Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([CH:10]2[O:11][CH2:12][CH2:13][O:14]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)ccc(C2OCCO2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(Cl)ccc(C2OCCO2)c1Cl
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a suspension of 2,6-dichloro-3-(1,3-dioxolan-2-yl)benzaldehyde (3.9 g) in methanol (19.5 ml) was added sodium borohydride (299 mg) under nitrogen atmosphere, and the mixture was stirred for 1 hour under ice-cooling. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 2,6-dichloro-3-(1,3-dioxolan-2-yl)-1-hydroxymethylbenzene (3.69 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:22])[CH3:21]>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:22][CH2:20][CH3:21])=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCN
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2ccccc21
Solvent: C1CCOC1
Product: CCCCn1c(=O)c([N+](=O)[O-])c(NCC)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
3.5 g (0.013 mole) of Compound d in Reference Example 4 was dissolved in 30 ml of tetrahydrofuran, and 8.0 ml (0.13 mole) of ethylamine was added with ice cooling, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure and ice water was added to the residue. The precipitate was collected by filtration and dried, to afford 3.5 g of Compound e (97%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[CH:44]=[C:43]([CH3:45])[O:42][N:41]=1>CC(C)=O.C(OCC)(=O)C>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([O:1][CH2:39][C:40]2[CH:44]=[C:43]([CH3:45])[O:42][N:41]=2)[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3C)c2)nc1
Reactant: Cc1cc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(OCc3cc(C)on3)cc(OCc3ccccc3C)c2)nc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 135.2 %

Procedure:
Methyl 6-{[3-hydroxy-5-(2-methylbenzyloxy)benzoyl]amino}-3-pyridinecarboxylate (150 mg, 0.38 mM), potassium iodide (13 mg, 0.08 mM) and potassium carbonate (56 mg, 0.41 mM) in acetone (3 ml) were heated to 55° C. and a solution of 3-chloromethyl-5-methyl isoxazole (55 mg, 0.421 mM) in acetone (2 ml) was added. The reaction was stirred for 1 hour at 55° C. and a further addition of 3-chloromethyl-5-methyl isoxazole (33 mg, 0.25 mM) in acetone (1 ml) was made. The reaction was stirred for 24 hours at 55° C. before being allowed to cool to ambient temperature. Ethyl acetate (15 ml) was added and the resulting mixture was washed with 1N aqueous HCl (10 ml), saturated aqueous sodium bicarbonate solution (10 ml) and water (10 ml). The solvent was removed under reduced pressure to give methyl 6{[3-(2-methylbenzyloxy)-5-(5-methylisoxazol-3-ylmethoxy)benzoyl]amino}-3-pyridinecarboxylate as a white solid (252 mg); H1 NMR δ (d6-DMSO) 2.24 (3H s) 2.26 (3H s) 3.85 (3H s) 5.08 (2H s) 5.15 (s 2H) 6.28–6.35 (1H m) 6.88 (1H s) 7.17–7.43 (7H, m), 8.29 (1H s), 8.9 (11H d). MS [MH]+488
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Yield: 79.1 %

Procedure:
To a suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxamide (example 38) (4.8 gm, 0.011 mol) in methanol (25 ml) was added activated raney nickel (1.44 gm, 30% w/w) and stirred at reflux for 10 min. Hydrazine hydrate (1.117 gm, 0.022 mol) was added dropwise to the above refluxing reaction mixture. The reaction was refluxed for further 30 min. and filtered through celite bed. The filterate was concentrated in vaccuo and the residue was purified using silica gel chromatography using 15% acetone in chlroform as the eluent to afford 3.5 gm of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide as white solid. mp: 249° C. (dec).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[C:31]([NH:32][C:33](=[O:35])[CH3:34])[C:26]([O:25][CH3:24])=[N:27][CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(C)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1NC(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 64.1.1) to give the title compound as a white solid. (HPLC: tR 2.51 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.52 (s, br, 1H), 8.96 (s, 1H), 8.50-8.41 (m, 1H), 8.15-8.09 (m, 2H), 8.06-8.02 (m, 1H), 7.88-7.83 (m, 1H), 7.55-7.49 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.57 (s, 3H), 2.14 (s, 3H), 1.93 (s, 3H))
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1CCC2O
Solvent: c1ccccc1
Product: O=C(O)c1cccc2c1CCC2Cl

