Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[N:47]1[CH2:52][CH2:51][C:50]2[C:53]3[CH2:59][CH2:58][CH2:57][CH2:56][C:54]=3[S:55][C:49]=2[C:48]1=[O:60])(=[O:29])[CH3:28]>>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[C:48](=[O:60])[C:49]3[S:55][C:54]4[CH2:56][CH2:57][CH2:58][CH2:59][C:53]=4[C:50]=3[CH2:51][CH2:52]2)=[CH:34][CH:35]=[CH:36][C:37]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][O:25][CH2:26]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C4COC4)CC3)cc2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C5COC5)CC4)cc3)n2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 68 %

Procedure:
Following Example 136e, 5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one 214b and (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a afforded 305a in 68% yield. LCMS: (M+H)+ 694
Reaction SMILES: [O:1]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[CH2:19]1[O:22][CH:20]1[CH3:21]>CO>[OH:22][CH:20]([CH3:21])[CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:2](=[O:1])[CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:14][CH2:15]1
Reactant: CC1CO1
Reactant: O=Cc1cccc(OCC(=O)N2CCNCC2)c1
Solvent: CO
Product: CC(O)CN1CCN(C(=O)COc2cccc(C=O)c2)CC1
Temperature: 70 °C
Yield: 50 %

Procedure:
3-(2-oxo-2-(piperazin-1-yl)ethoxy)benzaldehyde (50) (1 eq) was taken in MeOH to which propylene oxide (4 eq) was added and the reaction mixture was heated in a sealed tube at 70° C. for 16 h when LCMS showed completion of reaction. The reaction mixture was concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (50%) as a colorless oil. LCMS: 96.31% (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2cccc(OC)c2)c1

Procedure:
3-Methoxyphenylboronic acid (1.00 g) and ethyl 2-chloroisonicotinate (1.20 g) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2ncccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 377.15 g/mol.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH3:15])=[N:13][N:14]=3)[C:5]=2[CH:4]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Br)(=O)C>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=3)[C:5]=2[CH:4]=1
Reactant: Cc1nnc2n1-c1cc(C(F)(F)F)ccc1C(c1ccccc1)=NC2
Agent: CC(=O)Br
Agent: CCN(CC)CN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCc1nnc2n1-c1cc(C(F)(F)F)ccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 9-trifluoromethyl-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N',-tetraethyldiaminomethane and acetyl bromide (in 0.2 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 9-trifluoromethyl-1-[2-(diethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[CH:9]([N:12]=[N:13][C:14]1(Cl)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10].[OH-].[Na+]>>[CH:9]([N:12]=[N:13][C:14]1([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OO
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N=NC1(OOC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 24.7 grams (0.11 moles) of 25% potassium hydroxide in an erlenmeyer flask equipped with a magnetic stirrer, thermometer and addition funnel was added 14.0 grams (0.14 moles) of 90% tert.-butylhydroperoxide while holding the temperature below 30° C with a cold water bath. After the addition was complete, the reaction was stirred for 30 minutes at room temperature, cooled to 18° C and with rapid stirring 18.85 grams (0.1 mole) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise from the addition funnel over 40 minutes while holding the reaction temperature at 20° C ± 2° C. After the addition was complete, the reaction was stirred for 10 minutes at 15° C, cooled to 0° C and stirred an additional 30 minutes. At this point, 3.2 grams (0.04 mole) of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 100 ml of ice water and the product extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the pentane evaporated at 0° C under reduced pressure on a rotating evaporator. The product was a light yellow liquid weighing 18.7 grams (77% crude yield). It was stored in dry ice chest to prevent decomposition and it was not shock sensitive. The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(tert.-butylperoxy)cyclohexane (absence of the carbon-chlorine band of the starting material at 800-825 cm-1 and the presence of a tert.-butylperoxy band around 885 cm-1.) The presence of a weak OH band at 3350cm-1 indicates that a small amount of 1-isopropylazo-1-hydroxycyclohexane also formed.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([CH2:22][NH2:23])[CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[S:41]([NH:23][CH2:22][C:11]1[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=1)(=[O:42])=[O:43]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1S(=O)(=O)NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl amine hydrochloride (391 mg, 1 mmol) was suspended in dry dichloromethane (10 mL), and diisopropylethylamine (323 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. 2-Chloro-6-methyl-benzenesulfonyl chloride (225 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solution was then washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 2-chloro-N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-ylmethyl]-6-methyl-benzenesulfonamide which was purified by column chromatography using dichloromethane/methanol (98:2) (440 mg, 81% as a cream solid).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:32])[C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:6][CH2:5]1>[Pd].CO>[CH3:32][N:3]([CH3:2])[C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Reaction time: 20 h
Yield: 13 %

