Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:8][N:9]1[C:13]2[C:14]([CH2:18]C(OCC)=O)=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:24].BrC[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(N(C)C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:27]=1[O:28][CH3:29])[CH2:8][N:9]1[C:13]2[C:14]([CH2:18][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:24]
Reactant: CCOC(=O)Cc1cccc2[nH]c(=O)n(Cc3cc(OC)c(OC)c(OC)c3)c12
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1cccc2[nH]c(=O)n(Cc3cc(OC)c(OC)c(OC)c3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (14.1 mmol, 0.56 g, 60% mineral oil) is dissolved in dimethylacetamide (10 ml). 1-(3,4,5-trimethoxybenzyl)-3-hydrobenzimidazol-2-one (9.1 mmol, 2.86 g) (example 10) in dimethylacetamide (10 ml) is added dropwise to the ice cooled solution which is stirred for 1 hour. Ethyl 3-bromopropionate (14.1 mmol, 1.79 ml, 2.53 g) in dimethyl-acetamide (5 ml) is added, and the mixture is stirred 24 hours at room temperature. The solution is added dropwise into ice (300 g), and the precipitate is filtered off, added to a 1:1 dichloromethane/water mixture and is extracted with dichloromethane (3×20 ml). The combined organic layers are dried with MgSO4, filtered and evaporated. Recrystallisation from ethyl acetate (5 ml) yields the title compound (R1=(CH2)2—C(O)—OEt, R2=3,4,5-trimethoxybenzyl, x=2, n=0).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC([O-])(C)C.[K+:18]>CCOCC>[Cl:1]/[C:2](/[CH:8]=[O:9])=[C:3](\[O:5][CH2:6][CH3:7])/[O-:4].[K+:18]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCO/C([O-])=C(\Cl)C=O

Procedure:
A cooled (0° C.) suspension of ethyl 2-chloroacetate (17.47 ml, 163 mmol) and ethyl formate (13.18 ml, 163 mmol) in ether (250 ml) was treated slowly (over 3 hrs) with potassium 2-methylpropan-2-olate (18.31 g, 163 mmol) keeping the temperature below 5° C. The mixture was concentrated in vacuo and the resulting solid was washed with ether and dried (47° C. in a vacuum oven) to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:22][CH:20]([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)O
Temperature: 31 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (550 mg, 1.83 mmol) in THF (8 mL) was added NaBH4 (139 mg, 3.66 mmol) at 0° C. under N2. The reaction was stirred at 31° C. for 20 hrs. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous NaHCO3. The organic layer was concentrated in vacuo to afford the title compound (520 mg) as a yellow oil which was used directly without purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.B(O)O>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[N:27][CH:26]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: OBO
Product: COc1cncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=O)C=CC=CC=1.[C:21]([C:23]12[CH2:30][CH2:29][CH2:28][N:27]1[CH2:26][CH2:25][CH2:24]2)#[CH:22]>C1C=CC=CC=1>[CH2:7]([C:8]1[CH:22]=[C:21]([C:23]23[CH2:30][CH2:29][CH2:28][N:27]2[CH2:26][CH2:25][CH2:24]3)[O:11][N:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: C#CC12CCCN1CCC2
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(Cc2cc(C34CCCN3CCC4)on2)cc1
Yield: 52.2 %

Procedure:
2-Phenylnitroethane (895 mg, 5.92 mmol, from step 15b) and phenylisocyanate (1.3 mL, 11.8 mmol) were dissolved in benzene (12 mL) and added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (400 mg, 2.96 mmol, from step 13a). The solution was stirred at reflux for 5 hours, cooled and stirred for 48 hours at room temperature. The mixture was filtered and extracted with 6N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford an amber oil (415 mg, 52%). 1H NMR (CDCl3, 300 MHz) δ1.71-1.92 (m, 6H), 2.11-2.23 (m, 2H), 2.58-2.66 (m, 2H), 3.08-3.15 (m, 2H), 3.95 (s, 2H), 5.87 (s, 1H), 7.20-7.34 (m, 5H); MS (CI/NH3) m/z: 269 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[NH:9][C:10]1[S:11][CH:12]=[N:13][N:14]=1>C(O)CC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:12]2[S:11][C:10]([NH2:9])=[N:14][N:13]=2)[CH2:4][CH2:3]1
Reactant: BrNc1nncs1
Reactant: CN1CCNCC1
Solvent: CCCO
Product: CN1CCN(c2nnc(N)s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-methylpiperazine (0.742 ml, 6.6 mmol) and bromo-[1,3,4]thiadiazol-2-ylamine (63a) (0.60 g, 3.3 mmol) in n-propanol (15 ml) is heated at reflux for 6 hours. After cooling to room temperature the solvent is removed and the residue is trituated with ethyl acetate and methanol to afford the required compound as a pink solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of methyl 4-hydroxyphenylacetate (10.0 g) in acetic acid (55 ml) was added nitric acid (22.1 ml) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. After warmed to 20° C., the reaction mixture was diluted with water (200 ml) and precipitated crystals were collected. The crystals were dissolved in chloroform, and the solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of chloroform and hexane to give methyl 4-hydroxy-3-nitrophenylacetate (9.3 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C([O-])(=O)C.[K+]>CCO.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.200 g, 12.66 mmol), 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 14.86 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (514.9 mg, 0.7272 mmol), and potassium acetate (4.180 g, 42.59 mmol) were suspended in EtOH (50 mL) and water (10 mL) and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (80° C.), and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, poured into water (125 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel, 40:1 DCM/2 N ammonia in MeOH). The fractions with product were collected, concentrated, and washed repeatedly with hexanes and dried to give 6-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g), which was used for the next step. MS (ESI pos. ion) m/z 386 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>CO.O1CCCC1.[Pd]>[ClH:25].[C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)(Cc1ccccc1)c1ccc(O)cc1
Reaction time: 6 h

