Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]([NH:28]C(=O)OCC1C=CC=CC=1)[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[NH2:28][C@@H:4]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:1]([NH2:2])=[O:3]
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](N)C(N)=O)CC4)CC1
Temperature: 30 °C
Reaction time: 5 h
Yield: 39.6 %

Procedure:
To a solution of benzyl N-[(1S)-1-carbamoyl-2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl]carbamate (40 mg, 0.07 mmol, 1.00 equiv) in dichloromethane (2 mL) was added hydrochloric acid (conc., 1 mL) and the resulting solution was stirred for 5 h at 30° C. The resulting mixture was concentrated under vacuum and the crude product was purified by preparative HPLC under the following conditions (Waters): column: XBridge Prep C18 OBD column: 5 um, 19*150 mm; Mobile phase: water with 0.03% NH3.H2O and CH3CN (13.0% CH3CN up to 30.0% in 10 min, up to 100.0% in 2 min, down to 13.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and concentrated to remove CH3CN and water under reduced pressure. The residue was lyophilized overnight to give (2S)-2-amino-3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (11.2 mg, 37%) as a white solid. MS: m/z 404 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.40-1.50 (m, 4H), 1.68-1.75 (m, 2H), 2.00-2.10 (m, 2H), 2.12-2.18 (m, 1H), 2.25-2.35 (m, 2H), 2.33 (s, 6H), 2.50-2.60 (m, 1H), 2.65-2.75 (m, 1H), 2.90-2.95 (m, 1H), 3.00-3.15 (m, 1H), 3.35-3.48 (m, 2H), 5.20-5.30 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][CH:7]=1.[Li][CH2:34][CH2:35][CH2:36]C.C([Cu])#N.C(Br)C=C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.O>[CH2:36]([C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([CH3:24])[O:20][CH2:21][CH2:22][O:23]4)=[CH:17][CH:18]=3)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:5]2=[N:6][CH:7]=1)[CH:35]=[CH2:34]
Reactant: [Li]CCCC
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: N#C[Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cnc2c(n1)c(CC)c(-c1ccc(C3(C)OCCO3)cc1)n2COCC[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
2-Bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.500 g, 0.964 mmol, Preparation #5) in THF (6 mL) was cooled to about −75° C. then the n-BuLi (2.4 M in hexanes, 0.482 mL, 1.16 mmol) was added dropwise. After about 10 min CuCN (0.009 g, 0.010 mmol) was added followed by allyl bromide (0.250 mL, 2.89 mmol). The mixture was stirred at about −70° C. for about 30 min warmed to about −40° C. the mixture was treated with about 2 mL of saturated aqueous NaHCO3 then warmed to rt. The mixture was diluted with EtOAc (20 mL) and water (10 mL). The layers were separated and the aqueous layer extracted with EtOAc (10 mL). The combined organics were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified on a 10 gram silica column with 9:1 DCM/EtOAc as an eluent to give 2-allyl-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.323 g, 70%): LC/MS (Table 2, Method b) Rt=3.53 min; MS m/z 480 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:11]([CH3:19])[NH:10][C:9]2[CH2:20][O:21][C:22](=[O:23])[C:8]1=2.[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[C:11]([CH3:19])[N:10]([CH2:26][CH3:27])[C:9]2[CH2:20][O:21][C:22](=[O:23])[C:8]1=2
Reactant: CCI
Reactant: CC1=C(C(=O)OC(C)C)C(c2sccc2Cl)C2=C(COC2=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(C)=C(C(=O)OC(C)C)C(c2sccc2Cl)C2=C1COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of isopropyl 4-(3-chloro-2-thienyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3.4-b]pyridine-3-carboxylate are dissolved in 25 ml of dimethylformamide and deprotonated with NaH, and 20 mmol of ethyl iodide are added. After the mixture has been stirred at room temperature for 1 hour, it is concentrated, water is added to the residue and the product is filtered off with suction and recrystallized from methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23](C)(C)[CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC(OCC)=O>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OCC)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of tert-butyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (8.7 g, 24.3 mmol) in CH2Cl2 (40 mL) at rt was added TFA (20 mL) and stirred at rt for 3 hours before the solvent was removed by the nitrogen stream. