Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(C)[CH3:2].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([O:4][CH2:1][CH3:2])=[N:9][CH:8]=1
Reactant: CC(C)Oc1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2-isopropoxythiazole (300 mg, 2.32 mmol) in DMF (2 mL) was added N-bromosuccinimide (620 mg, 3.48 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a colorless oil (440 mg, 91% yield). LCMS (Conditions C): Tr 3.27 min.; (M+H)+: 207.88 (20%), 209.88 (20%), 179.87 (100%), 181.87 (100%).
Reaction SMILES: CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:18][C:19]1([CH3:34])[C:23]2=[N+:24]([O-:33])[C:25]3[C:30]([N+:31]([O-:32])=[C:22]2[CH2:21][O:20]1)=[CH:29][CH:28]=[CH:27][CH:26]=3>O>[OH:18][C:19]1([CH3:34])[C:23]2=[N+:24]([O-:33])[C:25]3[C:30]([N+:31]([O-:32])=[C:22]2[CH2:21][O:20]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: COC1(C)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(O)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Yield: 68 %

Procedure:
To a mixture of 1,500 ml. of acetone and 75 ml. of water, containing 3.78 g. (0.02 mol.) of 4-toluenesulfonic acid monohydrate, was added 63.6 g. (0.26 mol.) of 1-methoxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide. The reaction mixture was heated under reflux for 4.5 hours and then allowed to cool to ambient temperature. The solvent was removed by evaporation in vacuo, and the residue was washed with ether. This afforded 58.7 g. (98% yield) of crude product. The crude product was recrystallized from water with the aid of activated carbon, to give a 68% yield of product having m.p. 159°-160° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](O)=O)#[N:12].N>>[F:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1cc(-c2nc(-c3cccnc3)no2)ccc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ ppm 7.62-7.71 (m, 2 H), 8.54-8.63 (m, 2 H), 8.69 (dd, J=5.9, 2.2 Hz, 1 H), 8.75 (dd, J=4.9, 1.5 Hz, 1 H), 9.30 (dd, J=2.0, 1.0 Hz, 1 H); MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1.CO.[OH-].[Li+].S(=O)(=O)(O)O>ClCCl.O.O1CCCC1>[C:14]([O:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Cl:1])=[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[C:4]([C:18]([OH:20])=[O:19])=[C:5]2[CH2:10]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1c(-c2cccc(C#N)c2)c(Cl)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(=O)O)c2C1
Temperature: 60 °C
Yield: 63.2 %

Procedure:
To a suspension of 5.50 g (13.2 mmol) of 2-tert-butyl 8-methyl 6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 60 ml of a mixture of methanol, water and tetrahydrofuran (1:1:2) is added 0.38 g (15.9 mmol) of lithium hydroxide, and the mixture is heated at 60° C. for 18 hours. The mixture is then taken up in 100 ml of dichloromethane and 100 ml of water, and is then acidified by addition of aqueous 1N sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 3.35 g of 2-(tert-butyloxycarbonyl)-6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in the form of a white powder after triturating in acetonitrile, filtering off and drying.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25]>C(Cl)Cl>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:24](=[O:25])[NH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (500 mg, 2.33 mmol) in CH2Cl2 at −10° C. was added triethylamine (650 μL, 4.66 mmol) followed by the dropwise addition of 2-methoxyethyl chloroformate (325 μL, 2.79 mmol). The reaction was warmed to room temperature and quenched with water. The aqueous layer was extracted with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and evaporated. Purification via silica gel chromatography using 0 to 10% EtOAc in CH2Cl2 afforded 2-methoxyethyl((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 67%). LC/MS: m/z 317.3 (M+H)+ at 2.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]([CH2:6][C@H:7]([NH:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[NH:3][CH2:2]1.O=[CH:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][N:12]([CH3:13])[C@@H:7]([CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN[C@@H](CC1CNCN1)C(=O)OC
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)N(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of methyl (2S)-3-(4-imidazolidinyl)-2-(methylamino)propanoate (1 g, 4.55 mmol), of tert-butyl N-(2-oxoethyl)carbamate (833 mg, 5.23 mmol), sodium acetate (1.494 g, 18.22 mmol) and sodium cyanoborohydride (572 mg, 9.10 mmol) in methanol (30 ml) was stirred at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to room temperature then aqueous hydrochloric acid (5 ml, 1N) was added, followed by saturated aqueous sodium hydrogen carbonate solution. The solution was filtered and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol (100:5), to afford the title compound, 900 mg, 61% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:23].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([C:11](=[O:23])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of Example 2A (0.3g, 1.0 mmol) and pyridinium dichromate (0.98 g, 2.6 mmol) in chloroform (20 mL) was heated at reflux with a Dean-Stark trap for 18 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. Column chromatography on silica (5% →15% ethyl acetate/hexane) afforded the title compound as a white solid (0.18 g, 58%). 1H NMR (300 MHz, CDCl3) δ ppm 0.40(m, 1H), 0.72 (m, 7H), 1.37(m, 1H), 2.36(m, 2H), 3.61 (s, 3H), 3.83(s, 3H), 5.96 (s, 1H), 7.42 (m, 2H), 7.56 (m, 1H), 8.19 (d, J=7.72 Hz, 1H); MS m/z 303.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(C)CCCSCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCOC(=O)C(C)(C)CCCSCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 63 %