Procedure:
Palladium-on-charcoal (5%, 120 mg) was added to a solution of 2-[4-dimethylamino-4-(3-fluorophenyl)-cyclohexylidene]-N-[2-(1H-indol-3-yl)-ethyl]-acetamide (base of Example 25; 660 mg; 1.55 mmol) in abs. methanol (100 ml). The reaction mixture was hydrogenated at 40° C. under a pressure of 3 bar for 20 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue by chromatography on silica gel (45 g) with EA/methanol (5:1) and methanol, the less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)ethyl]acetamide was isolated in a yield of 13% (86 mg) and the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)ethyl]acetamide was isolated in a yield of 59% (391 mg). Both amides were colourless oils and diastereomerically pure.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:18])[C:3]=1[C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]>O1CCCC1.[Pt]=O>[NH2:15][C:13]1[CH:14]=[C:9]2[O:8][CH2:7][CH2:6][N:5]3[C:4](=[O:18])[C:3]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)=[O:20])=[C:2]([OH:1])[C:11]([CH:12]=1)=[C:10]23
Reactant: O=C(c1c(O)c2cc([N+](=O)[O-])cc3c2n(c1=O)CCO3)N1CCc2ccccc21
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Nc1cc2c3c(c1)c(O)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-nitro-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.5 g) and platinum oxide (0.1 g) in tetrahydrofuran (150 ml) was stirred under hydrogen (3 atm.) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (60 g) eluting with chloroform-methanol (20:1). The desired product was washed with ethanol to give crystals of 2,3-dihydro-9-amino-7-hydroxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.2 g).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](O)=[O:19])=[CH:16][C:3]1=2>O1CCCC1>[CH:16]1[C:3]2[CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][CH2:18][OH:19]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
A solution of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (100 g) in 450 ml dry tetrahydrofuran (THF) at -5° C. was treated with a 1M solution of boran-THF complex (373 ml in THF) under a nitrogen blanket. After stirring at ambient temperature for 72 hours, the reaction was quenched with methanol then diluted with water. Evaporation of the organic phase left an oily biphase which was basified with saturated sodium bicarbonate and extracted into dichloromethane. The organic phase was dried and evaporated to an oil which was purified by flash chromatography to give 14 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)ethanol as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Br:24][C:25]1[CH:26]=[N:27][C:28]([NH:21][CH2:20][C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:22][CH3:23])=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (3.47 g) is dissolved in dioxane (50 ml), and thereto are added 5-bromo-2-chloropyrimidine (5.30 g) and N,N-diisopropylethylamine (5.74 ml) and the mixture is stirred at 100° C. for 2 hours and a half. The reaction solution is allowed to cool to room temperature, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=50:1→22:3) to give (5-bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (4.82 g). MS (m/z): 482/480 [M+H]+
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15]O>C1COCC1.O.[O-2].[O-2].[Mn+4]>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:15][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: OO
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
In a 25 mL scintillation vial equipped with a magnetic stirrer, trans-stilbene (1.80 g, 10 mmol) was placed followed by addition of 2.8 mL THF.6 To this solution was added BTSP (2.8 g, 15 mmol). The vial was immersed into ice/water bath. After 5 minutes Re2O7 (24 mg, 0.05 mmol) was added dropwise as a solution in 1.2 mL THF.7 The reaction turned yellow and was allowed to warm up to room temperature and stirred for 10 h. Upon completion, water (3 drops) was added followed by manganese dioxide (ca. 5 mg) in order to decompose the remaining H2O2. The destruction of H2O2 was evident by the disappearance of yellow color. The mixture was then dried over Na2SO4. Concentration afforded trans-stilbene oxide (1.88 g, 96% yield) of as an off-yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([CH:11]([C:38](=[O:40])[NH2:39])[O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]=1)=[O:17])(C)C.N1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:31][O:30][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][C:25]=1[O:28][CH3:29])[C:18]([C:16](=[O:17])[C:15]1[CH:35]=[CH:36][CH:37]=[C:13]([O:12][CH2:11][C:38](=[O:40])[N:39]3[CH2:46][CH2:45][S:44][CH2:43][CH2:42]3)[CH:14]=1)=[N:19][CH:20]=[C:21]2[C:32]([OH:34])=[O:33]
Reactant: C1CSCCN1
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC(C(N)=O)C(C)C)c3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCSCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropyl-carbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.04 ml of thiomorpholine (0.4 mmol). The mixture was shaken for 15 minutes at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-[3-(2-oxo-2-thiomorpholin-4-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [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:17][C:16]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:3]=1.CO.O.C1C=C(C([O-])=[O:34])C(C(O[O-])=O)=CC=1.[Mg+2].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:34])[C:13]2[NH:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: -10 °C
Reaction time: 0.58 h
Yield: 91.3 %

