Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][C:41]([C@H:43]1[CH2:48][CH2:47][C@@H:46]([C:49]([N:5]2[CH2:6][CH2:7][CH2:8][N:2]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[N:19]=[C:20]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[O:21][C:22]=4[C:23]([F:26])([F:24])[F:25])=[O:17])=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCN(C(=O)[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (100 mg, 0.21 mmol), cis-cyclohexane-1,4-dicarboxylic acid monobenzyl ester (0.67 mg, 0.25 mmol), and triethyl amine (0.070 mL) in DMF (5 mL) was stirred for 5 minutes and PyBroP (116 mg, 0.25 mmol) was added. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. The residue was extracted with ethyl acetate and washed with saturated ammonium chloride (100 mL), water (50 mL), brine (100 mL) and dried with anhydrous sodium sulfate. The solvent was removed and the crude material was purified on a flash column chromatography eluted with ethyl acetate/hexanes to afford cis-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (100 mg, 71% yield) as a white solid. LCMS for C37H37F3N4O5 calcd. (m/e) 674, observed 675 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][N:19]=[C:18]4[O:23][CH2:24][O:25][C:17]=34)=[N:10][CH:11]=[N:12]2)=[C:7]([O:26][CH:27]([CH3:29])[CH3:28])[CH:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].[I-].[K+]>CC(N(C)C)=O>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:15][C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]5[O:23][CH2:24][O:25][C:17]=45)=[N:10][CH:11]=[N:12]3)=[C:7]([O:26][CH:27]([CH3:28])[CH3:29])[CH:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(C)Oc1cc(OCCCl)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Reactant: CC(=O)N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Nc4c(Cl)cnc5c4OCO5)ncnc3c2)CC1
Temperature: 100 °C
Yield: 90.2 %

Procedure:
A mixture of 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline (24 g), 1-acetylpiperazine (21 g), potassium iodide (18 g) and DMA (500 ml) was stirred and heated to 100° C. for 4 hours. The solvent was evaporated and the residue was partitioned between methylene chloride (1 liter) and water (500 ml). The aqueous layer was extracted with methylene chloride. The organic solutions were combined, washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol (from a 20:1 mixture to a 10:1 mixture) as eluent. After evaporation of the solvent, the material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a white solid (26.2 g); m.p. 208-210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].BrCC[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH2:2][CH2:24][C:25]#[N:26])=[CH:9][CH:8]=1
Reactant: N#CCCCBr
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCCCC#N)cc1
Temperature: 80 °C
Yield: 56.7 %

Procedure:
To a solution of Step 1 intermediate, Intermediate 10 (350 mg, 1.355 mmol) in DMF (10 ml) was added 4-bromobutyronitrile (280 mg, 1.897 mmol) at room temperature followed by K2CO3 (560 mg, 4.065 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography to afford 250 mg the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 3.80-3.85 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 45% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C35H42N5O4Cl2 [(M+H)+] 666.2609, observed 666.2606.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:23][CH:22]=[CH:21][N:5]2[C:6](=[O:20])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1.[CH:24]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH2:26][CH2:25]1.[O-]CC.[Na+]>C(O)C>[CH:24]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2/[CH:31]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:23][CH:22]=[CH:21][N:5]3[C:6](=[O:20])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:10][CH:9]=2)[CH2:25][CH2:26]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OCC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OCC(F)(F)F)cc2)c1OCC1CC1
Yield: 46.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 11 (325 mg, 0.95 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (255 mg, 1.20 mmol) in presence of sodium ethoxide (129 mg, 1.90 mmol) in ethanol (25 ml) according to the procedure of Example 24 to give 235 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.27 (br s, 2H), 0.51 (br s, 2H), 1.04-1.06 (m, 1H), 3.68-3.70 (m, 2H), 3.77 (m, 3H), 4.81-4.83 (m, 2H), 6.89-6.98 (m, 4H), 7.13-7.15 (m, 2H), 7.27-7.29 (m, 2H), 7.49 (br s, 1H), 7.98 (br s, 1H), 8.14 (d, J=16.2 Hz, 1H); ESI-MS (m/z) 529.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][C:20]#[N:21])[CH2:13][CH2:12][CH2:11][C:10](=[CH:14]N(C)C)[C:9]2=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][C:20]#[N:21])[C:9]3[N:47]=[C:45]([NH:44][C:34]4[CH:35]=[CH:36][C:37]([N:38]5[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]5)=[C:32]([O:31][CH3:30])[CH:33]=4)[N:46]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(CC#N)(c2ccc(Cl)cc2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(CC#N)(c2ccc(Cl)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from [1-(4-chloro-phenyl)-3-[1-dimethylamino-methylidene]-2-oxo-cyclohexyl]-acetonitrile (118 mg, 0.39 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (124 mg, 0.33 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (114 mg, 71%). MS ISP (m/e): 485.5 [(M+H)+]. mp 156-158° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[Br:29]Br>O>[Br:29][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:7](=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:17][CH:16]=3)[CH2:8][C:9]=2[CH:10]=1
Reactant: CC(=O)Oc1ccc2c(c1)Cc1ccccc1-2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 72.9 %

