Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([B:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:5]1.Cl.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:43](O)=[O:44])=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:43](=[O:44])[C@@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([B:27]4[O:28][C:29]([CH3:34])([CH3:35])[C:30]([CH3:32])([CH3:33])[O:31]4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:5]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C2CCOCC2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.50 g, 1.03 mmol) in a mixture of CH2Cl2 (10 mL) and methanol (1.0 mL) was added HCl (4M in dioxane, 6.00 mL, 24 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature and concentrated to dryness. The crude solid was suspended in CH2CL2 (10 mL), followed by the addition of (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.260 g, 1.20 mmol), HATU (0.475 g, 1.25 mmol) and DIPEA (0.60 mL, 3.44 mmol). The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2CL2 and washed with a mixture of sodium bicarbonate (aqueous, sat) and brine. The aqueous layer was back-extracted with CH2CL2. The combined organic layers were dried over Na2SO4 and concentrated to provide a crude oil. Purification by column chromatography (SiO2, 10-100% EtOAc (10% MeOH)/Hexanes) provided methyl (S)-2-((2S,4S)-4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (0.483 g, 80%). MS (ESI) m/z 583.333 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid (0.12 g) was reacted with 2-(piperidin-4-yl)propan-2-ol (1.2 eq), HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq) and DIPEA (3 eq) in DMF (3.2 mL) for 1 hour. The reaction was then extracted with EtOAc and bicarbonate solution and the organic layer was dried with Magnesium sulfate, filtered and concentrated to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone in quantitative yield.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[CH:38][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][N:28]5[C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=[C:27]5[CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CN(C=O)C>CO.C1COCC1.C(O)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[CH:38][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][N:28]5[C:31]([C:34]([F:37])([F:35])[F:36])=[N:32][N:33]=[C:27]5[CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCn5c(nnc5C(F)(F)F)C4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(N4CCn5c(nnc5C(F)(F)F)C4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (35 mg, 0.052 mmol) and 5M sodium hydroxide (0.21 mL, 1.04 mmol) in methanol (0.3 mL) and THF (1.0 mL) was heated 45° C. for 2 h. Acetic acid (1 drop) and DMF (0.3 mL) were added and mixture concentrated to ˜0.3 mL, diluted with methanol, filtered and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give product after lyophilization. LCMS-ESI+: calc'd for C31H29ClF3N6O3S: 657.2 (M+H+); Found: 657.3 (M+H1); NMR (400 MHz, CD3OD) δ 8.22 (d, J=5.5 Hz, 1H), 7.81 (s, 1H), 7.66 (dd, J=8.7, 1.8 Hz, 1H), 7.62-7.49 (m, J=10.0, 7.3 Hz, 4H), 7.32 (dd, J=5.5, 1.3 Hz, 1H), 5.24 (s, 1H), 5.07 (s, 2H), 4.36 (t, J=5.2 Hz, 2H), 4.20 (t, J=5.3 Hz, 2H), 2.57 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:1]1([CH2:6][CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C1CSCCN1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C1CCN(CC2CSCCN2)C1
Yield: 92.1 %

Procedure:
A solution of 1.6 g of 3-(pyrrolidine-1-carbonyl)thiomorpholine in 200 ml of tetrahydrofuran was added dropwise to a mixture of 1.0 g of lithium aluminum hydride and 100 ml of tetrahydrofuran under ice-cooling and a stream of nitrogen. Excess lithium aluminum hydride was decomposed using 15 g of sodium sulfate decahydrate. Celite filtration using methylene chloride was carried out. The solvent was concentrated under reduced pressure to yield 1.37 g (93%) of 3-(pyrrolidin-1-ylmethyl)thiomorpholine.
Reaction SMILES: COC(C)(C)C.CCCCCC.[CH2:13]([O:20][C:21]([NH:23][C:24]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>P([O-])([O-])([O-])=O.O1CCCC1>[CH2:13]([O:20][C:21]([NH:23][C@:24]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Yield: 36 %

Procedure:
0.5 g of esterase (PLE (21 kU/g); manufactured by Sigma-Aldrich Corporation, lyophilized powder) were dissolved in 200 mL of 0.07 mol/L phosphate buffer solution of which pH value was adjusted to 6-5 and thereto, a solution in which 10 g of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide were dissolved in 20 g of tetrahydrofuran was added. The resultant mixture was stirred at 30° C. for 48 hours and thereto, 100 mL of t-butyl methyl ether were added. Thereafter, the resultant mixture was filtered with Celite (No. 545) and washed with 50 mL of t-butyl methyl ether. After the filtrate was removed, the organic phase was washed with 100 ml, of water several times and the solvent was distilled off under reduced pressure. Thereafter, the product was recrystallized in ethyl acetate and hexane to thereby obtaining 3.6 g (yield: 36%) of (R)-2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide having an optical purity of 98.9% e.e. (enantiomeric excess) as a white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:4]2[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:14][CH2:13]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Br)cc1N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 36 h