Procedure:
from ethyl 8-bromo-2,2-dimethyl-6-thiaoctanoate and 4-chlorobenzenesulphonamide; yield 63% of theory; colourless oil;
Reaction SMILES: Cl.CCO.[CH2:5]([O:12][N:13]=[CH2:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO>[CH2:5]([O:12][NH:13][CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=NOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CNOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A 1M HCl/EtOH solution (50 mL) was added dropwise to the solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in EtOH at 0° C. The mixture was stirred at room temperature for 1 hour, volatiles were removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO3 solution (75 mL), water (75 mL), and dried over Na2SO4. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (7:1) to yield O-benzyl-N-methyl-hydroxylamine (1.72 g, 44%). 200 MHz 1H NMR (CDCl3, ppm) 7.40-7.27 (5H, m), 5.53 (1H, br s), 4.71 (2H, s), 2.73 (3H, s).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCN(C2CCNCC2)CCN1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H48N7O3Cl2 [(M+H)+] 720.319, observed 720.3196.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[O:6])[CH:2]=[CH2:3].C([SiH](CC)CC)C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)N(C)C
Agent: CC[SiH](CC)CC
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(=O)N(C)C
Yield: 89.9 %

Procedure:
The same operation as in Reference Example 4-2) was carried out by using (E)-3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]-N,N-dimethylacrylamide (the compound obtained in Reference Example 6-1); 2.02 g, 3.84 mmol) and triethylsilane (0.64 ml, 4.03 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with acetone-methylene chloride 1:1) to give the title compound (980 mg, 89.9% yield).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[NH2:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)=[O:24])=[O:20])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)c1ccc(N2CCN(CC(=O)O)CC2)cc1
Agent: Cl
Product: CC(=O)c1ccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)cc1
Yield: 20.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-acetylphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 229, (S)-2-(2-(4-(4-acetylphenyl)piperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (10.2 mg, 20.4%). 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.04 (d, 1H), 7.81 (d, 2H), 7.60 (d, 2H), 7.23 (m, 7H), 7.01 (m, 6H), 4.71 (m, 1H), 4.52 (s, 2H), 3.74 (m, 1H), 3.33 (m, 5H), 3.07 (s, 2H), 2.61 (m, 4H), 2.46 (s, 3H). MS (EI) for C36H37FN4O5: 625.6 (MH+).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:32])[C:2]=1[C:42]1[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 73 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[CH3:26][C:27]([CH2:29][CH3:30])=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:27]([CH2:29][CH3:30])[CH3:26])[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: CCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(C)cn2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 50.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with methylethyl ketone (1.12 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.26 g (50%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:26])[CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:16]2=[O:25])[N:6]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:26])[CH2:14][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:16]2=[O:25])[N:6]=1
Reactant: Cc1nc(-c2sccc2NC(=O)CN2C(=O)CCc3ccccc32)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2sccc2NC(=O)CN2C(=O)CCc3ccccc32)c[nH]1

