Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([NH:16][C:17](=[O:36])[CH:18]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:40][CH2:39][N:23]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:25])=[O:26])[CH:18]([CH2:19][CH:20]2[CH2:21][CH2:22]2)[C:17]1=[O:36])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)NC(=O)C(CC1CC1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC2CC2)C1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 2-[3-cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 12, (3.46 g, 6.59 mmol) and 1,2-dibromoethane (12.38 g, 65.9 mmol) in DMF (40 mL) is added potassium carbonate (9.10 g, 65.8 mmol). The reaction mixture is stirred for 15 hours at 65° C., cooled and quenched with aqueous NH4Cl solution. The mixture is then extracted several times with EtOAc and the combined extracts dried over Na2SO4 and concentrated in vacuo. The resulting residue is purified over silica gel (hexanes/EtOAc, 1:2) to afford 3.57 g (98% yield) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.01–8.08 (m, 1H), 7.58–7.84 (m, 7H), 7.43–7.52 (m, 2H), 7.35 (dd, J=8.4 Hz, 1H), 5.38 (dd, J=11.7, 4.8 Hz, 1H), 4.33–4.44 (m, 1H), 3.76–3.88 (m, 1H), 3.69 (s, 3H), 3.21–3.66 (m, 4H), 2.99–3.14 (m, 1H), 1.40–1.53 (m, 1H), 1.02–1.16 (m, 1H), −0.14–−0.02 (m, 3H), −0.34–−0.20 (m, 2H); MS (ESMS) m/z 552.2 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[S:8]1[CH2:13][CH2:12][CH2:11][S:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:7]1([CH2:6][C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:8][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:5][CH2:4]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C1SCCCS1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a suspension of NaH (95%, 2.8 g, 111 mmol) in dry toluene (120 mL) stirring at 0° C. was dropwise added, over 10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol), and ethyl 1,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry DMF (40 mL). The ice bath was removed and the solution was stirred overnight at rt. Water was added to the solution and the phases were separated. The organic phase was dried over MgSO4, then evaporated to give 19.6 g (50%) of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate, which was used in the next step without purification. 1H NMR (CDCl3): δ 4.26 (2H, q, J=7.2 Hz), 3.30-3.23 (2H, m), 2.69-2.64 (2H, m), 2.16-2.11 (1H, m), 1.96 (2H, d, J=6.8 Hz), 1.91-1.81 (1H, m), 1.34 (3H, t, J=7.2 Hz), 0.93-0.86 (1H, m), 0.52-0.47 (2H, m), 0.20-0.16 (2H, m).
Reaction SMILES: CO[C:3]1[CH:30]=C[C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[N:31]1C=CC=CC=1C=O>>[N:31]1[CH:30]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1ccccn1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccccn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-pyridinecarboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.27 (1H, s) 8.46 (1H, ddd, J=4.81, 1.66, 0.76 Hz) 8.07 (1H, t, J=5.61 Hz) 8.01 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.47 Hz) 7.68 (1H, td, J=7.68, 1.73 Hz) 7.47 (1H, d, J=5.42 Hz) 7.39 (1H, d, J=7.71 Hz) 7.29 (1H, d, J=2.64 Hz) 7.20 (1H, ddd, J=7.47, 4.91, 0.90 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.49, 1.98 Hz) 3.78 (2H, s) 3.36 (2H, q, J=6.12 Hz) 2.68 (2H, t, J=6.83 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11]Cl.CCOC(C)=O.CCCCCC>CCOC(C)=O>[Cl:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: ClCl
