Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
To a solution of 4-(benzyloxy)phenol (10.01 g, 50 mmol) and bromoacetaldehyde diethyl acetal (7.52 ml, 50 mmol) in dimethylformamide (100 ml) was added potassium carbonate (10.37 g, 75 mmol) and the mixture was heated at 170° C. After 2.5 hr, the reaction mixture was cooled to room temperature. The mixture was diluted with water and ethyl acetate, and aqueous layer was removed. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2-[4-(benzyloxy)phenoxy]acetaldehyde diethyl acetal (11.902 g, 75%, pale-brown oil).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:18])[C@H:14]([O:16][CH3:17])[CH3:15])[C:3]=12.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>CCCCO>[ClH:50].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:2]2[C:7]([F:8])=[CH:6][N:5]=[C:4]3[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:18])[C@H:14]([O:16][CH3:17])[CH3:15])[C:3]=23)[CH2:20]1
Reactant: ClCCl
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(F)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(F)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 140 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
A mixture of (R)—N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.21 g, 0.82 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.33 g, 1.65 mmol) and DIEA (0.43 mL, 2.47 mmol) in n-BuOH (2 mL) was stirred at 140° C. (bath) for 12 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water gradient, 25 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL) and 2N HCl in ether (3 mL) was added. The solid formed was collected to give (R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide hydrochloride (0.31 g, 93%) as a solid. 1H NMR (400 MHz, D2O) δ 8.08 (d, 1H), 7.38 (s, 1H), 4.02 (m, 1H), 3.80 (m, 1H), 3.46 (m, 2H), 3.37 (s, 3H), 3.30 (m, 1H), 3.20 (m, 1H), 2.07 (m, 1H), 1.76 (m, 1H), 1.62 (m, 2H), 1.33 (d, 3H). LCMS (APCI+) m/z 336(M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[O:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.O[Li].O.Cl.O1CCOCC1>O.C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[O:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Yield: 109.9 %

Procedure:
A solution of 406 (0.310 g, 1.01 mmol), THF (5 mL), LiOH.H2O (0.0508 g, 1.21 mmol) and water (1 mL) was stirred for 3 h. To the solution was added 4N HCl in dioxane (0.303 mL, 1.21 mmol) and concentrated to afford 0.31 g (95%) of (R)-2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxylic acid (408) which was used without further purification: MS m/z (APCI-pos) M+1=280.1.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[O-:19].[K+].[K+]>CN(C)C=O>[CH:18]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:19]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nn2ccccc2c1C=O
Temperature: 0 °C
Yield: 67 %

Procedure:
One gram of 2-isopropylpyrazolo[1,5-a]pyridine was dissolved in 0.6 ml of dimethylformamide, and 5 ml of phosphorus oxychloride was added to the resulting solution. The reaction mixture was refluxed for 20 min., poured into ice-water, and neutralized with potassium carbonate. The precipitate was collected by filtration and washed with water. Recrystallization from n-hexane gave 800 mg of colorless needles, mp 81.0°-81.5°. Yield 67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH:10]=4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1>[Pd].C(O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@H]1C3=CC[C@H](O)[C@@]3(C)CC[C@H]21
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@@]2(C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
i)—A mixture of (7α,17β)-3-methoxy-7-methylestr-1,3,5(10),14-tetraen-17-ol [Segaloff, et al, Steroids 22, 99 (1973); 86.2 g] and palladium on activated carbon (5%; 34.5 g) in ethanol (578 ml) and dichloromethane (414 ml) was stirred under hydrogen (3 bar) at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to give (7α,14β,17β)-3-methoxy-7-methylestr-1,3,5(10)-trien-17-ol (83.0 g). The product was used in the following step without further purification.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO[CH2:11][CH3:12].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=O>O>[CH3:20][C@H:16]1[CH2:17][CH2:18][CH2:19][C@@H:14]([CH3:13])[N:15]1[CH2:21][CH2:22][CH2:23][C:24]([C:12]1[CH:11]=[CH:3][CH:2]=[CH:1][CH:6]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:26]
Reactant: COC(=O)CCCN1[C@H](C)CCC[C@@H]1C
Reactant: [Li]c1ccccc1
Reactant: CCOCC
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCCC(O)(c1ccccc1)c1ccccc1

