[C:8](#[N:12])[CH2:9][C:10]#[N:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>CCOC(C)=O.C1C=CC=CC=1>[CH3:5][Si:4]([CH3:7])([CH3:6])[C:1](=[C:9]([C:8]#[N:12])[C:10]#[N:11])[CH3:2]
Reactant: N#CCC#N
Reactant: CC(=O)[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=C(C#N)C#N)[Si](C)(C)C
Temperature: 95 °C
Yield: 80 %

Procedure:
To a mixture of acetyltrimethylsilane (1.0 g, 8.6 mmol), malononitrile (625 mg, 9.46 mmol) and ammonium acetate (126 mg, 1.64 mmol), acetic acid (394 μL, 6.88 mmol) and benzene (30 mL) were added. The reaction flask was attached to a Dean-Stark trap filled with benzene and the solution was heated to 95° C. for 3 h. The orange reaction mixture was cooled, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by column chromatography on silica gel (using a solvent gradient from 1% to 30% EtOAc in hexanes) to give 2-(1-(trimethylsilyl)ethylidene) malononitrile as colorless oil (1.13 g, 79.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:22][CH2:21][C:16]3[N:17]=[C:18]([NH2:20])[S:19][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:22][CH2:21][C:16]3[N:17]=[C:18]([NH:20][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:19][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(s1)CC(N1CCN(c3ccccn3)CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nc2c(s1)CC(N1CCN(c3ccccn3)CC1)CC2)c1ccccc1

Procedure:
A solution of (±)-4,5,6,7-tetrahydro-6-[4-(2-pyridinyl)-1-piperazinyl]-2-benzothiazolamine (10.0 g) (Example 1) in 200 ml of chloroform is treated with triethylamine (6.06 g) and benzoyl chloride (4.21 g). The resulting red solution is refluxed for two hours under nitrogen. Saturated sodium bicarbonate solution is added. The organic layer is dried (magnesium sulfate) and evaporated. The residue is purified by MPLC (silica; 1.5% methanol, 98.5% dichloromethane). The title compound is obtained as a yellow solid; mp 230°-232° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>>[N+:12]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][C:1]([OH:11])=[O:10])=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(O)CCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
In a 2-liter, 3-necked, round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel was placed 361 g (2.41 mol) of hydrocinnamic acid which was warmed to 50° to maintain it in a liquid state. To the warm liquid was added slowly dropwise over a 4 hour period with good stirring a mixture of 241 g of nitric acid and 546 g of sulfuric acid. The reaction is very exothermic so that a water cooling bath was required to which ice was added occasionally to keep the temperature at 50° C. The very thick reaction mixture was stirred for an additional 2 hours and poured onto 3 liters of ice. The solid was collected by filtration and washed repeatedly with a total of 6 liters of water. After air drying, the entire sample was recrystallized from 800 ml of acetone, giving a first crop of 150.4 g mp. 162°-164° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:14]12CCN(CC1)C[CH2:15]2.O>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([C:15]#[N:14])=[N:6][CH:7]=1
Reactant: CC(C)COc1nc(Cl)ncc1Br
Reactant: C1CN2CCN1CC2
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: CC#N
Product: CC(C)COc1nc(C#N)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 5-bromo-2-chloro-4-isobutoxypyrimidine (2.16 g) and 1,4-diazabicyclo[2.2.2]octane (1.83 g) in acetonitrile (30 mL) was added tetraethylammonium cyanide (1.40 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) as a colorless oil.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.[CH2:26]=O>C(O)C>[ClH:1].[C:2]1([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:26][CH:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]3=[O:25])[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ccccc21
Reactant: C=O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2CCC1CN1CCC(O)(c2ccccc2)CC1

Procedure:
21.35 g. of 4-phenylpiperidin-4-ol hydrochloride, 14.6 g. of 1-tetralone and 10 ml. of 37% formaldehyde solution in 50 ml. of ethanol are heated under reflux for 1 hour. The mixture is evaporated and ether is added to the residue, after which the phases are separated by decantation to give 2-(4-phenyl-4-hydroxypiperidinomethyl)-1-tetralone hydrochloride; m.p. 164°-167°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:45])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[N:20][NH2:21])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([O:42][CH3:43])=[CH:37][CH:38]=3)[CH:33]=2)(=[O:31])=[O:30])[C:24]1=[O:44].[OH-].[Na+]>CCO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:21][N:20]=[CH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([OH:45])=[O:9])=[C:14]([CH2:22][N:23]2[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[C:24]2=[O:44])[CH:15]=1
Reactant: COC(=O)COc1ccc(C=NN)cc1CN1CCC(NS(=O)(=O)c2ccc3ccc(OC)cc3c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4cc(C=NN)ccc4OCC(=O)O)C3=O)cc2c1
Reaction time: 5 h
Yield: 388.9 %

Procedure:
To a solution of {4-(aminoiminomethyl)-2-[3-(7-methoxynaphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-phenoxy}-acetic acid methyl ester trifluoroacetate (0.1 g, 0.18 mmol), prepared as in EXAMPLE 120, Part F, in 2 mL of EtOH is added 10 N NaOH (0.05 mL). The solution is stirred for 5 hours. After this time, the solution is concentrated. The residue is dissolved in 2 mL of H2O and the pH is adjusted to 3 using 1 N HCl. The solid which forms is collected by filtration. The solid is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fraction are lyophilized to afford the title compound (0.05 g, 0.7 mmol) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH2:26][O:27]C2CCCCO2)=[CH:18][CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][N:22]3[CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3cnn(CCO)c3c2)c2ccccc21
Reaction time: 0.33 h

Procedure:
Intermediate A (212 mg, 1.3 mmol) was added portionwise to a suspension of sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol) in DMF (3 mL) at RT and stirred for 20 min. A solution of Intermediate 11a (264.3 mg, 1.0 mmol) in DMF (1 mL) was then added dropwise and the resulting mixture stirred at 60° C. for 2.5 h. After cooling, the mixture was diluted with EtOAc (50 mL) and poured onto ice water. The organic layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was loaded on to a SCX-2 cartridge, eluting with MeOH then 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM to give the title compound as a brown oil. LCMS (Method 1): Rt 1.80 min, m/z 323 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1ccc(OC)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c(Cl)c1

Procedure:
Compound of example 6 (1.0 g, 3.2 mmol) in dry DMF (25 mL) was reacted with methyl 2-chloro-4-methoxybenzoate (1.29 g, 6.4 mmol) in the presence of NaH (50%, 0.776 g, 16 mmol) as described in example 16 to obtain the title compound.