Procedure:
A mixture of 4-bromo-2-fluorobenzoic acid (2 g, 9.1 mmol), benzyl piperazine-1-carboxylate (2.4 g, 10.9 mmol) and K2CO3 (2.5 g, 18.26 mmol) in DMF (40 mL) was stirred at 150° C. for 36 h. The reaction was then cooled to RT and extracted with ethyl acetate, 3 N HCl, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(4-((benzyloxy) carbonyl)piperazin-1-yl)-4-bromobenzoic acid as yellow oil that was used without further purification.
Reaction SMILES: [S:1]([NH:11][C:12]1[N:17]2[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=[C:16]2[CH:15]=[CH:14][N:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[I:25]N1C(=O)CCC1=O>C(Cl)Cl>[I:25][C:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[N:24][C:18]=2[N:17]2[C:16]=1[CH:15]=[CH:14][N:13]=[C:12]2[NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(S(=O)(=O)Nc2nccc3cc4cccnc4n23)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2nccc3c(I)c4cccnc4n23)cc1
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
To a solution of 23a (10 mg, 0.03 mmol) in CH2Cl2 (5 ml) at −30° C. N-iodosuccinimide (7 mg mg, 0.03 mmol) was portionwise added and the mixture was stirred for 15 min. The solution was washed with water and the organic solutions was dried, filtered and evaporated to obtain 24a (14 mg, 95%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][C:13]2[CH:12]=[C:11]([C:16]#[N:17])[CH:10]=[CH:9][C:8]1=2)[CH3:3].CNCCC[C@]1(C2C=CC(F)=CC=2)OCC2C=C(C#N)C=CC1=2.C=O.O.O.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(O)C.C(O)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][C:13]2[CH:12]=[C:11]([C:16]#[N:17])[CH:10]=[CH:9][C:8]1=2)[CH3:3].[C:53]([OH:55])([C:52]([OH:57])=[O:56])=[O:54]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: C=O
Agent: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: O=C(O)C(=O)O
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To the crude Citalopram (90 g, 0.28 mol) having desmethyl citalopram (7%, HPLC), formic acid (98%, 2.7 g) was added followed by aqueous formaldehyde (35%, 2.37 g). The reaction mass was heated at 85-95° C. for 30 min. HPLC indicated complete conversion of desmethyl impurity into Citalopram. The reaction mass was cooled to 30° C. and diluted with ethanol (900 ml). Oxalic acid dihydrate (41.94 g, 0.33 mol) was added and mass was heated to reflux. The obtained solution was cooled to 20-25° C. and stirring was continued for 2 hours at 20-25° C. The product thus obtained was filtered and crystallized from ethanol to provide highly pure 92 g of crystalline Citalopram oxalate having HPLC purity 99.7% and desmethyl citalopram impurity: Not Detected.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C@@H:25](O)[CH2:24]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:7]([O:9][C@@H:25]2[CH:26]3[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(3-methoxyphenylamino)acetic acid (I46) (1.02 g, 3.25 mmol), (R)-quinuclidin-3-ol (496 mg, 3.90 mmol), DCC (805 mg, 3.90 mmol), and HOBT (597 mg, 3.90 mmol) in dry THF (30 ml) was stirred at r.t. overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 1M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(3-methoxyphenylamino)acetate (213 mg, 15.5% yield over two steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:12][CH2:13][CH:14]=[CH2:15])([C:8]([F:11])([F:10])[F:9])C=C)[CH3:2]>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1([C:8]([F:9])([F:10])[F:11])[CH:15]=[CH:14][CH2:13][O:12]1)=[O:16])[CH3:2]
Reactant: C=CCOC(C=C)(C(=O)OCC)C(F)(F)F
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CCOC(=O)C1(C(F)(F)F)C=CCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-allyloxy-2-trifluoromethyl-but-3-enoic acid ethyl ester (2.15 g, see above) in CH2Cl2 (100 mL) at room temperature was added Grubbs catalyst 2nd generation (Aldrich) (67 mg). The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was then filtered through a plug of Celite® and silica gel, rinsed with EtOAc and then concentrated to yield the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]Cl)#[N:8]>ClC1C=CC=CC=1>[N:1]1([C:7]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SCl
Reactant: C1CNCCN1
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 74.6 %