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, and concentrated to afford an crude residue that was re-dissolved in CH2Cl2 (40 mL) followed by saturated K2CO3 (30 mL), ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5 hour. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.5 g, 67%) as a clear oil. MS [M+H]+332. 1H NMR (CDCl3, 300 MHz): δ 7.00 (t, 1H, J=7.7 Hz), 6.82 (m, 1H), 6.71 (m, 1H), 4.62 (s, 2H), 4.02-4.31 (m, 4H), 3.82 (t, 1H, J=5.5 Hz), 2.82 (t, 1H, J=5.5 Hz), 1.20-1.24 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]2[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]2)[CH2:10][CH2:9]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3ccccc3F)CC2)OC1=O
Yield: 60.2 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.6 g (0.02 mol) of 1-(2-fluorophenyl)piperazine (Emka-Chemie), 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 mL of 1-butanol gave 3.7 g (61%) of white solid, mp 80°-82° C.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[Li]CCCC.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:1]([S:4][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH3:3]
Reactant: CCCS
Reactant: CCOC(=O)CCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCSCCCCCC(=O)OCC
Reaction time: 0.17 h

Procedure:
A solution of propanethiol (0.609 ml, 6.72 mmol) in anhydrous THF (10 ml) was cooled to −10° C. in a nitrogen atmosphere. 2 M nBuLi (4.03 ml, 8.07 mmol) was added dropwise and the mixture was then stirred for 10 minutes. A solution of ethyl 6-bromohexanoate in anhydrous THF (5 ml) was then added and the mixture was stirred for 40 minutes. The reaction mixture was quenched by adding water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give ethyl 6-(propylthio)hexanoate as a colorless oily substance (1.46 g, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cncnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cncnc1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(pyrimidin-5-ylmethyl)pyrrolidine (29.1 g) in methanol (146 ml) was added concentrated hydrochloric acid (12.9 ml) at 5° to 7° C. After the reaction mixture was stirred for an hour at room temperature, 28% sodium methoxide in methanol (29.7 ml) was dropped thereto at 5° C. to 10° C., and then the solution was stirred for 30 minutes at 10° C. Insoluble material was removed by filtration, then the filtrate was concentrated. Acetonitrile (120 ml) was added to the residue, and the mixture was stirred with magnesium sulfate. Magnesium sulfate was removed by filtration and the filtrate was concentrated until the volume amounted to 60 ml. Heptane (80 ml) was added thereto, and the acetonitrile layer was washed with Heptane (80 ml) four times. The acetonitrile layer was evaporated under reduced pressure and then the residue was distilled off with toluene (20 ml) to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(pyrimidin-5-ylmethyl) pyrrolidine (24.1 g) as an oil.
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25](=O)[C:26]([CH3:28])=[CH2:27])=[C:20]2[CH:19]=[CH:18][CH:17]=1>C(O)C.[Pd].C(OCC)(=O)C>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]3[C:26]([CH3:28])=[CH:27][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: C=C(C)C(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: [Pd]
Agent: CC[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cnc(NC2CCCC2)nc1-c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (68 mg, 0.42 mmol) in ethanol (1 mL) was added sodium ethoxide (138 μL, 3 M in ethanol, 0.41 mmol). A solution of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-methyl-2-propen-1-one in ethanol (1 mL) was added and the reaction mixture was allowed to stir at room temperature for 16 hours. An additional aliquot of N-cyclopentylguanidine hydrochloride (68 mg, 0.42 mmol) and sodium ethoxide (138 μL, 3 M in ethanol, 0.41 mmol) in ethanol (1 ml) was added to reaction mixture and allowed to stir an additional 24 hours. Palladium on carbon (10%, 30 mg) was added to reaction mixture and allowed to stir at room temperature for 30 minutes under an atmosphere of air, at which point additional palladium on carbon (10%, 100 mg) was added. The reaction mixture was allowed to stir at room temperature 16 hours. The suspension was diluted with ethyl acetate and filtered through Celite. Concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-5-methyl-2-pyrimidinamine (57 mg, 43%) as a clear oil. Rf 0.24 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.14 (s, 1H), 7.64 (m, 2H), 7.57 (d, 1H), 7.17 (m, 1H), 7.08 (t, 2H), 7.00 (d, 1H), 5.09 (d, 1H), 4.26 (m, 1H), 2.03 (m, 2H), 1.82–1.45 (m, 9H); MS m/z 422 (M+1). To a solution of the product in ether was added 1 M hydrochloride in ether. The precipitated solid was isolated to give the corresponding hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].N1C=CC=CC=1.