Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:7](=[O:19])[C:6]=2[N:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.C(Cl)Cl.CO>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:7](=[O:19])[C:6]3[N:20]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:3]=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: O=C1c2nc(Br)ccc2OCN1Cc1ccc(Cl)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(Cl)cc3)CO4)cc12
Temperature: 100 °C
Yield: 71.9 %

Procedure:
To a solution of 6-bromo-3-(4-chlorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (127 mg, 0.36 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol) and K3PO4.3H2O (159 mg, 0.60 mmol) in dioxane/water (2 mL/0.2 mL) was added Pd(dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 5 h, and after concentrated in vacuo, the residue was suspended in water. The mixture was extracted with EtOAc and the organic phase was washed with brine then dried over sodium sulfate. The product 5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (140 mg, yield: 72%) was obtained with prep-TLC (DCM:MeOH=30:1). 1H-NMR (CDCl3, 400 MHz) δ 7.95˜7.98 (m, 3H), 7.76 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.30˜7.36 (m, 4H), 7.20 (t, J=8.8 Hz, 2H), 6.07 (br s, 1H), 5.23 (s, 2H), 4.79 (s, 2H), 3.23 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.94 (s, 3H). MS (M+H)+: 649/651.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH2:25](Br)[CH3:26]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCBr
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Product: CCCCN1CCN(CCNC(=O)c2nn(CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-(2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and ethyl bromide according to the same process as in Example 12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[O:11])=[CH:7][C:6]=3[CH:36]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(NS(=O)(=O)c5ccccc5)ccc4o3)cc2)cc1)C(=O)O

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was sulfonylated with benzenesulfonyl chloride according to the procedure of Example 8 followed by cleavage from the resin to provide 4′-[(5-benzenesulfonylamino-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine. LCMS MH+ (m/z) 648. 1H NMR (300 MHz, CD3OD): δ 7.92-7.69 ppm (m, 9H), 7.58-7.43 ppm (m, 6H), 7.22-7.18 ppm (dd, 2H, J1=9.0 Hz, J2=2.5 Hz), 3.64 ppm (d, 1H, J=5.0 Hz), 2.09-2.01 ppm (m, 1H), 0.97 ppm (d, 3H, J=7.0 Hz), 0.90 ppm (d, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN1C(=O)CCC1>CN(C=O)C>[CH:11]1([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCOCC3)n3nc(C4CC4)cc3n2)cc1
Temperature: 25 °C

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2J, 100 mg, 0.27 mmol) and morpholine (47.0 mg, 0.54 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 15 minutes. After cooling to room temperature, DMF (1 ml) was added. The crude product mixture was filtered by syringe filter and purified by preparatory HPLC (35-45% ACN/water, TFA mode). Lyophilization of the collected fractions gave the titled compound product (42 mg, 37% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.84 (s, 1 H), 7.99 (d, J=8.1 Hz, 2 H), 7.59 (d, J=7.8 Hz, 2 H), 7.34 (s, 1 H), 6.06 (s, 1 H), 5.18 (s, 1 H), 3.97-3.58 (m, 8 H), 2.15-1.96 (m, 1 H), 1.45 (s, 5 H), 1.08-0.92 (m, 2 H), 0.88-0.74 (m, 2 H); ESI-MS: m/z 422.2 (M+H)+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][S:16][CH2:17][N:18]1[C:23](=[O:24])[N:22]2[CH:25]=[N:26][C:27]([C:28]([NH2:30])=O)=[C:21]2[N:20]=[N:19]1.C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:15][S:16][CH2:17][N:18]1[C:23](=[O:24])[N:22]2[CH:25]=[N:26][C:27]([C:28](=[S:2])[NH2:30])=[C:21]2[N:20]=[N:19]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CSCn1nnc2c(C(N)=O)ncn2c1=O
Solvent: ClCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CSCn1nnc2c(C(N)=S)ncn2c1=O
Yield: 36 %

