Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([C:28]#[C:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(C#CC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CCC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)benzoate (655 mg, 1.477 mmol) in ethanol (30 mL) and EtOAc (5 mL) was added palladium on activated carbon (10% wt., 400 mg). The reaction mixture was evacuated and backfilled with nitrogen gas. The reaction mixture was evacuated and backfilled with hydrogen gas. The reaction mixture was allowed to stir overnight at RT. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Ethanol (10 mL) and palladium on activated carbon (10% wt., 500 mg) were added. The reaction mixture was evacuated and backfilled with hydrogen and allowed to stir overnight at RT. The reaction mixture was filtered through a pad of celite. The solvent was removed under reduced pressure and methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoate was obtained as a yellow-tan residue and used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH:30][CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH3:31])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH3:29]
Reactant: CCNC
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: CCN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with ethylmethylamine at 22° C. to give the title compound as a white solid. MS: 417.3 ([M−H]−).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9].C(N(CC)CC)C.[C:23](#[N:26])[CH:24]=[CH2:25]>O>[C:23]([CH2:24][CH2:25][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9])#[N:26]
Reactant: C=CC#N
Reactant: NCCCCNC(=O)C(O)C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: N#CCCNCCCCNC(=O)C(O)C(O)C(=O)O

Procedure:
2.01 Grams (9.127 mmoles) of N-(4-aminobutyl)tartaric acid monoamide (IX) obtained in 1. was dissolved in 40 ml of water, and after adding 1.273 ml of triethylamine and then 0.726 ml of acrylonitrile, the resulting mixture was stirred for 27 hours at room temperature. The reaction solution was then dried to solid under reduced pressure. After adding 20 ml of water to the residual solid, the resulting solution was passed through a column packed with 300 ml of Dowex® 1×4(OH-), and after washing with 1.2 liters of water, eluted with 0.5N aqueous acetic acid solution. The fractions containing the objective compound were collected and concentrated under reduced pressure to obtain 2.235 g of a syrup-form N-[4-(2-cyanoethyl)aminobutyl]tartaric acid monoamide (XI) (yield, 89.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 69.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-methylphenyl boronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:3); mp 98-100° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:7]=1
Reactant: BrCC1CCCCC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCCC3)n(CC3CCCCC3)c2cc1F
Yield: 56 %

Procedure:
To the solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) (98 mg, 0.26 mmol) in acetone (10 ml) was added cesium carbonate (127 mg, 0.39 mmol) followed by bromomethyl-cyclohexane (42 mg, 0.31 mmol; CAS Reg. No. 2550-36-9) and the reaction was refluxed for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel (30-40% ethyl acetate/n-hexane) to afford the desired product as an off-white powder (56%). MS (Turbo Spray): m/z=473.0 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH:8][N:7]([CH3:10])[CH3:6])[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of Vilsmeyer reagent, (formed from a stirred mixture of 92.0 g. of phosphorus oxychloride and 73.0 g. of N,N-dimethylformamide at a temperature below 10° C.) is added 34.12 g. of 4-chlorophenylacetic acid. This mixture is stirred at ambient temperature for 30 minutes, then is heated to 70°-80° C. during which time the mixture becomes effervescent. The mixture is kept at 70°-80° C. for 5.5 hours, then is allowed to cool. The cooled mixture is slowly poured onto cracked ice, and ice is added intermittently to maintain the temperature of the mixture below 15° C. during the portionwise addition of potassium carbonate and until pH 10 is achieved. Then 150 ml. of toluene is added and the mixture is heated on a steam bath for one hour. After cooling, the layers are separated and the aqueous layer is extracted with an additional 100 ml. of toluene. The organic layers are combined, copiously washed with water, dried over anhydrous sodium sulfate and evaporated at reduced pressure to yield a yellow solid. The solid is recrystallized from hexane to give 27.3 g. of the product of the Example as a tan solid, mp. 121°-124° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(I)ccc1O
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1O[C@@H](CCCl)c1ccccc1
Yield: 69.5 %