Procedure:
To a solution of 3.44 g of pyrmetazole (10.5 mmol) in 30 mL of 9:1 v/v methanol/water at -10° C. was added dropwise a solution of 3.10 g of MMPP in 30 mL of 9:1 v/v methanol/water over a 10 minute period. The reaction mixture was stirred at -10° C. for 35 minutes then poured into a mixture of 100 mL of saturated aqueous sodium bicarbonate and 40 mL of methylene chloride. The layers were separated and the aqueous layer was extracted 3 times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was slurried in EtOAc and the slurry stirred for 10 minutes. The solid was collected and then dried to provide 3.31 g of omeprazole (92% yield). LC analysis showed that the product was 99.5% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
N-n-propyl-N-2-(2,4,6-trichlorophenoxy)-ethylamine is prepared by selectively chlorinating 2-phenoxy ethanol by reacting it with chlorine either in the presence of hydrogen chloride at a temperature of from -10° C. to 50° C. or in the presence of urea at a temperature of from 20° C. to 55° C. in a water/carbon tetrachloride solvent mixture to form 2-(2,4,6-trichlorophenoxy)ethanol; reacting the 2-(2,4,6-trichlorophenoxy)ethanol with thionyl chloride in the presence of a catalytic amount of tetraalkyl ammonium chloride, optionally in the presence of a solvent to form 2-(2,4,6-trichlorophenoxy)ethyl chloride; and reacting the 2-(2,4,6-trichlorophenoxy) ethyl chloride with n-propylamine at a temperature of from 20° C. to 150° C., optionally in the presence of water to form N-n-propyl-N-2-(2,4,6-trichlorophenoxy) ethyl amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:13]([CH3:18])=[C:14]([F:17])[C:15]=1[F:16])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:13]([CH3:18])=[C:14]([F:17])[C:15]=1[F:16])[C:5]([C:7](=[CH:20][O:21][CH2:22][CH3:23])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(Cl)c1F
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Yield: 100.8 %

Procedure:
Employing ethyl 3-chloro-2,4,5-trifluoro-6-methylbenzoylacetate (300 mg) and ethyl orthoformate (550 mg), the procedure of Reference Example 20 is repeated to give ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate (360 mg), as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][S:34]([CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:35])=[O:36])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (example 28) to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 649.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COCCN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with aminoethylmethyl ether using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 2.15 (brs, 1H); 2.76 (t, 2H); 3.25 (s, 3H); 3.46 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.51 (m, 2H); 8.33 (s, 1H); 8.44 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 391.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:14][C:15](Cl)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]1[C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[O:12][CH2:14][C:15]1=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1cnc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2c(cnc3ccccc23)N1
Reaction time: 0.5 h

Procedure:
In a 50 ml flask equipped with a reflux apparatus, 3-amino-quinolin-4-ol (421 mg, 2.628 mmol) was dissolved in N,N-dimethyl formamide (13 ml) under nitrogen atmosphere, and then chloroacetyl chloride (0.21 ml, 2.76 mmol) was added thereto dropwise at 0□, and then stirred at 0□ for 30 minutes. Potassium carbonate (24 g, 177 mmol) was added thereto and the mixture was heated to 100□ under reflux. After 16 hours, N,N-dimethyl formamide solvent was evaporated under reduced pressure and methanol was added to the residue, and then the mixture was filtered on celite. The filtrate was evaporated under reduced pressure to obtain the target compound, i.e., 1H-4-oxa-1,9-diaza-phenanthren-2-one, as brown solid (526 mg, quantitative yield).