Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[CH3:34]>COCCOC>[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:34]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)cc(F)c1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 66.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,6-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-ethylphenylboronic acid (71 mg, 0.468 mmol), and Pd[PPh3]4 (27 mg, 0.0234 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (70 mg, 66%). MS m/e 453.30 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A solution of 2-Amino-4-nitro phenol (6.0 g, 38.93 mmol) in methylene chloride (200 ml) was cooled to 0° C. Triethyl amine (16.3 ml, 116.9 mmol) was added followed by chloroacetyl chloride (3.42 ml, 42.8 mmol) portionwise. The mixture was stirred at room temperature for 18 hours, then diluted with methylene chloride. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.5 g of 6-nitro-4H-benzo[1,4]oxazin-3-one as a solid, 100%.
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:23]([Br:26])=[C:22]([CH3:27])[C:6]=1[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Br:26][C:23]1[CH:24]=[CH:25][C:5]([OH:4])=[C:6]([C:22]=1[CH3:27])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8]
Reactant: COc1cc(C)c(C(=O)c2c(OC(C)=O)ccc(Br)c2C)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(C(=O)c2c(O)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1D (0.7 g, 1.6 mmol), potassium carbonate (0.7 g), methanol (10 ml) and water (5 ml) is stirred at room temperature for 20 hours. The reaction mixture is poured into water and extracted with diisopropylether. The organic phase is separated and concentrated. The pure product is obtained as a yellow solid, 0.48 g (75.9%), mp. 119-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[ClH:20].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[ClH:29].[ClH:20].[CH2:15]([N:14]([CH2:17][CH3:18])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:19][C:6]=3[C:7]=2[CH2:13]1)[CH3:16]
Reactant: CCN(CC)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCN(CC)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 51.9 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) 8-amino-1,2,3,4-tetrahydro-2-diethylaminodibenzofuran and 0.059 gm (0.33 mMol) isonicotinoyl chloride hydrochloride, 0.068 gm (52%) of the title compound were recovered as a yellow solid by the procedure described in Example 17.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([C:10]2[NH:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][CH:15]([C:13]1[N:14]=[C:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:11][CH:12]=1)[OH:16]
Reactant: C[Mg]Br
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Solvent: C1CCOC1
Product: CC(O)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl magnesium bromide (15.3 ml., 2.5 molar in ether) is added dropwise to a solution of 2-phenyl-4-imidazolecarboxaldehyde (3.0 gm. 0.017 mole) in dry tetrahydrofuran (45 ml.; dried over a molecular sieve) while the temperature of the reaction mixture is maintained with cooling at 25° C. The mixture is stirred for 2 hours, and then decomposed by adding a large volume of water dropwise. The mixture is extracted with ether (3×75 ml.), the ethereal extract is partially evaporated to yield a white precipitate, the crystalline alcohol, m.p. 197°-198° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:41](O)=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].Cl.[CH2:45]([NH:51][CH3:52])[CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50]>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=4)[N:21]=3)[CH2:16][CH:15]2[C:41](=[O:42])[N:51]([CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50])[CH3:52])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reactant: C=CCCCCNC
Agent: Cl
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 81 %

Procedure:
The acid 167 was reacted with hex-5-enyl-methyl-amine hydrochloride as according to the same procedure described in example 157, which gave the title compound (0.838 g, 81%), LRMS (M+H) 691.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[C:15]=2[CH:14]=[CH:13][N:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH:11]1[C:20]2[C:15](=[C:16]([S:21]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolinesulfonyl chloride (2.64 g, 10.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was triturated from ether/hexane to give the title compound as a pale yellow solid (1.15 g, 37%). 1H-NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 9.60 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.37 (t, J=6.1 Hz, 2H), 7.86 (t, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(OCC)c1c(F)ccc(O)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(F)ccc(Oc2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 35.3 %