[CH2:20]([OH:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:29][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: OCC=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)OC/C=C/c1ccccc1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of methyl-2-isocyanatobenzoate (71)(1 g, 5.6 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with pyridine (7 mL, 84 mmol). Cinnamyl alcohol (2.25 g, 1.68 mmol) in CH2Cl2 (150 mL) was added dropwise to the stirring solution over a period of 1 hour and the reaction mixture was allowed to stir for 12 hours, under nitrogen. The reaction mixture was washed in brine (100 mL). The aqueous phase was washed with CH2Cl2 (3×100 mL). The organic phases were combined and washed with 1N HCl (200 mL) and dried over MgSO4. Purification was achieved through flash column chromatography (80% Pet ether:EtOAc) to furnish the carbamate (72) as a colourless solid (85%). 1H NMR (250 MHz, CDCl3) δ 10.9 (br, s, 1H, NH), 8.45 (dd. 1H, J=1.0, 8.5 Hz, aromatic H), 8.01 (dd, 1H, J=1.66, 8.0 Hz, aromatic H), 7.54 (ddd, 1H, J=1.67, 7.3, 8.5 Hz, aromatic H), 7.5-7.2 (m, 5H, coc aromatic H), 7.03 (ddd, 1H, J=1.2, 8.0 Hz, aromatic H), 6.71 (d, 1H, J=16 Hz, 3′-H), 6.35 (dt, 1H, J=6.3, 16 Hz, 2′-H), 4.48 (dd, 2H, J=1.3, 6.3, 1′-H), 3.91 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 169.0 (ester carbonyl), 153.5 (CO-carbamate), 141.9 (aromatic quat), 136.8 (aromatic quat), 135.0 (methine), 131.3 (methine), 129.0 (methine), 128.4 (methine), 127.1 (methine), 123.9 (alkenic methine), 122.0 (methine), 119.3 (methine). 114.8 (aromatic quat), 66.1 (methylene-Coc), 57.7 (OCH3). IR (neat) ν 3295, 3116, 3025, 2957, 2242, 1956, 1927, 1814, 1732, 1697, 1592, 1532, 1450, 1305, 1245, 1165, 1090, 1038, 976, 913, 856, 836, 819, 766, 743, 692 cm−1; MS m/z 311 (M+. +1), 268, 212, 188, 152, 117.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]=2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:31]=[CH:30][C:29]([NH:28]/[C:17](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]\2=3)=[CH:34][CH:33]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2cc(C(=O)OC)ncc21)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cn1)/C(=C(/Nc1ccc(N(C)C(=O)CN3CCN(C)CC3)cc1)c1ccccc1)C(=O)N2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (40 mg, 0.109 mmol) in DMF (0.2 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (28 mg, 0.109 mmol) at room temperature, and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was cooled to RT, piperidine (0.2 mL) was added and stirred for 10 minutes at room temperature. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([C:12]([C:14]3[CH:19]=[C:18]([Br:20])[C:17]([O:21]C)=[C:16]([Br:23])[CH:15]=3)=[O:13])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.ClCCl.CO>ClC(Cl)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[N:10]([C:12]([C:14]3[CH:15]=[C:16]([Br:23])[C:17]([OH:21])=[C:18]([Br:20])[CH:19]=3)=[O:13])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ccnc(Cl)c32)cc1Br
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
In a 5 ml flask equipped with a reflux apparatus, (5-chloro-2,3-dihydro -pyrido[4,3-b][1,4]oxazin-4-yl)-(3,5-dibromo-4-methoxy-phenyl)-methanone (48 mg, 0.1 mmol) was dissolved in dichloroethane (0.5 ml) and chloroform (0.5 ml). 1.0M Boron tribromide dissolved in dichloromethane (1 ml, 1 mmol) was added thereto dropwise at room temperature. The reaction mixture was stirred at 450 for 18 hours. After cooling to room temperature, methanol (1 ml) was added and then stirred at room temperature for 10 minutes. After evaporating under reduced pressure, dichloromethane was added and then stirred. The reaction mixture was filtered to obtain the target compound 30 as white solid (24 mg, 54%).
