Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37](Cl)=[O:38]>C1C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:38]
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)ccc1OC)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
Analogously to Example 47, 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 7.3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml of benzene to obtain, as reaction product, 15.0 g (94.1% of theory) of ethyl 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]butyrate as a viscous non-distillable oil. The saponification of this ester yields 12.4 g (88% of theory) of 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido-9 butyric acid, MP 160° to 162°.
Reaction SMILES: [CH2:1]([N:5]([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][Si](C(C)(C)C)(C)C)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
In 75 ml of tetrahydrofuran was dissolved 4.02 g (8.52 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldimethylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde, and 25.5 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.74 g of a blackish brown crystal (yield: 89.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:34])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[C:22]([NH2:24])=[O:23])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:24][C:22](=[O:23])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[N:20]=2)=[CH:11][CH:10]=1)([CH3:34])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cccc(OC)c2)C(N)=O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3cccc(OC)c3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3-methoxyphenylmethyl)semicarbazide (4.08 g, 8.65 mmol) was dissolved in ethyl acetate (7.5 mL). 1S (+)-10-camphorsulfonic acid (2.21 g, 9.51 mmol) was added in one portion and the solution was heated to reflux overnight. The solution was cooled to rt and washed with sat'd aq. NaHCO3 (40 mL×2) followed by 1N HCl (40 mL×2). The organic was concentrated to an orange oil. This oil was redissolved in ethyl acetate (40 mL). Amberlyst-15 resin (4.41 g) was added and the mixture was heated to 50° C. and stirred for 4 hours to remove de-ureated impurity. The mixture was then cooled to ambient temperature, filtered, concentrated, and purified by column chromatography (SiO2, 9:1 ethyl acetate: hexanes) to afford the title compound as an orange oil (1.93 g, 49.2%). 1H NMR (DMSO-d6) δ 11.47 (s, 1 H), 7.22 (t, 1H, J=8 Hz), 7.04 (d, 2H, J=8 Hz), 6.82 (d, 1H, J=2 Hz), 6.76 (m, 2H), 6.68 (d, 2H, J=2 Hz), 4.73 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.69 (s, 3H), 2.48 (t, 2H, J=8 Hz), 2.36 (t, 2H, J=8 Hz), 1.80 (quint, 2 H, J=7 Hz), 1.47 (s, 6H), 1.14 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 160.0, 155.0, 153.8, 146.7, 139.8, 135.5, 130.2, 129.8, 120.1, 119.5, 113.8, 113.2, 79.2, 61.6, 55.6, 47.8, 34.0, 28.4, 26.2, 25.7, 14.6; IR (CHCl3) 2940, 1692, 1508, 1467 cm−1; Anal. Calcd. for C25H31N3O5: C, 66.21.; H, 6.89; N, 9.26. Found: C, 66.29; H, 6.75; N, 9.19.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][N:14]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][C:9]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:7].C1C[O:33]CC1>>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH2:5].[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:8]=2[C:6]([OH:7])=[O:33])[N:14]([CH2:17][CH:18]([CH3:19])[CH3:20])[N:13]=[CH:12]3)=[CH:23][CH:24]=1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN(C)C)cc21
Reactant: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)O)cc21
Product: CN(C)CCN
Temperature: 65 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
Compound 11g-10 (0.05 g, 0.12 mmol), prepared as described in Example 59, was treated with 6 equivalents of BH3 in THF (1 M solution) and stirred at 65° C. for 6 hours and then at room temperature for 14 hours. The solvent was removed by evaporation, and the residue was purified on by preparative TLC using 1:1 hexane/ethyl acetate and 5% triethylamine to provide 0.014 g (30% yield) of product. MH+ observed: 385.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:29]2[CH2:30][CH2:31][N:27]([CH3:26])[C:28]2=[O:32])[CH:7]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Reactant: CN1CCNC1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 12.8 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (846 mg) described in Preparation Example 257 and 1-methylimidazolidin-2-one (300 mg) and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (113 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To the suspension of 4-(4-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (500 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.54 g, 94%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:38][CH2:37][CH2:41]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCC4)c(C)c3C)c2cc1OC
Yield: 92.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 84%).