Procedure:
To 30 ml. of benzene is added 5.35 g. of 1-hydroxyindan-4-carboxylic acid. Following the addition of 15 ml. of thionyl chloride, the mixture is stirred for 3 hours. Then, the reaction mixture is concentrated to dryness under reduced pressure and the resultant crystals are recrystallized from benzene. The described procedure gives 1-chloroindan-4-carboxylic acid melting at 135.5°-137.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccccc1CSc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CSc1cc(Cl)ccc1N
Yield: 106.9 %

Procedure:
Following General Procedure L, the title compound (158 mg, crude) was prepared from methyl 2-(((5-chloro-2-nitrophenyl)thio)methyl)benzoate (163 mg, 0.48 mmol), Zn (780 mg, 12.0 mmol) and saturated aqueous NH4Cl (10 ml) in MeOH (5 ml) and THF (5 ml). The crude product was used in the next reaction without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1.C(C1NC(C2C=C([NH:43][C:44](=[O:46])[CH3:45])C=CC=2)=NC=1C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[C:28]([NH:43][C:44](=[O:46])[CH3:45])[CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1
Reactant: CC(=O)Nc1cccc(-c2nc(C)c(C=O)[nH]2)c1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Product: CC(=O)Nc1cccc(-c2nc(CN3CCC(Nc4nc5ccccc5o4)CC3)c(C)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described for the synthesis of example 325 (benzooxazol-2-yl-[1-(5-methyl-2-phenyl-1H-imidazol-4-ylmethyl)-piperidin-4-yl]-amine) using N-[3-(5-formyl-4-methyl-1H-imidazol-2-yl)-phenyl]-acetamide instead of 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde. MS (ESI): 445.3 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)[CH2:35][CH3:36])[CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](O)=[O:23])([CH3:16])([CH3:15])[CH3:14].[C:51]([O:70][NH2:71])([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O.C1COCC1>[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][CH:42]=1)[CH2:35][CH3:36])[CH:21]([C:22](=[O:23])[NH:71][O:70][C:51]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
WSC.HCl (683 mg, 3.49 mmol) was dissolved in water (1 mL) and the pH was adjusted to 4.8. The compound of Example 55 (300 mg, 0.582 mmol) was dissolved in the same amount of THF and added to the former solution. O-Trityl hydroxylamine (505 mg, 1.746 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The water phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, a saturated sodium hydrogen carbonate solution, and brine. The solvent was evaporated, following drying over sodium sulfate, and the crude was flashed with 30% ethyl acetate in hexanes. 1H NMR(CDCl3, 400 MHz: 1.32(s, 9H); 1.50(m, 1H); 1.74(m, 1H); 2.32(m, 6H); 2.53(m, 2H); 3.46(m, 2H); 7.00(m, 1H); 7.16-7.57(m, 30H); FAB: 774(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1
Reactant: CN(C(=O)Oc1ccc([N+](=O)[O-])cn1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Yield: 102.6 %

Procedure:
A solution of methyl-phenyl-carbamic acid 5-nitro-pyridin-2-yl ester (10.41 g, 38.1 mmol) in tetrahydrofuran (100 mL) was hydrogenated in a Parr apparatus with wet 5% palladium on carbon and 20 psi hydrogen pressure. After 2 hours the solution was filtered over a short pad of Celite, washed thoroughly with ethyl acetate and evaporated in vacuo, yielding title compound (9.51 g, 103% yield) as a thick oil, which solidified upon standing.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])=[O:26]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)OCc1ccccc1Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCc4ccccc4Cl)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-chlorobenzyl chloroformate (135 μl, 0.89 mmol). The title compound was obtained as yellow powder (227 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[N:10]([CH2:14][CH:15]=O)[CH2:11][CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]([N:10]1[CH2:14][CH2:15][N:22]([C:19]2([CH3:18])[CH2:21][CH2:20]2)[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(N)CC1
Reactant: O=CCN(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 48.7 %