Procedure:
The compound [S]-(-)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 12) was prepared in the same manner as Compound 2 in Example 1 but using [R]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol) and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.58 g (69%) of Compound 12 as a thick pale yellow liquid: [α]25D +14.97 (c 10.73, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 7.42-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.6, 8.8 Hz, 1H), 3.83-3.73 (m, 1H), 3.65-3.55 (m, 1H), 2.55-2.40 (m, 1H), 2.29-2.13 (m, 1H), 2.25 (s, 3H), FTIR (neat) 3050, 3015, 2950, 2900, 1600, 1480 (s), 1460, 1395, 1350, 1300, 1250(s), 1200, 1135 cm-1. Anal C17H20INO; C, H.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:16][CH3:17])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc(Cl)c(Cl)c1=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.00 g (24.2 mmol) of 4,5-dichloro-2H-pyridazin-3-one (CAS: [932-22-9]) and 6.70 g (48.5 mmol) of potassium carbonate in 40 ml of acetone were added 3.92 ml (7.56 g, 48.5 mmol, 2 eq.) of ethyl iodide. The suspension was stirred for 8 h at 55° C. and allowed to cool to room temperature. The reaction was filtered and the solids were washed twice with acetone. The filtrate was concentrated in vaccuo, taken up in ethyl acetate and the precipitated salts were filtered off. The filtrate was concentrated in vaccuo, taken up in methylene chloride and purified by flash chromatography (SiO2, heptane:ethyl acetate 80:20 v/v) to yield the title compound as a light yellow crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCF)c2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 71.2 %

Procedure:
128 mg (0.21 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.25 ml tetrahydrofurane. 134 mg (0.41 mmol) cesium carbonate and 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 48 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane, 2 ml tetrahydrofurane and 134 mg (0.41 mmol) cesium carbonate were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 100 mg (65%) tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:25]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Brc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3Cc4ccc(Br)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 27.2 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:25][OH:26])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=NO
Temperature: 25 °C
Yield: 79.8 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.6 g, 5.19 mmol) obtained in Example 1 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (1.08 g, 15.57 mmol) and pyridine (1.64 g, 1.68 mL, 20.76 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.34 g of the titled compound (yield: 80%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cc(CO)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CO)ccc1OC(C)=O
Reaction time: 1 h

Procedure:
A partial solution of 4-hydroxy-3-methoxybenzyl alcohol (1.23 g, 8 mmol), triethylamine (810 mg, 1.12 mL, 8 mmol) and 32 mL of dry CH2Cl2 was chilled in an ice bath. To the cold mixture was added dropwise acetyl chloride (628 mg, 570 μL, 8 mmol). The mixture was stirred at ice bath temperature 1 for one hour. Stirring at room temperature was allowed to take place overnight. The reaction mixture was diluted with CH2Cl2 and extracted with 1N HCl, water and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Column chromatography on silica gel using CH2Cl2/MeOH (98:2, v/v) gave 548 mg (35%) of CO as a clear oil: Rf=0.22 (hexanes/ethyl acetate, 6:4 v/v); 1HNMR (CDCl3) δ 7.00 (d, 4J=1.5 Hz, 1H), 6.99 (d, 3J=8.5 Hz, 1H), 6.89 (dd, 3J=8.0 Hz, 4J=1.5 Hz, 1H), 5.27 (s, 2H), 4.66 (s, 2H), 3.83 (s, 3H) and 2.30 (s, 3H). Exact mass (FAB+) calculated for C10H12O4[M+] 196.0736. found 196.0739.
Reaction SMILES: [CH2:1]([N:3](C(C)C)[CH:4](C)C)C.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][N:12]=1.CNC.CCN=C=NCCCN(C)C>C1COCC1>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:3]([CH3:4])[CH3:1])=[O:16])=[CH:13][N:12]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (12.61 mL, 72.40 mmol) was added to 6-aminonicotinic acid (CAS no. 3167-49-5) (5 g, 36.20 mmol), dimethylamine (2M in THF) (21.72 mL, 43.44 mmol) and EDCI (9.02 g, 47.06 mmol) in THF (150 mL) under nitrogen. The resulting suspension was stirred at r.t. for 18 hours. The reaction mixture was dry loaded onto silica and purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to the product (4.50 g, 75%). 1H NMR (400 MHz, DMSO) δ 2.95 (6H, s), 6.28 (2H, s), 6.38-6.44 (1H, m), 7.42-7.47 (1H, m), 7.99-8.04 (1H, m)
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CN(C)C=O.[I-].C[N+](C)(C)[CH2:17][C:18]([C:20]1[C:29]2[CH:28]=[N:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=2[CH2:23][CH2:22][CH:21]=1)=[CH2:19]>C(N(CC)CC)C>[CH3:31][O:30][C:26]1[N:27]=[CH:28][C:29]2[C:20]([C:18]([CH2:17][C:2]3([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[CH2:19])=[CH:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ncc21
Reactant: CC1C(=O)CCC1=O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ncc21
Temperature: 25 °C