Procedure:
2-Acetoxyfluorene (70 g) was added to a mixture of acetic acid (330 mL) and acetic anhydride (110 mL) and heated up to 65° C. to obtain a homogeneous solution. Bromine (125 g) was dropwise added thereto in 40 minutes and stirred for further one hour. The reaction solution was poured into water (1 L) to obtain deposited crystals by filtration under reduced pressure. The dried crystals were ecrystallized from a mixed solution of ethanol (400 mL) and ethyl acetate (300 mL) to obtain colorless needle-shaped 2-bromo-7-acetoxyfluorene (69 g). The melting point of this compound was 130° C.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1SCCCS1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C(Cl)C1SCCCS1
Temperature: 25 °C

Procedure:
In a 500 ml. reaction flask equipped with a reflux condenser connected with a wash-bottle containing H2SO4, there are added 250 ml. of anhydrous benzene (distilled upon sodium), 42 g (0.25 mol) of 1.3-dithiane-2-carboxylic acid (as prepared in example 1) and 28 ml. (0.4 mol) of freshly distilled oxalyl chloride. The mixture is stirred at room temperature and at the end of gaseous evolution, the mixture is heated up to 45° C to complete the gas evolution. The solvent and the excess of oxalyl chloride are evaporated under reduced pressure and the residue is crystallized from dried cyclohexane to yield 1.3-dithiane-2-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.CC([O:15][C@H:16]1[CH:20]=[CH:19][C@@H:18](O)[CH2:17]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[CH2:20][C@H:16]([OH:15])[CH:17]=[CH:18]2)=[C:4]([Cl:11])[N:3]=1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reaction time: 0.08 h

Procedure:
2,6-Dichloropurine (10 g, 52.90 mmol), (1S,4R)-cis 4-acetoxy-2-cyclopenten-1-ol (10 g. 70.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.20 g, 3.50 mmol) and polymer supported triphenylphosphine (3 mmol/g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (80 ml) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 ml) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is allowed to cool, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). 1H nmr (CDCl3, 400 MHz); 8.30 (s, 1H), 6.40 (m, 1H), 5.90 (m, 1H), 5.50 (m, 1H), 4.95 (m, 1H), 3.05 (m, 1H), 2.10 (m, 1H), MS (ES+) m/e 271 (MH+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN(CC2(C(=O)O)CCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
In a 500 mL, 3-necked round bottom flask under N2, a mixture of 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobutane carboxylic acid (30 g, 92 mmol, step 2 of Example 7) in tetrahydrofuran (150 mL) was stirred at room temperature for 10 min. To this suspension, a solution of p-toluensulfonic acid monohydrate (52.4 g, 276 mmol) in tetrahydrofuran (150 mL) was added at room temperature. After stirring at that temp for 10 min, the resulting solution was heated under reflux condition for 3 h. After cooling down to room temperature, triethylamine (28.1 mL, 202 mmol) was added very slowly during the period of 1 h with seeding. The white precipitate was formed during the addition of triethylamine. The resulting white suspension was stirred at room temperature for 6 h and it was filtered and the obtained solid was washed with tetrahydrofuran (100 mL×2), dried at 50° C. for 5 h to give 35 g (96%) of the titled compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.C[Si](C)(C)Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.Br>O1CCCC1>[Br-:22].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S+:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=S(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Clc1ccc(Br)cc1
Agent: Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Clc1ccc([S+](c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Product: [Br-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 16.3 g (0.06 mol) of di(4-chlorophenyl)sulfoxide was dissolved in 250 ml dichloremethane. Into the resulting solution kept at 0 to 5° C., 10.8 g (0.10 mol) of trimethylchlorosilane was added dropwise; the mixture was stirred at 0° C. for 30 min. Thereafter, 200 g of a tetrahydrofuran (THF) solution of the Grignard reagent prepared by the usual process with 4-bromochlorobenzene (0.18 mol) was added dropwise over the period of 30 min into the reaction vessel cooled with 0 to 10° C. ice water. After agitated for one hr at 0° C., followed by another hr agitation at room temperature, the reaction solution was slowly poured into an aqueous solution containing 250 ml of an aqueous 12% hydrogen bromide solution and ice, then extracted with 250 ml dichloromethane. The extract was dried with sodium sulfate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][NH:10][CH:11]([CH2:13][CH3:14])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([N:10]([CH3:9])[CH:11]([CH3:12])[CH2:13][CH3:14])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCC(C)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(C)N(C)c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 40 h
Yield: 72 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), N-methylbutan-2-amine (1.31 ml), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 40 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.43 g, 72%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A mixture of 4-fluorophenylboronic acid (365 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 ml), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (139 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[CH:19]12[CH2:24][CH:23]1[C:22](=[O:25])[O:21][C:20]2=O>O1CCOCC1>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:20](=[O:21])[CH:19]3[CH:23]([CH2:24]3)[C:22]2=[O:25])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: O=C1OC(=O)C2CC12
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(N2C(=O)C3CC3C2=O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (1.41 g, 5 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.24 g, 20 mmol) in 1,4-dioxane (25 mL) was heated at 90° C. for 4 hours. The reaction was cooled to room temperature and the precipitated white solid was collected by filtration to give 2,6-dichloro-N-(2-(−2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-4-yl)benzamide (1.28 g, yield: 68%). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.67-7.59 (m, 3H), 7.55 (dd, J=9.2, 6.8 Hz, 1H), 2.74 (dd, J=8.0, 3.6 Hz, 2H), 1.69 (ddt, J=20.6, 8.1, 4.2 Hz, 2H). LCMS (ESI) m/z: 376.0 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][C:14]=2[CH2:13][CH2:12]1)=O>O.CO.C1COCC1>[CH2:13]1[C:14]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:15]=2[CH2:16][CH2:17][NH:11][CH2:12]1
Reactant: CC(=O)Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCNCC2
Temperature: 0 °C
Yield: 125.2 %