Reactant: Nc1ccc2ncsc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc2ncsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 6-aminobenzothiazole (2.0 g, 13.4 mmol) in 100 mL of ACOH was added a solution of Cl2 saturated AcOH and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 37.5 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (140 mg, 0.60 mmol) and benzimidazole (78 mg, 0.66 mmol) furnished the product (71 mg, 38%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:14][NH2:15])=[O:13].C[Al](C)C.[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([NH:15][NH:14][C:12](=[O:13])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: COC(=O)c1cccc(Nc2cc(C)nc3ccccc23)c1
Reactant: NNC(=O)CN1CCc2ccccc2C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1C
Product: Cc1cc(Nc2cccc(C(=O)NNC(=O)CN3CCc4ccccc4C3)c2)c2ccccc2n1
Yield: 63.2 %

Procedure:
To a solution of 91 (205 mg, 1.0 mmol) in xylene (5 mL) was added trimethyl aluminum (2 M solution in hexanes, 0.75 mL, 1.5 mmol). The mixture was stirred under nitrogen for 10 minutes before the addition of methyl 3-(2-methylquinolin-4-ylamino)benzoate (49) (150 mg, 0.5 mmol). The reaction was heated at reflux overnight, quenched with water (2 mL), basified to pH 9 (2 N NaOH), and extracted with 7:3 CH2Cl2/MeOH. The organic layer was dried (K2CO3) and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution) to give 92 as a pale yellow oil (147 mg, 63%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:30]1=[O:41])(C(C)(C)C)(C)C.CO>O1CCCC1>[OH:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C:30]1=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (4.35 ml) was added to a solution of tert-butyl 3-[2-(tert-butyldimethylsilanyloxy)ethyl]-2-oxoimidazolidine-1-carboxylate (1.50 g) in tetrahydrofuran (15 ml), and the mixture was stirred for 1 hour at room temperature. Methanol (1 ml) was added to the reaction solution, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1→10:1) to yield tert-butyl 3-(2-hydroxyethyl)-2-oxoimidazolidine-1-carboxylate (940 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methylbenzoic acid (1.00 g, 4.65 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([O:4][C:5]([NH:7][CH:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:9]([OH:38])[CH2:10][N:11](CC1C=CC=CC=1)[CH2:12][CH:13]([OH:30])[CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])[CH3:3].CO>CN(C=O)C>[CH3:28][C:25]([O:24][C:23](=[O:29])[NH:22][CH:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:13]([OH:30])[CH2:12][NH:11][CH2:10][CH:9]([OH:38])[CH:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:46])=[O:6])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 27a by a procedure analogous to that used for the preparation of Compound 4b (except that MeOH at 55° was used in place of DMF) to give the title Compound 27b as a mixture of diastereomers. m.p. 156°-159° C.; MS: (CI/NH3): 544 (M+H). Anal. Calc. for C30H45N3O6 ·0.16 H2O
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:29]1([NH:35][C:36]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:42]([C:41]5[CH:40]=[CH:39][C:38]([C:36](=[O:37])[NH:35][C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:45][CH:44]=5)=[N:1][C:4]=4[CH:5]=3)=[O:28])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(C(=O)Nc6ccccc6)cc5)nc4c3)cc2)CC1

Procedure:
Compound 216 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(1-methyl-4-piperazinyl)benzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C32H30N6O2: 531.25; found: 531.05.
