Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:31])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: CC(Br)c1ccccc1
Product: CC(c1ccccc1)n1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and (1-bromoethyl)benzene and was isolated as a white solid (4.5 mg, 37% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.65-7.58 (m, 1H), 7.50-7.44 (m, 2H), 7.44-7.38 (m, 1H), 7.38-7.28 (m, 4H), 7.18-7.12 (m, 1H), 7.12-7.04 (m, 1H), 6.02-5.96 (m, 1H), 5.34 (s, 1H), 4.58-4.22 (m, 1H), 3.69 (s, 3H), 1.93-1.82 (m, 3H), 1.02-1.04 (m, 9H); LCMS (m/z) ES+=493 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:15]>>[I:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH:13]=[CH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(I)cc1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2-naphthaldehyde and 4-iodoacetophenone, 1-(4-iodophenyl)-3-(2-naphthalenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCCN1CCCC1=O
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCCN2CCCC2=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 85.1 %

Procedure:
Following the general procedure outlined in Example 225, the product of Example 48 (100 mg, 0.22 mmol) and N-(3′-aminopropyl)-2-pyrrolidinone (96 mg, 0.67 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (70/30/2, v/v/v), followed by recrystallization from ethanol and hexane, gave the desired product 95 mg (85%). LC-MS: 508.2 (MH+, m/z), 2.02 (Rt, min).
Reaction SMILES: [C:1]([CH2:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=1[N+:24]([O-])=O)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2]>[Fe].C(O)(=O)C>[NH2:2][C:1]1[CH2:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[N:24]=1
Reactant: CCOC(=O)/C(=C/c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-])CC#N
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
To a solution of (E)-ethyl 2-(cyanomethyl)-3-(2-nitro-4-(perfluoroethyl)phenyl)acrylate (2.60 g, 6.87 mmol) was added iron powder (2.30 g, 41.2 mmol). The mixture was heated to 90° C. for 5 hours. Upon cooling the acetic acid was removed under vacuum and the resulting semisolid was dissolved in 50% K2CO3 (100 mL) and EtOAc (100 mL). The mixture was filtered to remove insoluble material and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organics were dried and concentrated. The concentrate was purified via flash chromatography (100% CH2Cl2 to 2% MeOH) to yield (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (1.8 g, 74%). 1H NMR (CDCl3) δ 1.39 (t, 3H), 2.95 (s, 2H), 4.32 (q, 2H), 5.12 (br s, 1-2H), 7.22-7.27 (m, 2H), 7.47-7.51 (m, 2H), 7.80 (s, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccnn2-c2ccccc2)n1
Reactant: Nc1cccc(Cl)c1
Product: Clc1cccc(Nc2nccc(-c3ccnn3-c3ccccc3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-(methylsulfonyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-7, 96 mg) and 3-chloroaniline (0.5 mL, excess) was heated at 100° C. for 24 hours. The residue was purified by flash column chromatography (hexanes, initially, grading to 40% hexanes in ethyl acetate) to give N-(3-chlorophenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine (1-8) as an off-white foam. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=5.2 Hz), 7.78 (d, 1H, J=1.8 Hz), 7.56 (m, 1H), 7.46–7.32 (m, 5H), 7.12 (m, 1H), 7.08 (m, 1H), 6.96 (m, 1H), 6.92 (d, 1H, J=1.8 Hz), 6.66 (d, 1H, J=5.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][CH:39]([CH3:56])[CH2:40][C@@H:41]([B:43]1[O:47][C@@H:46]2[CH2:48][C@@H:49]3[CH2:52][C@H:51]([C@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:54])[CH3:53])[NH2:42].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C>CN(C)C=O>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:42][C@H:41]([B:43]1[O:47][C@H:46]2[CH2:48][C@H:49]3[CH2:52][C@@H:51]([C@@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:53])[CH3:54])[CH2:40][CH:39]([CH3:56])[CH3:38])=[O:10])=[O:5]
Reactant: O=C(O)CNC(=O)c1cccc(F)c1F
Reactant: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1cccc(F)c1F)B1O[C@H]2C[C@H]3C[C@H](C3(C)C)[C@@]2(C)O1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of [(2,3-difluorobenzoyl)amino]acetic acid (0.205 g, 0.95 mmol) in dimethylformamide (10 mL) were added TBTU (0.337 g, 1.0 mmol) and (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine as its trifluoroacetate salt (0.362 g, 0.95 mmol). The mixture was allowed to cool to 0° C. and DIEA (0.498 mL, 2.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the product partitioned into DCM. The organic layer was dried over sodium sulfate and the solvent removed to give 2,3-difluoro-N-[2-({(1R)-3-methyl-1-[(3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18]1[CH2:22][O:21][CH2:20]C1>>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:22]3[CH2:20][O:21]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
At rt a solution of 3,6-dibromo-9H-carbazole (5.23 g, 16.10 mmol) in anhydrous THF (200 mL) is treated with NaH (0.703 g, 16.10 mmol, 55% in mineral oil) and a solution of (±)-3-nitro-benzene sulfonic acid oxiranyl methyl ester (4.17 g, 16.10 mmol) in anhydrous THF (30 mL). After 16 hours of stirring at rt the reaction mixture is quenched with a saturated aqueous solution of sodium hydrogenocarbonate (200 mL). Extraction with Et2O (500 mL+2×250 mL), drying over MgSO4 and evaporation under reduced pressure gives a yellow solid. Flash chromatography on a 7×27 cm2 column of SiO2 using DCM/Petroleum Ether (1/1) gives the title compound (3.65 g, 9.58 mmol) as a white solid in a 59% yield.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.C(Cl)(=[O:27])C1C=CC=CC=1>>[O:27]1[CH:6]=[CH:7][C:2]([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])=[CH:3]1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccoc1
Yield: 24 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 3-furanoyl chloride for benzoyl chloride, the title compound was obtained as a yellow oil in 24% yield: 1H NMR (300 MHz, CDCl3) δ 8.03 (m, 1H), 7.44 (m, 1H), 6.76 (m, 1H), 4.12 (q, J=6.9 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.29 (t, J=7.5 Hz, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.37 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.18, 24.04, 24.69, 28.82(2), 34.18, 40.23, 60.13, 108.56, 127.69, 144.09, 146.98, 173.68, 195.10.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:18])[CH:15]([CH3:17])[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:18])[CH:15]([CH3:17])[OH:16]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOC(=O)C(C)O
Temperature: 60 °C
Yield: 83 %