Procedure:
Bis-(2-oxoethyl)carbamicacidbenzylester (0.90 g, 3.81 mmol) and 1-methyl-cyclopropylamine (0.41 g, 3.81 mmol) were dissolved in dichloroethane (20 mL), and sodium triacetoxyborohydride (3.23 g, 15.24 mmol) was added thereto. The mixture was stirred for 4 days at room temperature. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 20 minutes, and then extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, n-hexane/ethyl acetate=5/1 to ethyl acetate), to obtain the title compound (509 mg, 49%) as an oily matter.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)Nc3cccnc3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)Nc3cccnc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(3-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (230 mg), 1 N aqueous sodium hydroxide solution (1.2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. After 1 N hydrochloric acid (1.2 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(3-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (190 mg, yield: 86%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 131–132° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:21]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2′-deoxyuridine dU (2.5 g, 10.95 mmol), TBSCl (7.26 g, 48.2 mmol) and imidiazole (6.56 g, 96.4 mmol) in anhydrous DMF (25 mL) was stirred at 0° C. for two hours and then warmed to room temperature over one hour. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxyuridine dC.11 (4.62 g, 92%) as a white foam.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[O:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0° C. under nitrogen was added DIAD (6.69 mL, 34.5 mmol) in anhydrous THF (40 mL) over 15 minutes. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. Solvent was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=2)[C:6]=1[CH:7]=[O:8]
Reactant: BrCc1ccc(Br)cc1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A solution of 8.0 g (32.0 mmol) of 4-chloro-5-formyl-2-phenylimidazole (prepared according to Chem. Pharm. Bull. 24 (1976) 960-969) and 5.3 g (32.0 mmol) of K2CO3 in 200 ml of abs. DMF was stirred at RT for 20 min. A solution of 9.6 g (32.0 mmol) of 4-bromobenzyl bromide in 200 ml of abs. DMF was then added dropwise and the reaction solution was stirred at RT for 6 h. It was concentrated in vacuo, and the residue obtained was taken up in EA, washed with water, 10% strength KHSO4, 10% strength NaHCO3, and satd sodium chloride solution, and dried over Na2SO4. Chromatographic purification on SiO2 using EA/heptane (1:4) as eluent of the residue which remained after stripping off the EA yielded 11.5 g of the title compound in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 37.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.196 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.10 g, 36%) as a solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9][N:8]1[C:32](=[O:33])[CH2:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[CH3:23])=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(OC)CCN1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1cc(C)ccc1C
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester hydrochloride salt (1.33 g, 4.84 mmol), triethylamine (1.68 ml, 1.22 g, 12.07 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (20 ml) at 0-5° C. was added a solution of (2,5-dimethyl-phenyl)-acetyl chloride (0.93 g, 5.09 mmol) in tetrahydrofuran (5 ml) dropwise. The suspension was stirred at 0-5° C. for one hour, and at room temperature for 4 hours. The solvent was evaporated, the residue diluted with ethyl acetate (50 ml) and water (20 ml), the layers separated and the aqueous phase extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1). Yield: 1.1 g of 2-[2-(2,5-dimethyl-phenyl)-acetyl]-5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester (compound P3.3) as a viscous oil. 1H-NMR (400 MHz, CD3OD): δ 1.14-1.39 (br m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.83-3.09 (br m, 4H), 3.13-3.32 (br m, 2H), 3.48 (s, 3H), 3.62 (br s, 2H), 3.78-4.32 (br m, overlapping signals, total 4H), 6.91 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H) ppm.