Reaction SMILES: NC1C=C2C(=CC=1N)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.NC1C=C2C(C(NC3C=C(OC)C=CC=3C)=C(C#N)C=N2)=CC=1N(CCN1CCOCC1)C(N)=S.[NH2:60][C:61]1[CH:62]=[C:63]2[C:68](=[CH:69][C:70]=1[NH:71][C:72]([NH:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1)=S)[N:67]=[CH:66][C:65]([C:83]#[N:84])=[C:64]2[NH:85][C:86]1[CH:91]=[C:90]([O:92][CH3:93])[CH:89]=[CH:88][C:87]=1[CH3:94].[S]>O1CCOCC1.C(O)C>[CH3:93][O:92][C:90]1[CH:89]=[CH:88][C:87]([CH3:94])=[C:86]([CH:91]=1)[NH:85][C:64]1[C:63]2[CH:62]=[C:61]3[N:60]=[C:72]([NH:74][CH2:75][CH2:76][N:77]4[CH2:82][CH2:81][O:80][CH2:79][CH2:78]4)[N:71]=[C:70]3[CH2:69][C:68]=2[N:67]=[CH:66][C:65]=1[C:83]#[N:84]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(NC(=S)NCCN4CCOCC4)c(N)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N(CCN4CCOCC4)C(N)=S)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Agent: [S]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(C)c(Nc2c(C#N)cnc3c2C=C2N=C(NCCN4CCOCC4)N=C2C3)c1
Temperature: 100 °C

Procedure:
A mixture of 0.1 g (0.3 mmol) of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile and 0.11 g (0.62 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.3 mL of dioxane is heated at 100° C. for 2 hours under nitrogen. The mixture is cooled and solvent is evaporated to dryness to yield an oil consisting of N-[7-amino-3-cyano-4-(5-methoxy-2-methylanilino)-6-quinolinyl]-N-[2-(4-morpholinyl)-ethyl]thiourea and N-[6-amino-3-cyano-4-(5-methoxy-2-methylanilino)-7-quinolinyl]-N′-[2-(4-morpholinyl)ethyl]thiourea. The oil is dissolved in 3.0 mL of ethanol. To this is added 0.3 g of mercuric oxide and 20 mg of sulphur powder and the resulting mixture is heated at reflux temperature for 2 hours. The product mixture is filtered hot through diatomaceous earth, washed with methanol and solvent is evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 85:15) to yield 0.062 g of 8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,5-g]quinoline-7-carbonitrile as a pink solid, mp 148–150° C. (shrinks at 140° C.).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH3:26])[CH:16]=[CH:15][C:14]([C:17]([NH:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.C(OCC)(=O)C>[C:11]1([CH3:26])[CH:12]=[CH:13][C:14]([C:17]([NH:19][C@H:20]([CH:24]=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](C=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
Dimethylsulfoxide (2.2 ml, 31 mmol ) was slowly added via syringe to a stirred−78° C. solution of oxalyl chloride (15 ml, 171 mmol) in methylene chloride (35 ml) under inert atmosphere. After 10 min., a solution of N-p-toluoyl valinol (6.0 g, 29 mmol) in methylene chloride (50 ml) was added and the stirring was continued for additional 15 min. Triethylarine was added (6 ml, 389 mmol) and the reaction was allowed to warm to ambient temperature. After 1.5 h, the reaction was diluted with 50% ethyl acetate in hexanes and washed with water and brine. Filtration through a pad of silica gel and subsequent solvent removal left a solid residue. Chromatography eluting with 20% ethyl acetate in hexanes, then 33% ethyl acetate in hexanes gave N-p-toluoyl valinaldehyde (3.6 g) as a solid, which was utilized in Step 6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1c[nH]cn1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1cnc(CC(COc2noc3ccc(Cl)cc23)NC(=O)OC(C)(C)C)c1
Yield: 141.1 %

Procedure:
To a solution of 0.12 g of 3-[2-tert-butoxycarbonylamino-3-(4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 3 ml of pyridine is added 0.05 g of dimethylcarbamoyl chloride at room temperature, and they are subjected to reaction at 50° C. for two hours. After cooling, water and ethyl acetate are added and shaken, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent is removed by distillation under reduced pressure, to obtain 0.2 g of oily 3-[2-tert-butoxycarbonylamino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20](OC)[C:21](=C=O)[C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:24]([CH2:37][CH3:38])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:43]=[CH:44][CH:45]=[CH:46][C:6]=2[NH:5]1.C1[CH2:51][O:50]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:51]([OH:50])=[O:2])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[C:24]([CH2:37][CH3:38])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:43]=[CH:44][CH:45]=[CH:46][C:6]=2[NH:5]1
Reactant: CCc1cc(C(=C=O)[C@H](OC)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc(C)c1OCc1ccccc1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 50 mg (2.09 mmol) LiOH in 5 mL water was added to a solution of 800 mg (1.33 mmol) (R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 15 mL THF and the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 50 mL water, and 2 M HCl was added until an acidic reaction was obtained. The precipitate formed was filtered off, washed with water and dried. Further purification was carried out by decocting with 150 mL water, filtration and drying again.