Reaction SMILES: Br[C:2]([F:26])([F:25])[C:3](F)([F:23])[O:4][C:5]1[CH:10]=[C:9]([O:11][C:12](F)([F:17])[C:13]([F:16])([F:15])Br)[CH:8]=[CH:7][C:6]=1[S:19]([F:22])(=[O:21])=[O:20].C(#N)C1C=CC=CC=1>[Cu]Cl.[Zn].C(Cl)Cl>[F:23][C:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]([F:17])=[C:13]([F:16])[F:15])[CH:8]=[CH:7][C:6]=1[S:19]([F:22])(=[O:21])=[O:20])=[C:2]([F:26])[F:25]
Reactant: O=S(=O)(F)c1ccc(OC(F)(F)C(F)(F)Br)cc1OC(F)(F)C(F)(F)Br
Agent: Cl[Cu]
Agent: [Zn]
Solvent: N#Cc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(F)c1ccc(OC(F)=C(F)F)cc1OC(F)=C(F)F
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Into a 250 ml of round bottom flask were placed 16.5 g (0.03 mol) of the 2,4-di(2-bromotetrafluoroethoxy)benzenesulfonyl fluoride, 5.94 g (0.06 mol) of copper(I) chloride and 6.54 g (0.1 mol) of activated zinc powder. Then 120 mL of well-dried benzonitrile was added to the mixture. The solution was stirred at 110° C. for 2 days with the protection of dry nitrogen gas. After being cooled down to room temperature, 120 mL of methylene chloride was added to the flask and the mixture was stirred at that temperature for eight hours, followed by filtration to remove the solid materials. Then 5 g of active carbon was added to the filtrate and the mixture was refluxed for overnight. After being cooled down to room temperature, the mixture was filtered to remove active carbon and the solvents were removed under the reduced pressure. The crude material was purified by sublimation at 120° C. oil bath temperature at 10−2 torr to give 2,4-di(trifluorovinyloxy) benzenesulfonyl fluoride, identified by 19F and 1H NMR.
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([SH:13])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.C(O)C>[C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([S:13][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc2[nH]c(S)nc2c1
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Reaction time: 6 h
Yield: 71 %

Procedure:
5-Carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2O (1 ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈6.6 mmol) as a crude material were added and the mixture was heated to boiling. NaOH (0.26 g, 6.6 mmol) in H2O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. Crystallizing from CH3CN gave the desired product (1.75 g, 71%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH2:12][CH2:13][O:14][CH3:15]>C([O-])(O)=O.[Na+].CCOCC>[CH3:6][C:3]1[CH:4]=[CH:12][C:13]2[O:14][C:15]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:8][C:9]=2[CH:2]=1
Reactant: COCCOC
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakistriphenylphosphine palladium (0) (1.5 g) in DME (200 ml) and 8% NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with system A (1:9) to give the title compound (10.58 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(F)c(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (933 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (4 g) in MeCN (18 mL) was stirred at room temperature for 3 days. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-THF/IPE to give (9S)-9-[4-(3-chloro-4-fluorophenoxy)phenyl]-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (290.6 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>>[Br:22][CH2:23][CH2:24][C:25]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:26]
Reactant: O=C(Cl)CCBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Product: O=C(CCBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Yield: 65 %

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (5 g, 0.018 mol) was reacted according to the procedure of Example 9 with 3-bromopropionyl chloride (6.8 g, 0.04 mol, 4 mL) using a bath temperature of 100° C. A white crystalline product was obtained in 65% yield (4.9 g), m.p. 133°-134° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.79; H, 4.12; N, 6.69; Br, 19.25. The product had the formula: ##STR74##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)=[CH:5][CH:6]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccncc3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccncc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
To a solution of 7-(4-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (O.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(4-pyridyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 147) (0.07 g) as pale brown crystals.
Reaction SMILES: [CH2:1]([C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:3]/[CH:2]=[CH:1]/[C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC1(O[Si](C)(C)C)CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](C/C=C/C1(O[Si](C)(C)C)CCCCC1)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16])(=O)=O.[I-:26].[Na+]>CC(C)=O.C(Cl)Cl>[F:16][C:15]([F:18])([F:17])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][I:26]
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2C(F)(F)F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1CI
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A 200 mL round bottomed flask was charge under dry nitrogen with 35.08 g of 2-(trifluoromethyl)-6-nitrobenzyl tosylate dissolved in 100 mL of dry acetone. To this was added slowly with cooling 28.06 g of anhydrous sodium iodide dissolved in 75 mL of dry acetone. This reaction mixture was stirred overnight at room temperature. The mixture was stripped of acetone under vacuum redissolved in methylene chloride and filtered. The filtrate was extracted with 50 mL of distilled water, dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. By this procedure 29.92 g (97% yield) of product was obtained.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C1C=CC=CN=1)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([O:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:29])[CH3:28]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)+