Procedure:
Phosphorus pentasulfide (25 mg, 0.11 mmol) was added in one portion to a suspension of 3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide and hexamethyldisiloxane (85 mg; 0.112 mL, 0.525 mmol) in DCM (5 mL) and the mixture was refluxed overnight. The crude product was absorbed on silica and purified by flash chromatography using DCM:MeOH (95:5) as eluent to give 39 mg of the title compound as an orange solid (36% yield). δH (DMSO d6): 9.95 (1H, s), 9.47 (1H, s), 8.85 (1H, s), 5.43 (2H, s), 2.26 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]([OH:35])[CH2:14][N:15]1[CH2:22][CH:21]3[N:23]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=4)[CH2:24][CH:16]1[CH2:17][CH:18]=[CH:19][CH2:20]3)[CH:7]=[CH:6][CH:5]=2>[Pd].CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]([OH:35])[CH2:14][N:15]1[CH2:22][CH:21]3[N:23]([CH:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26]4)[CH2:24][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(OCC(O)CN3CC4CCCCC3CN4C3CCc4ccccc4C3)cccc2[nH]1
Reaction time: 8 h

Procedure:
1-(2-Methyl-1H-indol-4-yloxy)-3-(9-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-en-7-yl)-propan-2-ol (0.05 g, 0.107 mmol), 10% Pd/C (0.05 g), methanol (15 mL) were placed in an hydrogenation bottle under H2 atmosphere (60 psi) and shaken overnight. The resulting mixture was filtered and the solvent evaporated under reduced pressure to yield a crude solid. The crude solid was purified with flash chromatography [20% Ethyl acetate/heptane] to yield the title compound as a residue.
Reaction SMILES: O1C(C(O)=O)C(C(O)=O)C(C(O)=O)C1C(O)=O.[CH:18]1([C:33]([OH:35])=[O:34])[CH2:23][CH:22]([C:24]([OH:26])=O)[CH:21]([C:27]([OH:29])=[O:28])[CH2:20][CH:19]1[C:30]([OH:32])=O>>[CH:23]1[C:18]2[C:33]([O:35][C:30](=[O:32])[C:19]=2[CH:20]=[C:21]2[C:27]([O:28][C:24](=[O:26])[C:22]=12)=[O:29])=[O:34]
Reactant: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Agent: O=C(O)C1OC(C(=O)O)C(C(=O)O)C1C(=O)O
Product: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12

Procedure:
tetrahydrofuran-2,3,4,5-tetracarboxylic acid and 1,2,4,5-cyclohexanetetracarboxylic acid .
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[C:13]1(=[O:19])[NH:17][C:16](=[O:18])[CH:15]=[CH:14]1.C(=O)=O.C([O-])(=O)C.[Na+]>Cl.O.CC(C)=O>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:14]2[C:13]([NH:17][C:16](=[O:18])[CH:15]=2)=[O:19])=[CH:3][CH:4]=1
Reactant: O=C1C=CC(=O)N1
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C2=CC(=O)NC2=O)cc1
Reaction time: 0.5 h