Procedure:
A 2M solution of phenyl lithium in benzene-ether (70 to 30), 100 ml., is added to 100 ml. of dry ether with stirring under a nitrogen atmosphere. The mixture is stirred and cooled to 0°-5° while a solution of 20 g. of cis-2,6-dimethyl-1-piperidinebutyric acid, methyl ester, in 100 ml. of dry ether is added slowly over a period of 15 minutes. After the addition is complete, the mixture is stirred an additional 2.5 hours at 0°-5°, then treated dropwise with 30 ml. of water. The organic layer is separated, washed with water and extracted with an excess of dilute acetic acid. The acid extract is washed with ether, basified with aqueous sodium hydroxide, then extracted with ether. The ether extract is washed with water, dried and evaporated to give cis-2,6-dimethyl-α,α-diphenyl-1-piperidinebutanol; m.p. 90°-91° C. after two crystallizations from petroleum ether.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21][CH3:22])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClC(Cl)C.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21]([CH3:22])=[O:31])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CSC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl)S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.25 g (30 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-methylthioethyl)pyrimidine were placed in 120 ml of dichloroethane, and a solution of 7.40 g (30 mmol) of 70% 3-chloroperbenzoic acid in 50 ml of dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hours and extracted by stirring with sodium bicarbonate solution and water. The organic phase was dried and concentrated, to give 10.5 g (98% of theory) of a colorless resin (diastereomer mixture).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([Cl:19])=O.BrCCCCCCCl.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:19].[N:28]1([C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:17]([C:13]4[S:12][CH:16]=[CH:15][CH:14]=4)=[CH:10][C:9](=[O:11])[C:3]=3[CH:4]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: ClCCCCCCBr
Product: Cl
Product: O=c1cc(-c2cccs2)oc2ccc(N3CCCCC3)cc12

Procedure:
The compound was prepared by a method similar to Example 11 from 2',5'-dihydroxyacetophenone, 2-thiophenecarbonyl chloride, 1-bromo-6-chlorohexane, and piperidine: mp 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[O:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[CH:23]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[O:26][CH:25]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)furan-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 14%). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.40-8.35 (m, 2H), 8.16 (m, 1H), 8.02-7.94 (m, 4H), 7.82-7.80 (m, 1H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.36-7.31 (t, J=9.0 Hz, 2H), 3.53-3.51 (d, J=6.1 Hz, 2H), 1.30 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O4: 500.14. found: 499.5 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.[Si]([O:25][CH2:26][C@H:27]1[O:31][C@@H:30]([N:32]2[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@H:29]([O:41][CH2:42][CH2:43][O:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C@@H:28]1[OH:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH2:48]([N:45]([CH2:46][CH3:47])[O:44][CH2:43][CH2:42][O:41][C@@H:29]1[C@H:28]([OH:50])[C@@H:27]([CH2:26][OH:25])[O:31][C@H:30]1[N:32]1[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]1=[O:34])[CH3:49]
Reactant: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
A mixture of triethlyamine trihydrogenfluoride (4.39 mL, 26.81 mmol) and triethylamine (1.87 mL, 13.41 mmol) in THF (53.6 mL) was added to 5′-O-tert-butyldiphenylsilyl-2′-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine (3.28 g, 5.36 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed in vacuo. The residue was placed on a silica gel column and eluted with CH2Cl2/MeOH/NEt3, 89:10:1, to yield the title compound (1.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of 5-bromo-2-chlorophenol (1.0 g) in tetrahydrofuran (10 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.20 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.97 g) was added in tetrahydrofuran (7 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.96 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 77 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 5 mL of acetone, and 5 mL of acetonitrile. The resulting mixture was refluxed under stirring at 79-75° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.3%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28]CC(O)[CH2:25][CH2:24]1.[Na].[ClH:31]>C1(C)C=CC=CC=1.CCOCC>[ClH:31].[CH:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH:11]2[CH2:25][CH2:24][N:23]([CH3:28])[CH2:22][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCCC1
Reactant: CN1CCC(O)CC1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCCC2)CC1

Procedure:
This ester was prepared by a method similar to the ones described above from the reaction of ethyl α-cyclohexyl-α-phenylethynyl-glycolate (4.3 g., 0.015 mole), 1-methyl-4-piperidinol (2.3 g., 0.020 mole) and sodium (~0.05 g.) in toluene. The chloroform extract of the basic phase of the reaction mixture, when stripped of volatile components in vacuo, yielded an oil. The oil was dissolved in dry ether and treated with HCl (gas) to give an oily solid. Recrystallization from a chloroform-benzene mixture gave about 0.6 g. (10%) of the desired hydrochloride, m.p. about 198°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[NH:11][CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.N(CC(O)=O)C(N)=O.O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: NC(=O)NCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Clc1ccccc1
Solvent: O
Product: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 15 °C
Yield: 95.6 %

