Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH:13]([C:15](=O)[CH3:16])[CH3:14])[C:9]2=O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[C:13]([CH3:14])=[C:15]([CH3:16])[N:30]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:9]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(C(C)C(C)=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(c(C)c(C)n1C[C@@H](C)O)C2
Reaction time: 1.42 h
Yield: 70.2 %

Procedure:
A solution of 1.5 g of rac-6-methoxy-2-(3-oxo-2-butyl)-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 1.94 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 85 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.23 g (70%) of (R)-1-(7-methoxy-2,3-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:35])[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]1([CH2:7][C:8](=[O:35])[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(O)Cc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-3-hydroxy-1-oxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (494 mg, 0.98 mmol) from Step F in methylene chloride (10 mL) at room temperature was added Dess-Martin reagent (621 mg, 1.5 mmol). After 3 h, the reaction was diluted with ether and quenched with 1N sodium hydroxide. After stirring for 30 min, the mixture was diluted with water and extracted twice with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexanes) to afford the title product (343 mg).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4NCC(C3C=CC=CC=3)C3C=CC=CC=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:45][CH2:46][CH:47]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1>>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4[NH:45][CH2:46][CH:47]([C:48]3[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=3)[C:55]3[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2nnn(Cc3ccccc3)n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Product: Oc1ccc(C(CNc2nc(Cl)nc3c2ncn3[C@@H]2O[C@H](c3nnn(Cc4ccccc4)n3)[C@@H](O)[C@H]2O)c2ccc(O)cc2)cc1

Procedure:
The title compound is prepared in an analogous fashion to (2R,3S,4R,5R)-2-(2-benzyl-2H-tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol (WO 99/38877) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bis-phenol (Intermediate A).
Reaction SMILES: N[C:2]1C=C(C#N)C=CC=1NC1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:33]=1[NH:40][C:41]1[N:46]=[CH:45][C:44]([CH2:47][C:48]([NH2:50])=[O:49])=[C:43]([NH:51][CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)[CH:42]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]2[N:31]=[CH:2][N:40]([C:41]3[N:46]=[CH:45][C:44]([CH2:47][C:48]([NH2:50])=[O:49])=[C:43]([NH:51][CH2:52][C:53]4[CH:54]=[C:55]([F:60])[CH:56]=[C:57]([F:59])[CH:58]=4)[CH:42]=3)[C:33]=2[CH:34]=1)#[N:39]
Reactant: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1
Reactant: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Product: N#Cc1ccc2ncn(-c3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)c2c1

Procedure:
From the mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide in a manner similar to step 2 of Example 365, the title compound was obtained as a yellow solid (yield 45%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]1=[O:1])[CH3:15]
Reactant: Cc1cccnc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cccc(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-hydroxy-3-methyl-pyridine (4.1 g, 37 mmol), ethyl bromoacetate (5.9 g, 35 mmol) and potassium carbonate (4.9 g, 35 mmol) in DMF (60 ml) was stirred at rt for 16 h. After evaporation of the solvent and extractive workup (ethyl acetate/water) the organic phase was concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 40:60). The title compound elutes as the second product and was isolated as a colorless liquid (6.1g, 84%). MS: m/e=196.0[M+H]+.
Reaction SMILES: [Na].CO.[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH2:14]>CCOC(C)=O>[CH3:9][O:8][C:6]([CH:5]([CH2:14][CH2:13][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: C=Cc1ccncc1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CCc1ccncc1)C(=O)OC
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a stirred solution of elemental sodium (20 g, 840 mmol) and CH3OH (600 ml) was added dimethyl malonate 10-1 (135 ml, 1120 mmol). After 5 minutes, 4-vinyl pyridine 10-2 (15.3 ml, 140 mmoles) was added and the solution was heated to 50° C. for 18 h. The reaction was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatoraphy (silica, 60% EtOAc/hexanes) furnished the diether 10-3 (19.1 g) as a yellow oil.
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23].C([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: CC(=O)OO
Reactant: C=CCC(O)C1=C(C)CCCC1(C)C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCC(O)C12OC1(C)CCCC2(C)C