Procedure:
A 53.6 g portion of p-toluidine was dissolved in a mixture of 150 ml of 12N-hydrochloric acid and 100 ml of water, cooled in an ice-salt bath. A 100 g portion of ice was added and then a solution of 35 g of sodium nitrite in 80 ml of water was added dropwise with stirring over 1/2 hour. A solution of 48.5 g of maleimide in 400 ml of acetone was then added in one portion and the mixture was cooled in an ice-salt bath with 20 g of dry ice added to the reaction mixture. A 125 g portion of sodium acetate was added to achieve pH 3. Ten minutes later 5.0 g of cupric chloride dihydrate was added. The mixture was filtered and the filtrate was allowed to stand 64 hours. The solid was collected, added to 30 ml of 2,6-lutidine and heated on a steam bath for 1/2 hour, then poured into one liter of water and filtered. The filtrate produced pale yellow crystals which were collected, giving 2-(p-tolyl)maleimide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][N:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: O1CCCC1.[OH-].[Na+].C([N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=O>CO>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:13]2[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2CCN(C=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)cc2)N2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
6 ml of tetrahydrofuran, 9 ml of methanol and 9 ml of 10% aqueous sodium hydroxide were added to 1.68 g of the above-mentioned compound (2) followed by stirring for 2 hours at 60° C. After concentrating the reaction solution to roughly 10 ml and saturating it with sodium chloride, the concentrate was extracted with dichloromethane (20 ml×4). After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.48 g of the target compound. Yield: 95%
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([OH:51])[CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:47]=[N:46][C:45]([CH3:48])=[N:44]3)=[C:39]([O:49][CH3:50])[CH:38]=2)[CH:27]=[CH:28][C:29]=1[Cl:30].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O.C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([C:31](=[O:51])[CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:47]=[N:46][C:45]([CH3:48])=[N:44]3)=[C:39]([O:49][CH3:50])[CH:38]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COc1cc(C#CCCCC(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc(C#CCCCC(=O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Dess-Martin reagent (248 mg) was added to a mixture of 1-(3,4-dichlorophenyl)-6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-yn-1-ol (210 mg), acetonitrile (2.1 mL) and DMSO (200 μL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (198 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[CH3:15][CH:16]([CH3:24])[C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH:16]([C:17]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:18]=1[C:19]([O:21][CH3:22])=[O:20])([CH3:24])[CH3:15]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Yield: 36.5 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-(trifluoromethyl)acetophenone (13.4 g) and methyl 4-methyl-3-oxopentanoate (7.2 g) to give the title compound (5.7 g, 36%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].[NH:29]([C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1)[NH2:30]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:30][N:29]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:10][CH:11]=1
Reactant: Cn1nccc1NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Product: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2). The crude material was purified by silica gel column chromatography (1% ammonia/7.5% MeOH/CH2Cl2) and triturated in Et2O. tR: 0.92 min (LC-MS 2); ESI-MS: 473 [M+H]+ (LC-MS 2); Rf=0.34 (1% ammonia/7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3H) 2.43 (s, 3H) 2.60 (s, 3H) 3.85 (s, 3H) 6.55 (s, 1H) 6.58-6.68 (m, 1H) 7.31 (s, 1H) 7.37 (m, J=8.6 Hz, 2H) 7.45 (m, J=8.6 Hz, 2H) 7.56 (d, J=2.4 Hz, 1H) 8.44 (s, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([OH:22])=[CH:16][C:17]=3[OH:21])[O:12][C:11]=2[C:23]([O-])=[O:24])=[CH:8][CH:7]=1>CO>[OH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([OH:22])=[CH:16][C:17]=3[OH:21])[O:12][C:11]=2[C:23]([NH:4][CH2:3][CH2:1][OH:2])=[O:24])=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: O=C([O-])c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Solvent: CO
Product: O=C(NCCO)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
Ethanolamine (100 mg), was added to a solution of 4',5,7-trihydroxyisoflavonecarboxylate (100 mg) in 2 ml methanol, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced presure, the residue was purified by silica gel column chromatography (chloroform:methanol=95:5), and the solid thus obtained was recrystallized from a methanol/diethyl ether mixed solvent, giving 40 mg of 4',5,7-trihydroxy-N-(2-hydroxyethyl)-2-isoflavonecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)([O-])=O.C1CCC=CC=1>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(CNCCNc2ccccc2[N+](=O)[O-])c1)N1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCC=C1
Product: Nc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To a solution of (3-{[2-(2-nitro-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 11; 0.060 g, 0.16 mmol) in EtOH (1.6 mL) was added cyclohexadiene (0.55 mL) followed by Pd/C (10 wt %, 0.02 g), and the resulting suspension was heated to 100° C. for 45 min. The suspension was filtered (diatomaceous earth), and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0-5% CH3OH/CH2Cl2) to provide the desired product as a colorless oil (0.034 g, 61%). MS (ESI): mass calculated for C21H28N4O, 352.23. m/z found, 353.2 [M+H]+, 375.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 3H), 7.26-7.24 (m, 1H), 6.80 (d t, J=5.4, 1.9 Hz, 1H), 6.72-6.64 (m, 3H), 3.84 (br s, 2H), 3.70 (br s, 2H), 3.32 (br s, 2H), 3.21 (t, J=5.7 Hz, 2H), 2.94 (t, J=5.7 Hz, 2H), 1.67 (br s, 4H), 1.50 (br s, 1H). 13C NMR (100 MHz, CDCl3): 170.3, 140.7, 137.7, 136.7, 134.6, 129.1, 128.4, 126.5, 125.3, 120.5, 118.7, 116.3, 112.0, 53.3, 48.1, 43.8, 29.7, 26.5, 24.6.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:11][C@H:12]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)N[C@@H](C)P(=O)(O)O
Reaction time: 8 h
Yield: 86.6 %