Procedure:
N-(2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (125 mg, 205 mmol) in TFA (5 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield N-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide. Method [8] Retention time 4.05 min by HPLC (MH+ 367). 1H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 7.57 (m, 2H), 7.43 (d, J=4.8 Hz, 2H), 7.22 (m, 2H), 6.99 (m, 2H), 4.68 (s, 2H), 2.92 (m, 2H), 2.59 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [C:1]([N:4]([CH2:17][CH2:18][O:19][C:20](=[C:28]1[CH:35]2[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:37][CH:29]1[CH2:30]3)[CH2:34]2)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:6])(=[O:3])[CH3:2].[OH:38][C:39]1C=CC2N=C(C(NCCOC(=C3C4CC5CC(CC3C5)C4)C3C=CC=C(O)C=3)=O)SC=2[CH:40]=1>C(OCC)(=O)C.CCCCCC>[C:39]([O:27][C:23]1[CH:22]=[C:21]([C:20](=[C:28]2[CH:35]3[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:37][CH:29]2[CH2:30]4)[CH2:34]3)[O:19][CH2:18][CH2:17][N:4]([C:1](=[O:3])[CH3:2])[C:5]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:6])[CH:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:40]
Reactant: CC(=O)N(CCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)C(=O)c1nc2ccc(O)cc2s1
Reactant: O=C(NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)c1nc2ccc(O)cc2s1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Oc1cccc(C(OCCN(C(C)=O)C(=O)c2nc3ccc(O)cc3s2)=C2C3CC4CC(C3)CC2C4)c1

Procedure:
The second product was obtained with 35% ethyl acetate/hexane and was found to be {[2-(N-acetyl-N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane (3a): 1H NMR (CDCl3) δ1.80-1.96 (m, 12H), 2.18 (s, 3H), 2.67 (bs, 1H), 3.33 (bs, 1H), 3.65 (m, 4H), 6.74 (bs, 1H), 6.96-7.92 (m, 7H), 7.79 (bs, 1H).; 13C NMR (CDCl3) δ20.97, 28.22, 30.53, 32.35, 37.07, 39.01, 39.14, 39.97, 67.79, 107.09, 117.16, 120.75, 122.35, 125.13, 126.71, 129.10, 133.50, 136.72, 138.86, 140.98, 147.39, 150.65, 155.72, 160.34, 160.43, 169.36. The third product was identified as {[2-(N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane ##STR35##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>CCN(CC)CC>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Yield: 52.8 %

Procedure:
Prepared from 0.500 g of 6-amino-4-(3-bromophenylamino)quinoline-3-carbonitrile, 0.194 g of Et3N and 0.202 g of methacryloyl chloride in the same manner as EXAMPLE 380. There was obtained 0.317 g of N-[4-(3-bromophenylamino)-3-cyanoquinolin-6-yl]-2-methylacrylamide as a yellow solid: mass spectrum (electrospray, m/e): M+H 406.8, 408.8.
Reaction SMILES: [O:1]=[C:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)[CH:3]=[CH2:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:4][CH2:3][C:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:1])[CH2:24][CH3:25])[CH3:22]
Reactant: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Product: CCN(CC)CC1CCCCN1CCC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 1h from 5,10-dihydro-5-(1-oxopropen-1-yl)-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(diethylamino)methyl]piperdine to give colorless crystals mp. 125°-127° C. (acetonitrile).
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([NH:24][C:25]([NH2:27])=[O:26])=[O:23])=[CH:12][CH:13]=1
Reactant: NC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: NC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (415.5 mg, 1.35 mmol) and urea (202.3 mg, 3.37 mmol, 2.5 equiv) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 7.7 mL, 5.39 mmol). The resulting reaction mixture was then heated under reflux for 23 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded (2-biphenyl-4-yl-3-cyclopentyl-propionyl) urea (67.8 mg, 15%) as a white solid: mp 184-185° C.; FAB-HRMS m/e calcd for C21H24N2O2 (M+H)+ 337.1917, found 337.1924.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](O)=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]2[S:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([N:9]4[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(S)c2N)CC1
Product: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from tert-butyl 4-(5-amino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 3-(4-fluorophenyl)propionic acid, yielding the title compound in 80% yield.