Procedure:
To a solution under Ar of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (320 mg) in CH2Cl2 (10 ml) was added copper(II)acetate (230 mg), 4-fluorobenzeneboronic acid 516 mg) and powdered MS4 Å (2 g). After addition of triethlyamine (622 mg) the mixture was stirred 40 h at rt. The solids were filtered away and the solvent was evaporated. Column chromatography (CC) (AcOEt:Hept 1:9 to 1:1) afforded 154 mg of (RS)-[2,6-difluoro-3-(4-fluoro-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester as a brownish oil.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[N:56]1([C:62](Cl)=[O:63])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:55])=[O:4])=[O:24])[N:26]([C:62]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[O:63])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:44][CH:43]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N3CCOCC3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (21 mg) was reacted with morpholine-4-carbonyl chloride according to General Procedure H. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (11 mg). LCMS (m/z): 852.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31](O)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:11]>CN(C=O)C.O>[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31]([O:4][CH3:1])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:11]
Reactant: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2OC)CC1

Procedure:
The [11C]MeI was trapped at 0° C. in a mixture of 2,4-dichloro-N-{[4-(3-hydroxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide (0.25 mg) in DMF (0.2 mL) containing Cs2CO3 (1-2 mg). This mixture was transferred to a vial at 100° C. and heated for five minutes. The reaction was diluted with H2O (0.8 μL) and purified by HPLC (Waters C18 XTerra, 7.8×150 mm, 5 μm, 15 minutes linear gradient 20% MeCN:(95:5:0.1) H2O:MeCN:TFA to 90% MeCN @ 3 mL/min, product elutes at 8.5 minutes). The product fraction was collected in a heated round bottom flask attached to a rotary evaporator, the solvent was removed and the product was transferred to a vial using physiologic saline to give to give 65 mCi of [11C] 2,4-dichloro-N-{[4-(3-methoxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:21]=2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.C1CCCCC=1.[Pd]>[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:21]=2)[CH2:12]1
Reactant: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)OCc5ccccc5)C4)oc3-c3ccncc3)ccc21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C1CCc2cc(-c3cc(C4CCCNC4)oc3-c3ccncc3)ccc21
Temperature: 90 °C
Yield: 87.8 %

Procedure:
A solution of the product of Step 5 (2.3 g, 4.67 mmol) in ethanol (100 ml) and cyclohexene (60 ml) was treated with 10% palladium on charcoal (0.8 g) and heated at 90° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered through celite and washed several times with ethanol. The filtrate was evaporated in vacuo and the residue purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (95:4.5:0.5) followed by (90:9:1) to yield the title compound (1.47 g, 88%); MS(ES+) m/e 359 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]#[N:21])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](N)[CH2:25][NH2:26]>C(Cl)(Cl)Cl.C(O)C>[C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]4[NH:26][CH2:25][CH2:24][N:21]=4)[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: N#CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1CC1=NCCN1
Temperature: -15 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of (7-benzenesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetonitrile (0.156 g., 0.475 mmol) in 10 mL anhydrous chloroform was added ethanol (0.029 mL, 0.5 mmol), and the resulting solution was cooled in a water ice/acetone bath to −15° C. Hydrogen chloride gas was bubbled through the solution for 10 minutes, and the flask was sealed and kept at −15° C. for 18 hours. The reaction mixture was concentrated in vacuo and 0.5 Torr vacuum was applied to the residue for 2 hours. The crude imidate was dissolved in 5 mL anhydrous chloroform, and to this solution was added ethylene diamine (0.033 mL, 0.5 mmol) in 4 mL anhydrous chloroform and 5 mL ethanol. The resulting solution was stirred at room temperature for 3 hours, and was then concentrated in vacuo. The residue was purified by flash chromatography (30% “magic base” (6:1:0.1 methylene chloride:methanol:ammonia) in dichlormethane) to give 0.130 g (0.35 mmol, 74%) of 7-benzenesulfonyl-4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4H-benzo[1,4]oxazin-3-one as a clear oil. MS: 372 (M+H)+, mp: 113.7-116.0° C. (HCl salt).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13](C)=[CH2:14]>>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[C:13]([CH3:14])[C:12]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=C(C)C(=O)OCC
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1
Yield: 29.4 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.23 g (0.05 mol) of p-formylbenzoyl chloride and 7.13 g (0.0625 mol) of ethyl methacrylate are used. After a reaction time of 2 hours at 120° C., 3.2 g (0.0147 mol) of ethyl p-formyl-α-methylcinnamate are obtained, corresponding to a yield of 29.4% of theory; boiling point 127°-131° C./7 Pa.
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C([B:27]([OH:29])[OH:28])C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:29])[OH:28])[CH:3]=1
Reactant: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1 H), 7.09 (s, 1 H), 5.37 (s, 2 H), 3.84 (t, 2 H, J=8.4 Hz), 2.76 (s, 3 H), 0.98 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H). Anal. (C13H22BClO4Si—H2O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H, 6.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[N:3]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1cccc(C)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2ccncc2)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and pyridine-4-carbaldehyde (4.9 ml, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 4:1 (5 L), then with toluene/acetone 3:1 (5 L) and finally with toluene/acetone 2:1 (15 L). The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 0.956 g of white crystals are isolated. (melting point: 72-73° C.).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Solvent: CC(=O)N(C)C
Product: Fc1ccc2nnc(N3CCCC3)n2c1
Temperature: 175 °C
Yield: 46.1 %