Procedure:
A mixture of enzyme (275.07 g; lipase B from Candida antarctica immobilized on macroporous acrylic resin beads; Novozym® 435), molecular sieves (2301 g), 1-dodecanol (551 mL), and ethyl lactate (1400 mL) in a 12″×20″ stainless steel tray (bed depth 1.25″) was maintained at 60° C. in a convection oven for 32 hour. Upon work-up, 538 g of lauryl lactate (83% yield) was obtained as a pale yellow liquid. The purity of the product was >95% as assessed by HPLC-RI.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[C:6]1([CH:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:15][CH:14]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCC(Oc1ccc(N)cc1)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)CCC(Oc1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.25 g of N,N-dimethyl-γ-(4-aminophenoxy)benzenepropanamine in 30 ml of pyridine cooled to 10° C. by means of an external ice bath was treated with 1.86 ml of methanesulfonylchloride under a nitrogen atmosphere. The ice bath was removed and the reaction mixture stirred at room temperature overnight. The solution was poured into 30 ml of water, treated with acid and evaporated in vacuo. The residue was purified by high pressure liquid chromatography over silica gel eluting with methylene chloride/methanol/ammonium hydroxide (100:5:1). The appropriate fractions were combined and concentrated in vacuo providing 4.15 g of an oil which crystallized upon cooling. Recrystallization from ethanol provided 2.5 g of the desired title product as off-white crystals, m.p. 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:36]([CH3:37])=[CH:35][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH:17]4[N:13]([CH2:12][CH2:11][C:6]2=3)[CH2:14][CH2:15][CH2:16]4)=[CH:39][CH:40]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)C1CCCN1CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg, 0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg, 0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added 1-(1-bromoprop-1-en-2-yl)-4-fluorobenzene (95 mg, 0.44 mmol). The reaction mixture was stirred at 120° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was filtered through Celite. The filtrate was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 7-(2-(4-fluorophenyl)prop-1-enyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole. 1H NMR, (CD3OD, TFA salt) δ (ppm): 7.65 (t, 2H), 7.35 (s, 1H), 7.19 (t, 2H), 7.1 (m, 2H), 6.95 (s, 1H), 5.1 (t, 1H), 3.79 (m, 1H), 3.62 (m, 2H), 3.41 (m, 1H), 3.1 (m, 2H), 2.75 (m, 1H), 2.41 (s, 3H), 2.28 (m, 3H), 1.95 (s, 3H). Chiral HPLC provided the enantiomers 194a and 194b.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].[CH3:20]O>>[Cl:8][C:7]1[C:2]([CH3:20])=[C:3]([CH:9]([NH2:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: NC(Cc1ccccc1)c1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(Cl)cccc1C(N)Cc1ccccc1
Yield: 75 %