Procedure:
A mixture of 40% peracetic acid (105 g.) and anhydrous sodium acetate (3.0 g.) was added at 25° with stirring to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (97 g.) and anhyd. sodium acetate (60 g.) in 175 ml. of CH2Cl2 (1.5 h.). Stirring was continued for one night and 500 ml. of water were then added to the reaction mixture. The organic layer was separated and, after the usual treatments, distilled to give 98 g. (83%) of two diastereoisomers of the epoxy product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1sc(Cl)nc1Cl
Reactant: CSCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSCCC(=O)N(C(=O)OC(C)(C)C)c1sc(Cl)nc1Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of (2,4-dichloro-thiazol-5-yl)-carbamic acid tert-butyl ester (1.0 g, 3.7 mmol) in dichloroethane (20 mL) stirring at room temperature was added triethylamine (935 mg, 9.25 mmol), followed by dropwise addition of methylsulfanyl-propionyl chloride (776 mg, 5.6 mmol) and the mixture was stirred for 5 min before DMAP (45 mg, 0.37 mmol) was added. The mixture was stirred at 75° C. for 4 h. The reaction mixture was cooled, quenched with H2O (30 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layer was dried over Na2SO4 and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a colorless oil (1.11 g, 81%): 1H NMR (300 MHz, CDCl3) δ 3.32 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.46 (s, 9H); ESIMS m/z 371.2 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>O.C(O)C>[O:7]([CH2:11][CH2:12][CH2:13][Cl:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ClCCCOc1ccccc1

Procedure:
A mixture of phenol (1 mole), sodium hydroxide (1 mole) and 3-bromo-1-chloro-propane (2 moles) in water (1000 ml) and ethyl alcohol (250 ml) is refluxed during 20 hours, with stirring. After cooling, sodium hydroxide (30 g) is added to the reaction medium which is then extracted with methylene chloride. The organic phase is washed with water to neutral pH. It is then dried over sodium sulfate, concentrated in vacuo over a water-bath and the residual oil is distilled. B.p. = 118°-120° C./15 mm Hg.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH:50]([F:52])[F:51])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:55][CH3:56]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH2:49][CH:50]([F:51])[F:52])[CH2:45][CH2:44]5)=[O:41])=[CH:38][C:37]=4[O:55][CH3:56])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 60.3 %

Procedure:
A mixture of 0.10 g (0.30 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.086 g (0.45 mmole) of toluenesulfonic acid monohydrate, 0.095 g (0.30 mmole) of 4-amino-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.110 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-266)
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[CH2:27][CH2:28][CH3:29]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Zn+]
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (8 mg, 30%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), n-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 270 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][C:32]([O:31][CH3:30])=[O:42])=[CH:39][CH:38]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
[4-(3-Aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.39 g, 1.0 mmol) and (4-formyl-phenyl)-acetic acid methyl ester (0.17 g, 0.96 mmol) were mixed in THF (15 mL) and then treated with NaBH(OAc)3 (0.43 g, 2.0 mml) and acetic acid (0.5 mL). After stirring at 40° C. under a N2 atmosphere for 2 h the mixture was quenched with water and then extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate as an orange solid (0.30 g, 54%): MS (EI) m/z 555.3 (M+H)+; 1H NMR (DMSO-d6): δ 3.61 (s, 3H), 3.66 (s, 2H), 4.12 (d, J=6.0 Hz, 2H), 6.40 (d, J=6.8 Hz, 2H), 6.49 (d, J=6.8 Hz, 2H), 6.98 (t, J=7.7 Hz, 1H), 7.18-7.22 (m, 4H), 7.36 (t, J=7.5 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.72 (t, J=8.6 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 8.30 (d, J=7.3 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:13]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-(2,4-Dichloro-phenyl)-1-(4-nitro-phenyl)-2-(4-bromo-benzyl)-1H-imidazole (5.0 g, 10 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH2:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15]
Reactant: COc1cccc(CCN)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(CCNC(C)=O)c1OC

Procedure:
In close analogy to the procedure described above, 2-(2,3-dimethoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].C(OO)(=[O:17])C>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:11][CH2:12][CH:13]1[O:17][CH2:14]1)=[O:10]
Reactant: CC(=O)OO
Reactant: C=CCOC(=O)/C=C\C(=O)OCC=C
Product: C=CCOC(=O)/C=C\C(=O)OCC1CO1