Procedure:
A mixture of Intermediate 24b (515 mg, 3.00 mmol), pyrrolidine (0.85 g, 12.0 mmol) and DMA (10 mL) was heated to 175° C. for 4 h using microwave irradiation. After cooling, the solvent was removed in vacuo and the resulting residue purified by FCC, using 0 to 15% MeOH in DCM, to provide the title compound as a brown gum (285 mg, 26%). LCMS (Method 3): Rt 1.95 min, m/z 207 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]([CH2:39][C:40](O)=[O:41])[C:35](=[O:43])[N:34]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:40](=[O:41])[CH2:39][N:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([O:29][CH2:28][C:27]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:31])=[N:34][C:35]1=[O:43])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1OC
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)c(OC)c2)nc1=O
Yield: 85.4 %

Procedure:
The title compound (5.31 g, 81%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (3.26 g, 9.5 mmol) and [4-N-(3,4dimethoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid (3.28 g, 9.03 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.72 (s, 1H), 8.27 (dd, 1H), 8.17 (dd, 1H), 7.90 (d, 0.6H), 7.82 (d, 0.4H), 7.69˜7.62 (m, 2H), 7.02 (s, 1H), 7.00 (t, 1H), 6.94 (s, 2H), 5.09 (s, 2H), 4.80 (s, 1.2H), 4.61 (s, 0.8H), 4.34 (s, 0.8H), 4.13 (q, 0.8H), 4.05 (s, 1.2H), 4.03 (q, 1.2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.58 (t, 1.2H), 3.42˜3.37 (m, 2H), 3.20 (t, 0.8H), 1.20 (t, 1.2H), 1.14 (t, 1.8H).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1O)=[O:10].C(=O)([O-])[O-].[K+].[K+].N>CC(C)=O>[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:6][CH3:7])=[O:10]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(F)cc1C(C)=O

Procedure:
Dimethyl sulphate (30 ml) was added dropwise over 45 min to a stirred mixture of 5-fluoro-2-hydroxyacetophenone (32.43 g) and potassium carbonate (40.5 g) in acetone (500 ml) and the mixture was then heated under reflux for 8 hr. Concentrated ammonia solution was added and the inorganic solids removed by filtration. The solvent was removed under reduced pressure and the product was dissolved in ether and washed with water. After drying the ethereal solution (Na2SO4) the ether was removed under reduced pressure and the residue was distilled to give 5-fluoro-2-methoxyacetophenone (28.4 g); b.p. 58°-64 ° C./0.2 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN1C(=O)CCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:34][CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: NCCc1ccccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCc4ccccn4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-(2-aminoethyl)-pyridine in NMP. ES-MS m/e (%): 491 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: C1COCCN1
Reactant: O=Cc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3cccc(CN4CCOCC4)c3)cc2s1
Reaction time: 18 h

Procedure:
290 mg (3.32 mmol) of morpholine and 31 mg (0.50 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.17 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 33A) in 1.0 ml of a 6:1 mixture of methanol and acetic acid. After 18 h at 80° C., purification is carried out by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated: Drying under high vacuum results in 47 mg (49.8% of theory) of the title compound.