Procedure:
To 2,3-dichlorobenzaldehyde (2.58 g, 19.2 mmol) in THF (5 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1M in THF, 23 mL). The ice-water bath was removed and the reaction mixture was stirred from 0° C. to room temperature for 2 h. The reaction mixture was then cooled back to 0° C. and benzylmagnesium chloride (1M in THF, 23 mL) was added. The reaction mixture was stirred from 0° C. to room temperature for 1 h then quenched with NH4Cl (Sat.), extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. HCl (1.25M in methanol) was added to the above residue until a pH of 2 to form the amine salt solution. Methanol was removed to give yellow solid. To the solid was added dichloromethane. The suspension was filtered and washed with dichloromethane to yield white solid as pure amine salt. The amine salt was converted to free amine by dissolving the white solid in methanol, basified with NaOH (1N) and extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated to produce 1-(3-chloro-2-methylphenyl)-2-phenylethanamine (3.26 g, 75%) as light yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.57-2.65 (m, 1H), 3.11-3.17 (m, 1H), 4.68-4.72 (m, 1H), 7.20-7.35 (m, 6H), 7.36-7.40 (m, 1H), 7.51-7.54 (m, 1H).
Reaction SMILES: [CH2:1]([N:13]1[CH:17]([OH:18])[CH:16]([OH:19])[N:15]([CH2:20][O:21]C)[C:14]1=[O:23])[N:2]1[CH:6]([OH:7])[CH:5]([OH:8])[N:4]([CH2:9][O:10]C)[C:3]1=[O:12].C(N1C(O)C(O)N(CCO)C1=O)N1C(O)C(O)N(CCO)C1=O.OC1C(O)N(COC)C(=O)N1COC>>[CH2:1]([N:2]1[CH:6]([OH:7])[CH:5]([OH:8])[N:4]([CH2:9][OH:10])[C:3]1=[O:12])[N:13]1[CH:17]([OH:18])[CH:16]([OH:19])[N:15]([CH2:20][OH:21])[C:14]1=[O:23]
Reactant: COCN1C(=O)N(CN2C(=O)N(COC)C(O)C2O)C(O)C1O
Agent: COCN1C(=O)N(COC)C(O)C1O
Agent: O=C1N(CCO)C(O)C(O)N1CN1C(=O)N(CCO)C(O)C1O
Product: O=C1N(CO)C(O)C(O)N1CN1C(=O)N(CO)C(O)C1O

Procedure:
1,1'-methylenebis(3-methoxymethyl-4,5-dihydroxyimidazolidin-2-one) (Ex. 4); 1,1'-methylenebis[3-(2-hydroxyethyl)-4,5-dihydroxyimidazolidin-2-one] (Ex. 5); and 4,5-dihydroxy-1,3-di(methoxymethyl)-2-imidazolidinone (Ex. 6) are evaluated as adhesion promoters in natural rubber as follows:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:36][CH:37]1[C:58](=[O:59])[N:39]2[C:40]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=3)=[O:46])=[C:41]([OH:44])[CH2:42][S:43][C@H:38]12>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([NH:36][CH:37]2[C:58](=[O:59])[N:39]3[C:40]([C:45]([O:47][CH2:48][C:49]4[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=4)=[O:46])=[C:41]([OH:44])[CH2:42][S:43][C@H:38]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 0.54 g.), N,N-dimethylformamide (0.16 g.), phosphoryl chloride (0.34 g.) and ethyl acetate (10 ml.) were treated in a similar manner to that of Example 15 to give the activated acid solution. On the other hand, trimethylsilyacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.62 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.7 g.) in ethyl acetate (10 ml.) and stirred at 40° C. for 30 minutes. The activated acid solution obtained above was added to the solution at -20° C. all at once, and stirred at the same temperature for an hour. Water (10 ml.) was added to the resultant solution, and the organic layer was separated, washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1.09 g.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3([CH3:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3([CH3:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: CN1CCC(C)(C(=O)Nc2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C)(C(=O)Nc2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,4-dimethylpiperidine-4-carboxamide (5 mg, 0.010 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (2 mg) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.49 (bs, 1H), 7.64 (m, 4H), 7.29 (m, 2H), 3.49 (m, 2H), 3.18 (m, 2H), 2.91 (s, 3H), 2.59 (m, 2H), 1.46 (m, 2H), 1.28 (s, 3H); ESI-MS [M+H]+: 389.3.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCC(C)(C)c1ccc(NC(C)=O)cc1
Solvent: CC(=O)OC(C)=O
Product: CCC(C)(C)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a stirred solution of N-[4-(1,1-dimethylpropyl)phenyl]acetamide (Preparation 99, 12 g, 0.058 mol) in acetic anhydride (50 mL) at −5° C. was added HNO3 slowly. The reaction was maintained at 0° C. for 1 hour and then room temperature for 18 hours. The reaction was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford the title compound (15 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(-c2ccccn2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(-c2ccccn2)nc1CBr
Temperature: 90 °C
Yield: 100.5 %

Procedure:
A mixture of the compound prepared in Example 151 (3.50 g) and N-bromosuccinimide (2.66 g) and benzoyl peroxide (0.362 g) in carbon tetrachloride (80 mL) was heated at 90° C. for 18 hours. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (4.70 g) having the following physical data.