Procedure:
86.2 g (1.00 mol) of piperazine and 7.5 g of chlorobenzene were placed in a four-neck 500 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 53.5 g (0.25 mol) of 2-cyanobenzenesulfenyl chloride was added dropwise in the melted state at about 130 ° C. over 1 hour while stirring, which was thereafter stirred for 4 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 40.9 g (m.p. 89° to 90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 2-cyanobenzenesulfenyl chloride was 74.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(C2=Nc3ccccc3Oc3ccc(Cl)cc32)CC1
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 3.4 g of 2-chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine, 2.00 g of ethyl bromoacetate and 1.38 g of potassium carbonate in 16 ml of N,N-dimethylformamide was stirred at 60°-70° C. for 3 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 3.12 g of yellow crystals, which were recrystallized from n-hexane to give yellow prisms, mp 123°-123.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][CH:15](OCC)OCC)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[K+]>CO.O>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][NH:13][C:11]1=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(CNC(=O)NCCNC(=O)OC(C)(C)C)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1cc[nH]c1=O
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Dissolve {2-[3-(2,2-diethoxy-ethyl)-ureido]-ethyl}-carbamic acid tert-butyl ester (6.5 g, 20.35 mmol) in methanol (75 mL) and water (40 mL). To the reaction mixture add HCl (0.4 N, 50 mL) dropwise over 30 min. Stir the mixture overnight and neutralize by adding KOH (0.4 M, 50 mL), and concentrate in vacuo. Extract the residue in chloroform and wash with saturated aqueous sodium chloride, dry over MgSO4, filter and remove solvent on a rotovap to give a crude white solid. Purify by column chromatography 1% to 10% MeOH in dichloromethane to afford the pure product as a white solid (2.53 g, 11.13 mmol). GCMS (EI) m/z 227 M+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](OB(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCCC1>[CH3:30][CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:35][CH:34]=1)[CH3:31]
Reactant: CC(C)Oc1ccc(OB(O)O)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (6.00 g), 4-isopropoxyphenylboric acid (5.85 g), copper(II) acetate (5.90 g), pyridine (18 mL), triethylamine (9 mL), molecular sieves 4A (18.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 1 day. Ethyl acetate (100 mL) was added to the reaction mixture, the mixture was stirred at room temperature for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile as a colorless solid (6.53 g, 80%). A mixture of 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (6.53 g) and 25% hydrobromic acid-acetic acid solution (10 mL) was stirred under refluxing for 2 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with 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 to give the title compound as a colorless solid (4.38 g, 73%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)(=O)[CH3:2].Br[C:14]1C=CO[CH:15]=1>C1COCC1.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.[Cl-].[Zn+2].[Cl-]>[O:4]1[CH:1]=[CH:2][C:6]([C:7]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[C:14]=[CH2:15])=[CH:5]1
Reactant: CC(=O)OCC#Cc1ccoc1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=C=C(c1ccoc1)c1ccoc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
To a mixture of 3-(3-acetyloxy-l-propynyl)furan (1.44 g, 8.7 mmol), 3-bromofuran (2.55 g, 0.017 mol), and Pd(P(C6H5)3)4 (1.0 g, 0.8 mmol) in THF was added added zinc chloride (0.5M in THF, 34 ml, 0.017 mol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica column chromatography (methylene chloride/hexane, 2:1) to afford 1.25 g (85%) of [1,1-di(3-furyl)]-1,2-propadiene (Formula III: R3 and R4 together form =CH2 ; R5 =R6 =3-furanyl) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11](=[O:27])[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=1)[CH2:13]OCC.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11](=[O:27])[C:12]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=1)=[CH2:13]
Reactant: CCOCC(C(=O)c1ccc(OC)cc1OC)c1ccc(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=C(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1

Procedure:
0.0406 g (1.08 mmol) of 1-(2,4-dimethoxyphenyl)-2-(3′,4′-dimethoxyphenyl)-1-oxo-3-ethoxy-propane were reacted with boron tribromide (10.84 mmol) in 22 mL dichloromethane for three days by the method of Bannwart C. et al., Finn. Chem. Lett. 11 120 (1984). Workup and chromatography of the reaction product afforded 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene as the minor product and 1-(2,4-dihydroxy)-2-(3′,4′-dihydroxyphenyl)-1-oxo-3-bromo-propane as the major product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:10]=[C:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:10]=[C:9]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:6][CH:7]=1)(=[O:32])[CH3:31]
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-n2c(-c3ccccc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
1-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(1-piperidinyl)-1H-imidazole-4-carboxamide (Example 45) (51 mg, 0.12 mmol) was dissolved in dry dichloromethane (2 mL) and treated with acetic anhydride (14 μL, 0.15 mmol) dropwise. The solution was stirred at rt for 4 h, and then the solvent was evaporated to give an amber oil. It was purified by HPLC (YMC-packed Pro C18 15×200 mm column, 30-90% CH3CN in H2O/TFA, 20 mL/min.) to afford an off-white solid (13 mg, 15%): LC-MS m/z 452.3 (MH+), retention time 2.31 min (method 1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>>[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(O)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 17 %

Procedure:
In a manner similar to that describe in Example 425, a mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 3-hydroxy-1-ethynylbenzene were reacted to give the title compound as an off-white solid (19 mg, 17%).