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].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)#[CH:21]>>[O:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]#[C:21][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:27][CH:26]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C#Cc1ccc(Oc2ccccc2)cc1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(Oc3ccccc3)cc2)c1)c1ccccc1
Yield: 68 %

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 1-ethynyl-4-phenoxybenzene were reacted to give the title compound as an off-white solid (95 mg, 68%).
Reaction SMILES: [C:1]([O:4][C:5]1([C@@:9]2([C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:13][C@H:12]([N:14]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C@@H:15]3[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]3)[CH:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt].[Pd]>[C:1]([O:4][C:5]1([C@:9]2([C:29]([OH:31])=[O:30])[CH2:10][CH2:11][C@@H:12]([N:14]([C:23](=[O:28])[C:24]([F:27])([F:25])[F:26])[C@@H:15]3[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]3)[CH2:13]2)[CH2:6][CH2:7][CH2:8]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(OC(C)=O)CCC2)C1
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)O)(C2(OC(C)=O)CCC2)C1
Yield: 102.6 %

Procedure:
A mixture of 2.62 g (4.86 mmol) of 3-[{(1S,4R)-4-[1-(acetyloxy)cyclobutyl]-4-[(benzyloxy)carbonyl]cyclopent-2-en-1-yl}(trifluoroacetyl)amino]-1,5-anhydro-2,3-dideoxy-4-O-methyl-D-erythro-pentitol and 750 mg each of 5% Pt/C and 5% Pd/C in 10 mL of acetic acid was stirred rapidly under 50 psi hydrogen gas for 18 h, then filtered through diatomaceous earth to remove catalyst. The filtrate was concentrated under reduced pressure, with added toluene to azeotropically remove acetic acid, to provide 2.25 g (103%) of the title compound as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.71 (m, 3H) 1.74-1.84 (m, 1H) 2.02 (s, 3H) 2.04-2.17 (m, 1H) 2.34-2.55 (m, 5H) 2.60 (dd, J=14.3, 8.5 Hz, 1H) 2.66-2.81 (m, 2H) 3.30 (d, J=13.0 Hz, 1H) 3.35-3.39 (m, 1H) 3.42 (s, 3H) 3.47-3.56 (m, 1H) 3.83-3.91 (m, 1H) 4.13 (dd, J=11.6, 4.4 Hz, 1H) 4.16-4.23 (m, 1H) 4.26-4.38 (m, 1H). LC-MS ES+ 452.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:11]2[NH:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:36])=[C:11]2[NH:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)C2
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)C2

Procedure:
The desired product was prepared from 6-(2-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=8.4 Hz, 2H), 7.53-7.44 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.19-7.09 (m, 4H), 7.06-7.99 (m, 2H), 6.84 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 6.61 (t, J=7.6 Hz, 1H), 5.20 (s, 2H), 4.24 (dd, J=4.0, 12.0, Hz, 1H), 4.07 (dd, J=12.0, 12.0 Hz, 1H), 3.56-3.41 (m, 3H). MS (ESI, m/e) [M+1]+ 425.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of chloroform (4 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with chloroform (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (141 mg, 42%, 94% e.e.) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)cc1
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Yield: 92 %

Procedure:
A solution of 4-chlorophenyl-2-(pyridin-4-yl)ethan-1-one (20.0 g, 86.4 mmol) and N,N-dimethylformamide dimethylacetal (57.6 mL, 0.43 mole) was heated at 100° C. for 3½ hours. The reaction mixture was concentrated in vacuo, and the residue crystallized from methyl butyl ether to give 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 93%). 1H NMR (CDCl3/300 MHz) δ 8.52 (d, 2H), 7.38 (d, 2H), 7.29 (d, 2H), 7.08 (d, 2H), 2.83 (s, 6H).