Reaction SMILES: C([O:4][C:5]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:6]=1[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])(=O)C.[OH-].[Na+].Cl>C(O)C.O>[Cl:25][C:24]1[C:5]([OH:4])=[C:6]([CH:21]=[C:22]([Cl:26])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]
Reactant: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
One hundred and eight grams of ethyl ester of N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine were dissolved in 1 L of anhydrous ethyl alcohol and placed in a 2 L round bottomed flask equipped with a magnetic stirring bar and placed in water bath at ambient temperature. Into this mixture a solution of 33.33 g of sodium hydroxide in 37.2 mL of water was added in a single portion and the mixture stirred at ambient temperature for 17 h (overnight). A volume of 68.6 mL of concentrated hydrochloric acid was added under stirring, which was maintained for an additional of 2 h. The precipitated sodium chloride was filtered off and the filtrate evaporated to dryness at 60° C. under 30 T of pressure. The residue of 88.9 g (98% yield) solidified after cooling in form of a colorless glassy product, which was well soluble in toluene or acetonitrile, thereby producing an OTA template (e.g., for use in MIP-OTA production). MS: M+ 354 and 356 1H NMR (CDCl3, ppm): 12.2 very broad s, 1H, 7.49 d, J 2.4, 1H, 7.35-7.28 m, 3H, 7.20 d, J 2.0, 1H, 7.18-7.16 m, 2H, 6.80 br d, J 6.4, 1H, 6.4 very broad s, 1H, 5.07 dd, 5.2 and 5.2, 1H, 3.34 dd, J 14.0 and 5.2, 1H, 3.27 dd, J 13.6 and 5.2, 1H.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]([CH3:36])([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21](O)=[O:22]>>[F:19][C:20]([CH3:36])([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(F)(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Product: CN1C(=O)[C@@H](NC(=O)C(C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2RS)-2-fluoro-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1ccccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccccc2F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 7.98 (s, 1H), 7.47-7.42 (m, 1H), 7.33-7.26 (m, 2H), 7.18-7.07 (m, 1H), 4.08-4.04 (m, 2H), 3.85 (s, 2H), 3.69-3.56 (m, 3H), 3.20-2.93 (m, 4H), 2.69-2.62 (m, 1H), 2.40-2.19 (m, 3H), 1.88-1.85 (m, 2H), 1.14 (d, J=6.6 Hz, 3H). MS: (M+H m/z 412.1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:18](=[O:19])[CH:17]3[NH:20][CH:13]([CH2:14][CH2:15][CH2:16]3)[C:12]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:23]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[C:26]([O:33][CH3:34])=[CH:25][CH:24]1[CH2:35][C:36]([OH:38])=O.C1C=CC2N([OH:48])N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:48]=[C:35]([C:24]1[CH:25]=[C:26]([O:33][CH3:34])[C:27]([O:31][CH3:32])=[C:28]([O:29][CH3:30])[CH:23]=1)[C:36]([N:20]1[CH:17]2[CH2:16][CH2:15][CH2:14][CH:13]1[C:12](=[O:21])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]2=[O:19])=[O:38]
Reactant: COC1=CC(CC(=O)O)C(=O)C(OC)=C1OC
Reactant: On1nnc2ccccc21
Reactant: O=C1C2CCCC(N2)C(=O)N1CCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)C(=O)N2C3CCCC2C(=O)N(CCCCc2ccccc2)C3=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
3-(4-Phenylbutyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (Compound 14, 0.42 g, 1.47 mmol) and 2-oxo-3,4,5-trimethoxyphenylacetic acid (0.35 g, 1.47 mmol) were dissolved in CH2Cl2 (5 mL), and the solution was cooled to 0° C. HOBt (0.21 g, 1.54 mmol) was added, followed by EDC.HCl (0.30 g, 1.54 mmol) and TEA (0.15 g, 1.47 mmol). The reaction was allowed to reach room temperature and stirred for 5 hours. The volatiles were removed using a high-vacuum rotary evaporator. The residue was dissolved in EtOAc and washed with 10% citric acid solution (10 mL), followed by water (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL). The combined organic layers were dried over Na2SO4 and were concentrated. Flash chromatographic purification of the residue (30% EtOAc/hexanes) gave Compound 15 as a pale-yellow solid (0.25 g, 34%, one isomer). mp=101-103° C.; Rf=0.32 (50% EtOAc/hexanes); IR: 2939, 2866, 1739, 1682, 1651, 1582, 1503, 1454, 1416, 1361, 1337, 1243, 1167, 1126, 1067, 991, 914, 862 cm−1; 1H NMR (major rotamer): δ 1.56-1.64 (m, 5H), 1.93-2.01 (m, 5H), 2.61-2.66 (m, 2H), 3.80-3.85 (m, 2H), 3.95 (s, 9H), 4.51 (brs, 1H), 5.46 (brs, 1H),7.14-7.29 (m, 7H); HRMS (M+H+): expected 509.2288, observed 509.2275; EA: calculated, C (66.13), H (6.34), N (5.51); found, C (66.00, H (6.37), N (5.50).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([O:22]C)=O)[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([NH:30][O:29][CH2:28][CH2:27][O:26][CH:24]=[CH2:25])=[O:22])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Reaction time: 0.33 h

Procedure:
To a mixture of methyl 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.100 g, 0.294 mmol) and O-(2-(vinyloxy)ethyl)hydroxylamine (0.045 ml, 0.441 mmol) in THF (2 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.18 ml, 1.18 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for 20 minutes, quenched with 1 M HCl, and then partitioned between EtOAc and sat NaCl. The layers were separated and the aqueous layer was backextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude yellow solid that was used without purification in the next step.