Procedure:
To a solution of 1-phenyl-2-[4-(phenylmethoxy) phenyl)-2-propylamine (3.50 g, 0.011 mol) in methanol (100 mL), tetrahydrofuran (50 mL) and 1N hydrochloric acid (20 mL) was added 5% palladium on carbon (0.8 g) and the mixture was shaken on a Parr apparatus at approximately 40 psi for 6 h. The catalyst was removed by filtration and the solvent removed under vacuum. Crystallization from 2-propanol and ether and vacuum drying at 80° C. for 48 h provided 1.3 g of 1-phenyl-2-(4-hydroxyphenyl)-2-propylamine hydrochloride; mp 160°-161° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)CO.C1C[O:21][CH2:20]C1>>[OH:21][CH2:20][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)CC[C@]1(CO)COc1cccnc1
Reactant: C1CCOC1
Product: CN1C[C@H](CO)C[C@H]1COc1cccnc1

Procedure:
A 1.0 g (4.2 mmol) sample of 3-((-1-methylhydroxymethyl-5-oxo-2-(S)-pyrrolidinyl)methoxy)pyridine, from step 48a above, was dissolved in 15 mL of anhydrous THF, 12.7 mL of BH3 was added, and the mixture was heated at reflux for 2.5 hours. The reaction was quenched with methanol, the solvent was evaporated, and the residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent and purification of the residue on a silica gel column, eluting with 100:8 to 10.1 chloroform:methanol gave 600 mg of the title compound as a mixture of cis and trans product.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].[CH3:19][NH:20][CH3:21]>O1CCCC1>[CH:1]([C:4]1([CH3:18])[NH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([N:20]([CH3:21])[CH3:19])=[O:16])=[N:6][C:5]1=[O:17])([CH3:2])[CH3:3]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)C1(C)NC(c2ccccc2C(=O)N(C)C)=NC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a cold solution of 180 g of 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2-(3H),5-dione in 300 ml of dry tetrahydrofuran in a pressure bottle is added 68 g of dimethylamine. The bottle is sealed and the mixture heated to 50° C. with stirring for 16 hours. The mixture is cooled, and the contents of the bottle transferred to a flask. The solvent is then removed in vacuo. The crystalline residue is then suspended in ether, filtered, washed with ether, and air-dried to give 195 g of o-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-N,N-dimethylbenzamide, melting point 144°-146° C. This product is recrystallized from acetonitrile to give an analytically pure product, melting point 147°-150° C.
Reaction SMILES: [C@H:1]1([CH2:11][OH:12])[C@@H:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:12][CH2:11][C@H:1]2[C@@H:10]3[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4][CH2:3][CH2:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1
Reaction time: 2 h

Procedure:
(1R,9aR)-1-(Octahydroquinolizin-1-yl)methanol (2.5 g) was added to a suspension of sodium hydride (60% in oil, 710 mg) in DMF (20 ml) and, after gas evolution ceased, 4-fluoronitrobenzene (2.51 g) was added. After 2 hours, the reaction mixture was hydrolyzed with water and then partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous phase was made alkaline with sodium hydroxide solution and extracted twice with ethyl acetate. The two ethyl acetate phases were combined, dried over magnesium sulfate and concentrated. The product with the molecular weight of 290.37 (C16H22N2O3); MS (ESI): 291 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(C)=O
Reaction time: 1 h
Yield: 45.3 %