Procedure:
A solution containing 0.75 parts of 2-methylcyclopentane-1,3-dione in 19 parts of dimethylformamide is treated sequentially with 1.0 part by volume of triethylamine and 1.9 parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)ammonium iodide. The resulting homogeneous solution is heated at about 135° for 4 3/4 hours. It is allowed to cool to room temperature and solvent is removed under reduced pressure. The remaining material is diluted with water-ether and enough 5% sodium hydroxide solution is added to bring the pH to 10. The aqueous and organic layers are separated and the aqueous layer is extracted with ether. The extracts are washed sequentially with 5% sodium hydroxide solution, 2.5% aqueous formic acid and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. Upon solvent removal, an oil remains which is taken into ether. Then n-hexane is added until the solution becomes turbid. Charcoal is added and the mixture is filtered. Solvent is removed under reduced pressure to yield an oil which crystallizes upon standing. Recrystallization from acetone-water gives pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline, which is identical to the product obtained in Example 9 A.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: C1COC(CN2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CCCO3)CC2)cc1
Yield: 12 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 12%. White crystals, m.p. 220-221° C.; IR (KBr): ν 1708 (ester C═O), 1660 (amide C═O) cm−1.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3]([O:5][CH3:6])=[O:4].[CH3:20]S(N)(=O)=O>CC(O)(C)C.O>[OH:1][C@H:2]([C@@H:7]([OH:19])[CH:8]1[CH2:10][N@@:9]1[C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:3]([O:5][CH2:6][CH3:20])=[O:4]
Reactant: CS(N)(=O)=O
Reactant: COC(=O)[C@@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Agent: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Agent: COC(=O)[C@@H](O)[C@@H](O)C1C[N@]1[C@H](C)c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H](O)[C@@H](O)C1C[N@@]1[C@H](C)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of (2S,3S)-methyl 2,3-dihydroxy-3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)propanoate (3.3 g, 13.3 mmol) in t-BuOH/H2O (60 mL, 0.2 M/60 mL, 0.2 M) were added AD-mix α (33 g, 1000 w/w %) and methanesulfonamide (1.9 g, 19.9 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred for 24 hrs and quenched with water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over MgSO4, filtered through a pad of celite, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (2/3) to afford the title product (diastereomeric mixture, ratio=7/1). Yield: 2.3 g (62%); yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]>>[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:35][CH2:36]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
Using the method of Examples 61-75, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 476.3039.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[O:18]([C:25]1[CH:30]=[CH:29][C:28](O)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=3[CH:8]=2)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2o1

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 4-phenoxy-2-propylphenol as a colorless solid.