Procedure:
3.27 g (7 mmol) of (1R)-1-[(N-benzyloxycarbonyl-L-histidyl-L-alanyl)amino]-ethylphosphonic acid were ground to a powder and then stirred vigorously at room temperature for 6 hours with a mixture of 15 ml of 45% hydrogen bromide in glacial acetic acid and 5 ml of glacial acetic acid. 75 ml of diethyl ether were added to precipitate a gum which was washed by decantation with a further 75 ml of diethyl ether. The residual gum was dissolved in 50 ml of methanol and two 3 ml portions of propylene oxide were added to the stirred solution to give a solid. The mixture was left to stand overnight and the solid was then filtered off and washed successively with methanol and diethyl ether to give 2.47 g of crude product of melting point 220°-230° C. (decomposition). Recrystallisation from a mixture of 50 ml of water and 125 ml of ethanol gave 2.02 g (87%) of (1R)-1-(L-histidyl-L-alanylamino)-ethylphosphonic acid of melting point 242°-245° C. (decomposition); [α]36520 =-166° (c=0.5% in water).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OB(O)c1ccsc1
Product: c1ccc(Cc2ccsc2)cc1
Yield: 74 %

Procedure:
3-benzylthiophene was prepared in the same manner as described in Example 32C using 3-thienylboronic acid and benzyl bromide, 74% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(CO)nc3-c3ccccc3Cl)c(Cl)c2)c1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a −78° C. solution of ethyl 1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-1H-imidazole-4-carboxylate (1.00 g, 1.94 mmol) in 10 mL dichloromethane was added diisobutylaluminum hydride (9.7 mL, 9.70 mmol). The reaction was stirred from 78° C. to room temperature for 12 h. The reaction was quenched with 5 mL MeOH, followed by 10 mL Rochelle's salt. Dilute with ethyl acetate and stir for 1 h. The organic layer was separated and the water layer was extracted with ethyl acetate 1×10 mL. The combined organic layers were washed with brine and dried with MgSO4 to afford (1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)methanol (770 mg, 84%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 8.21-8.20 (m, 1H), 8.10-8.07 (m, 1H), 8.05-8.04 (m, 1H), 7.95-7.92 (m, 1H), 7.80-7.77 (m, 1H), 7.74 (t, J=7.84 Hz, 1H), 7.49-7.46 (m, 2H), 7.45-7.31 (m, 4H), 5.11 (t, J=5.69 Hz, 1H), 4.50 (d, J=5.79 Hz, 2H), 3.29 (s, 3H); MS (ES) 473.3 [M+H]+ and 495.0 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC[C@@H]1[C@@H]2CCN(C(OCC3C=CC=CC=3)=O)[C@@H]2C2C=CC=CC=2N1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@H:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: COCC(Nc1ccccc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: COC[C@H]1Nc2ccccc2[C@@H]2[C@H]1CCN2C(=O)OCc1ccccc1
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OCc1ccccc1

Procedure:
In the same manner as in Reference Example 37 except that (2R,4R)-3,5-xylyl-skewphos was used as an asymmetric ligand instead of (2S,4S)-skewphos, benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate was hydrogenated, and area percentage of the resultant product, (3aS,4S,9bS)-benzyl 4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, was determined by high performance liquid chromatography to find production at an area percentage of 48%.