Procedure:
MeMgBr (1 M solution in THF, 4 mL, 12 mmol) was added dropwise at −78° C. to a solution of N,4-dimethoxy-N-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxamide (1.43 g, 4 mmol) in THF (15 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and recrystallized from hexane/AcOEt to give the title compound (566 mg, 45% yield) as a white solid: mp 136-138° C.; NMR (300 MHz, CDCl3): δ ppm 2.57 (3H, s), 3.93 (3H, s), 6.31 (1H, s), 7.63 (1H, t, J=7.9 Hz), 7.69 (1H, d, J=7.9 Hz), 7.84-7.88 (1H, m), 7.91 (1H, s). Anal. Calcd for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.96; H, 3.57; N, 8.96.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OC(O)C)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Agent: CCOC(C)O
Product: Nc1ccc(-c2nc3cc(N)ccc3o2)cc1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
2-(4-Nitrophenyl)-5-nitrobenzoxazole (30 g, 0.105 mol), ethoxyethanol (300 mL) and 10 percent Pd/C (300 mg) were placed in a 600 mL Parr Reactor. The reactor was heated to 70° C. at 50 psi hydrogen (340 kPa) for 3 hours, then 90° C. at 150 psi hydrogen (1033 kPa) for an additional 16 hours. After the hydrogen was vented off, the solution was filtered hot under nitrogen. A portion of the solvent (100 mL) was removed from the solution and deionized water (100 mL) was added thereto, causing product to precipitate. The solution containing the precipitated product was stirred and refluxed for 1 hour. The solution was cooled to room temperature, and the product was filtered and washed with methanol (50 mL). The product was dried and 20.7 g (87 percent yield) of an off-white solid having a melting point of 226° C. to 228° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([OH:12])=[C:6]([F:13])[CH:5]=1.CO>C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([F:13])[C:7]([OH:12])=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: C=Cc1cc(C(=O)OC)cc(F)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(C(=O)OC)cc(F)c1O
Yield: 99 %

Procedure:
A suspension of 3-fluoro-4-hydroxy-5-vinylbenzoic acid methyl ester (121 mg) and 10% palladium carbon (20 mg) in THF (1 mL)-methanol (1 mL) was hydrogenated at room temperature over night at medium pressure (3 kgf/cm2). The catalyst was filtered off through a Celite pad, and the filtrate was concentrated to give the title compound (121 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
3-[2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (11 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11.5 g (80%) of 3-[2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])([O-:8])=[O:7].[H-].[Na+].C(Cl)Cl>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:18]([CH2:19][CH2:20][CH3:21])[S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7])(=[O:16])=[O:17]
Reactant: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
1,3-Dibromopropane (8.5 mL, 82.0 mmol, 10 eq.) was added to a solution of compound 49 (2.0 g, 8.2 mmol) in DMF (20 mL). Then NaH (0.6 g, 15.0 mmol) was added in portions. The temperature rose to 50-60° C. The mixture was stirred at this temperature for 20 min (TLC monitoring, eluent: CH2Cl2). Then the mixture was carefully poured into ice. The product was extracted with ethyl acetate, and the extract was evaporated. The residue was washed from 1,3-dibromopropane with hexane. The resulting product was dissolved in CH2Cl2 and purified on a short thick column with silica gel, eluent: hexane-CH2Cl2 100:0→0:100. Compound 50 (1.87 g, 62%) was isolated as rapidly crystallizable oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][NH2:13]>C1COCC1>[Cl:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:13][CH3:12])=[O:6]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a suspension of crude 3-chloroisonicotinoyl chloride hydrochloride in 25 mL of THF was added methylamine solution (2M in THF, 20 mL, 40 mmol, 8.4 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude material was dissolved in EtOAc (75 mL) and water/brine/saturated sodium bicarbonate solution (1/1/1, 75 mL) and phase separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water/brine/saturated sodium bicarbonate solution (1/1/1, 25 mL) and brine (25 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as an off-white solid (321 mg, 39.7%), which was used without further purification. ES/MS m/z 171.0, (MH+), Rt=0.65 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[O:5][CH:6]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[O:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cc(Br)co1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)co1
Temperature: 150 °C
Yield: 50.5 %

Procedure:
A solution of 4-bromofuran-2-carboxylic acid (380 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4(aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 190 mg of 4-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.07.
Reaction SMILES: [CH2:1]([P:4]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)N)([CH2:6][CH2:7]C)=[O:5])[CH2:2]C.C(P(=O)CC)C.IC1C=CC([N+:29]([O-])=O)=CC=1>>[CH2:1]([P:4]([C:9]1[CH:10]=[CH:11][C:13]([NH2:29])=[CH:14][CH:15]=1)([CH2:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCCP(=O)(CCC)c1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: CC[PH](=O)CC
Product: CCP(=O)(CC)c1ccc(N)cc1

Procedure:
The title compound was prepared according to the procedures leading to 3-(dipropylphosphoryl)aniline (Compound 168C) starting with the commercially available diethyl phosphine oxide and 4-iodonitrobenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.47 (dd, J=8.46, 10.48 Hz, 2H), 6.74 (dd, J=2.27, 8.59 Hz, 2H), 3.97 (br. s., 2H), 1.76-2.02 (m, 4H), 1.11 (td, J=7.71, 16.67 Hz, 6H); MS (ES+): m/z: 198.0939 [MH+]. HPLC: tR=0.83 min (UPLC TOF MS: polar—3 min).