Procedure:
The reaction of diallyl maleate with peracetic acid is reported in J. Am. Chem. Soc. 81, page 3354 (1959). In spite of a 4-fold excess of ester, the reaction time was 11.5 hours at 50° C. Allyl glycidyl maleate was obtained in a yield of only 71%. The preparation of diglycidyl maleate is not mentioned.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([C:20](Cl)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:20]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: O=C(OCCN1CCOCC1)c1cccc2ccccc12
Yield: 94 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 1-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 1-naphthalenecarboxylate in a yield of 94%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)ncn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(CCc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 4,6-dimethylpyrimidine (1.08 g, 10 mmol) in THF (40 ml) was added dropwise at −78° C. a solution of n-butyllithium. To the solution was added benzylbromide (1.71 g, 10 mmol). The mixture was warmed up to 0° C. and stirred for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The obtained residue was chromatographed on silica gel (n-hexane-ethyl acetate). The obtained fraction was concentrated to give 4-methyl-6-phenethylpyrimidine (1.7 g).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[C:28]([O:27][C:25]([N:14]1[C:15]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:18])[NH:11][CH2:12][CH2:13]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(CCNC(=O)OCc1ccccc1)c1c(F)cccc1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCNC(=O)c2cccc(F)c21

Procedure:
A solution of 2-[(2-benzyloxycarbonylaminoethyl)-tert-butoxycarbonylamino]-3-fluorobenzoic acid from Example 20B (390 mg, 0.87 mmol), 10% palladium/carbon (˜100 mg) and acetic acid (1.0 ml) in methanol (25 ml) was hydrogenated at atmospheric pressure for 1.5 h. The mixture was filtered, evaporated in vacuo and azeotroped with toluene. The residue was taken up in a mixture of IPA and acetic acid (90:10, 35 ml) and heated at reflux for 4 h. The mixture was cooled, evaporated in vacuo and azeotroped with toluene to give a white solid; yield 250 mg, 100%.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]([O:11]CC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.[Cl-].[Na+].O>[CH:1]1([CH2:7][CH:8]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
A solution comprised of ethyl 2-cyclohexylmethyl-N-phenethylmalonamate (366 mg, 1.106 mmol) in ethanol (10 mL) was treated with 1N aqueous sodium hydroxide (1.3 mL) for 2.5 hours and then diluted with water (30 mL) and brine (10 mL). The dilution was extracted with diethyl ether (3×30 mL). The aqueous layer was cooled to 0° C., acidified with 1N hydrochloric acid (2 mL) and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to provide 2-cyclohexylmethyl-N-phenethyhnalonamic acid (138 mg, 0.45 mmol).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)cccc2c1

Procedure:
Synthesized using 1-naphthylboronic acid (217 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 130 mg, 0.46 mmol, 72%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.25 (s, 2H), 7.00 (t, J=1.3 Hz, 1H), 7.16 (t, J=1.3 Hz, 1H), 7.46-7.52 (m, 2H), 7.54-7.60 (m, 4H), 7.65 (br, s, 1H), 7.90-7.93 (m, 2H), 8.03-8.05 (m, 1H), 8.70 (dd, J=2.5, 0.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.19, 119.1, 125.2, 125.2, 125.3, 126.0, 126.6, 127.6, 128.4, 129.2, 130.1, 130.3, 131.0, 135.3, 137.3, 137.6, 148.3, 159.5; MS (ESI): m/z=286.05 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[Cl:28][C:29]1[C:30]([NH:44][CH3:45])=[CH:31][C:32]([O:42][CH3:43])=[C:33]([CH:41]=1)[C:34](N1C=CN=C1)=[O:35]>>[Cl:28][C:29]1[C:30]([NH:44][CH3:45])=[CH:31][C:32]([O:42][CH3:43])=[C:33]([CH:41]=1)[C:34]([O:14][CH:13]1[CH:12]2[CH2:11][CH2:10][N:9]([CH2:16][CH2:15]2)[CH:8]1[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:35]
Reactant: OC1C2CCN(CC2)C1CN1CCCCC1
Reactant: CNc1cc(OC)c(C(=O)n2ccnc2)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CNc1cc(OC)c(C(=O)OC2C3CCN(CC3)C2CN2CCCCC2)cc1Cl

Procedure:
2-(1-Piperidinylmethyl)-1-azabicyclo[2.2.2]octan-3-ol cis isomer (2.47 g, 11 mmoles) was treated with n-butyllithium/hexane, and then with 1-[5-chloro-2-methoxy-4-(methylamino)benzoyl]-1H-imidazole, following the procedures described above for the corresponding trans isomer.