Procedure:
To a suspension of 3-(3,5-dichlorophenyl)-ureidoacetic acid (813 g.) in chlorobenzene (3,500 cc.) is added concentrated sulphuric acid (d = 1.83) (16 cc.), representing 0.095 mol per mol of ureidoacetic acid. The water formed in the reaction is removed by azeotropic distillation. After 45 minutes' distillation, a limpid solution is obtained. After cooling to about 15° C, the precipitate formed is filtered off and washed on the filter with ethanol (500 cc.) at 10° C. After drying, 3-(3,5-dichlorophenyl)-hydantoin (724 g.) melting at 199° C is obtained. Yield: 95.4%.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:21])[N:5]=1)[CH3:3].[H-].[Na+].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[CH3:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:20])[N:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([CH:2]([O:1][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][N:29]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH3:3])=[N:5]2
Reactant: Cc1cccc2nc(C(C)O)n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)Oc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reaction time: 0.17 h

Procedure:
A solution of compound 181 (0.069 g, 0.25 mmol) in THF (5 mL) was treated with sodium hydride (0.007 g, 0.27 mmol) and stirred for 10 min. A solution of intermediate compound 13 (0.077 g, 0.27 mmol) in THF (1 mL) was added to the reaction mixture. The flask originally containing the intermediate compound 13 was washed with additional THF (1 mL) and the washings were also added to the reaction mixture. The reaction was allowed to proceed, and additional sodium hydride (0/005 g, 0.21 mmol) was added at 21.5 h and 23 h. The reaction was quenched after a total of 24 h by addition of saturated ammonium chloride solution (5 mL). The mixture was extracted with dichloromethane (3×5 mL), and the combined organic extracts were dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (1:1 EtOAc:hexanes->3:2 EtOAc:hexanes) to give compound 182. ESI-MS m/z=529 (MH+). The reaction described above and compound 182 are shown below.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:13]=[C:12](CO)[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)=O>ClCCl>[C:5]([C:9]1[CH:13]=[C:12]([CH2:1][Cl:4])[NH:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)c1cc(CO)[nH]n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(CCl)[nH]n1

Procedure:
To a chloroform (20 mL)-dichloromethane (10 mL) mixed solution of [3-(tert-butyl)-1H-pyrazol-5-yl]methanol (617 mg, 4.00 mmol), thionyl chloride (577 μL, 8.01 mmol) was added at room temperature and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (931 mg) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), (R)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown foam (69%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15](O)=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[O:56]1[CH:60]=[C:59]([CH2:61][NH2:62])[N:58]=[CH:57]1>CN(C)C=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([NH:62][CH2:61][C:59]3[N:58]=[CH:57][O:56][CH:60]=3)=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: NCc1cocn1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cocn1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
A solution of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid (0.35 g, 1.11 mmol), diisopropylethylamine (0.86 g, 6.66 mmol), 1-hydroxybenzotriazole monohydrate (0.39 g, 2.89 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.28 g, 1.44 mmol) in anhydrous N,N-dimethylformamide (10.0 mL) was stirred at ambient temperature for 10 minutes, followed by the addition of oxazol-4-ylmethanamine (0.23 g, 1.67 mmol). The resulting reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (60 mL), washed with saturated aqueous sodium bicarbonate (10 mL) solution, water (2×10 mL) and brine (10 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(oxazol-4-ylmethyl)isonicotinamide as a colorless solid (0.21 g, 49%): mp 197-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.15 (t, J=5.6 Hz, 1H), 8.65 (s, 1H), 8.37-8.30 (m, 2H), 7.95 (s, 1H), 7.35-7.06 (m, 5H), 4.49-4.33 (m, 4H), 3.93 (t, J=8.0 Hz, 2H), 3.37-3.25 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 163.6, 160.4, 156.8, 153.5, 152.5, 148.4, 143.3, 137.8, 136.6, 133.6, 133.6, 130.4, 130.3, 116.0, 115.7, 115.2, 110.5, 46.6, 41.6, 35.7; MS (ES+) m/z 396.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COC(=O)CC(=O)OC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OC
Temperature: 25 °C
Yield: 105.8 %

Procedure:
2,4-Dimethoxybenzaldehyde (10.0 g, 0.060 mol), dimethyl malonate (9.5 g, 0.072 mol), piperidine (1.5 g, 0.017 mol), benzoic acid (1.8 g, 0.015 mol) and 100 mL of toluene are stirred at reflux for 5.5 hours under a Dean Stark trap to remove water. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with 10% hydrochloric acid, water and brine. The resulting solution is dried over anhydrous magnesium sulfate and then concentrated to yield 17.8 g of an orange syrup which is purified by chromatography on silica gel (2:1, heptane:ethyl acetate) to provide 12.8 g of the title compound as a pale yellow solid melting at 71–73° C.