Procedure:
29.2 g potassiumcarbonate in 100 mL of water was added to 17.5 g N-[3-(2,2,2-Trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-acetamide in 400 mL MeOH and 50 mL THF at 5° C. The reaction mixture was stirred in the ice bath for 2 h and 2 h at RT. The solvent was removed and the residue was extracted with brine and dichloromethane, the organic fraction was dried and the solvent removed to yield 14.9 g of the desired product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)[CH3:3].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](B(O)O)=[CH:30][N:29]=1>>[OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=[N:29][CH:30]=3)[CH:22]=2)[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)[CH3:3]
Reactant: OB(O)c1cncc2ccccc12
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(C)O)cc2=O)cc1
Product: COc1ccc(COc2cn(-c3cccc(-c4cncc5ccccc45)c3)c(C(C)O)cc2=O)cc1
Temperature: 80 °C

Procedure:
To a 100 mL round-bottom flask were added 4.20 g (9.76 mmol) of 2-(1-hydroxyethyl)-1-[3-bromophenyl]-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 3.38 g (19.52 mmol) isoquinolin-4-ylboronic acid, 0.75 g (0.97 mmol) 1,-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The flask was equipped with a condenser, evacuated, and purged with nitrogen. Evacuation was repeated three times and 50 mL THF and 40 mL 1 M aq cesium carbonate were added. The reaction mixture was heated at 80° C. for 3 h, Upon cooling, the organic layer was separated, washed with 15 mL water, dried over Na2S04 filtered, stirred over Quadrapure TU resin (Aldrich), concentrated in vacuo, and used without further purification, LCMS (M+H)+ 479.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: C1=COCCC1
Reactant: Sc1ccc(Cl)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccc(SC2CCCCO2)c(Br)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of 2-bromo-4-chlorothiophenol (3.74 g, 16.8 mmol), p-toluene sulfonic acid (0.427 g, 1.7 mmol) and 3,4-dihydro-2-H-pyran (0.985 ml, 16.8 mmol) in CH2Cl2 (30 mL) was stirred at 23° C. for 18 hours. After the addition of NaOH, the organic phase was separated, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil, (4.91 g, 95%) 1H NMR (CDCl3) δ7.6-7.5 (m, 2H), 7.35-7.2 (m, 1H), 5.37 (t, J=4.5 Hz, SCHO, 1H), 4.25-4.1 (m, CH2O, 1H), 3.7-3.55 (m, CH2O, 1H), 2.2-2.05 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.6 (m, 3H): IR 1566, 1542, 1450, 1367, 1257, 1188, 1101, 1037, 1024, 1008, 867, 809, 783 cm−1; Anal. Calcd. for C11H12BrClOS: C, 42.95; H, 3.93. Found: C,43.15; H, 3.91.