Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
A solution of 11F (163 mg, 0.198 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene) (0.108 mL, 0.218 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.276 mL, 1.978 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred for 16 h. Solvent was removed and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (102 mg, 60.7% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with an IA column to give 11G (43 mg, 0.051 mmol, 43.0% yield). MS (ESI) m/z: 850.1 [M+1]+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.ClC1C=C(C=CC=1Cl)CN.[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38](C)[C:39](C1CN(C)C(=O)C=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH2:39][N:38]([CH2:37][C:36]2[CH:50]=[CH:51][C:52]([Cl:53])=[C:34]([Cl:33])[CH:35]=2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: NCc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(Cc2ccc(Cl)c(Cl)c2)C1

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 3,4 dichloro-benzylamine as described in the preparation of Compound 12. The title compound was isolated as a white foam (155 mg, 66% yield). 1H NMR (500 MHz, CDCl3) δ: 10.70 (bs, 1H), 7.42 (d, 1H, J=3.05), 7.40 (d, 1H, J=3.05), 7.34 (d, 2H, J=1.83), 7.09 (dd, 2H, J=8.24, J=1.83), 4.62 (s, 2H), 4.57 (s, 2H), 4.06 (s, 2H), 3.00 (s, 3H). HRMS (M−H) calcd for C20H15N2Cl4O3: 470.9836. found: 470.9832.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:20][CH3:21])[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]=2[CH:7]=1.[I-:24].[Na+].CC(C)=O>O>[CH2:20]([N:10]1[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][I:24])[CH:23]=[CH:22][C:9]1=2)[CH3:21]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Temperature: 25 °C
Yield: 99.7 %

Procedure:
7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (2.18 g) and sodium iodide (4.8 g) were added to acetone (50 ml), and heated under reflux for 8.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to give the title compound (2.76 g) as a colorless oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15](C(=O)C(F)(F)F)=[CH:14][CH:13]=2)[N:7]=1)=[O:4].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][CH:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH3:2])[CH2:10]1
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(C(=O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5), 5.0 ml. of acetic anhydride and 100 mg. of 4-dimethylaminopyridine is allowed to stand at room temperature for 3 hours. The mixture is filtered to give a white solid. The solid is dissolved in dichloromethane and is columnized and recrystallized as for Example 14 (B) to give 0.90 g. of the desired product as colorless plates, m.p. 144.5°-146.5° C.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([NH:35][NH2:36])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C[O-].[Na+]>CO>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:36][N:35]=2)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(=O)N1CCN(CC(=O)NN)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Yield: 5.2 %

Procedure:
The procedure described for Example 283 B was followed using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (600 mg, 1.88 mmol), 2-(4-acetylpiperazinyl)-N-aminoacetamide (1.12 g, 5.64 mmol), sodium methoxide (1.3 mL, 5.64 mmol), and methanol (8 mL) to yield the title compound (41 mg, 5% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.6 (s, 1H), 8.0 (m, 5H), 7.6 (m, 2H), 7.4 (t, 3H), 4.6 (m, 2H), ES-MS (m/z) 420 [M+1]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:8](Cl)(=[O:11])[CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+]>CCOCC>[C:8]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCC(=O)NCC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
In a round bottomed flask, at 0° C., to a stirred suspension of methyl glycinate hydrochloride (0.68 g, 5.4 mmol) in Et2O (2.0 mL), propanoyl chloride (1.0 g, 10.8 mmol) and saturated K2CO3 solution (3.8 mL) were added. The reaction mixture was stirred at 0° C. for 3 h, then extracted with Et2O (3×10 mL) and the resulting organic layer washed with saturated NaHCO3 solution, H2O, and brine. The aqueous phase was saturated with NaCl and further extracted with AcOEt (50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.55 g, 71%) as colorless oil, which was used in the next reaction. MS (ESI) m/z: 168 [M−Na]+, 146 [M−H]+.
Reaction SMILES: [CH:1](N(CC)C(C)C)([CH3:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:19][CH:18]2[NH:20][C:21]2[C:22]3[N:36]=[N:35][N:34]([CH:37]4[CH2:41][CH:40]([CH2:42][OH:43])[CH:39]([OH:44])[CH:38]4[OH:45])[C:23]=3[N:24]=[C:25]([S:27][CH2:28][CH2:29][C:30](F)(F)F)[N:26]=2)=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:19][CH:18]2[NH:20][C:21]2[C:22]3[N:36]=[N:35][N:34]([CH:37]4[CH:38]5[O:45][C:1]([CH3:3])([CH3:2])[O:44][CH:39]5[CH:40]([CH2:42][OH:43])[CH2:41]4)[C:23]=3[N:24]=[C:25]([S:27][CH2:28][CH2:29][CH3:30])[N:26]=2)=[CH:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCC1CC(n2nnc3c(NC4CC4c4ccc(F)cc4)nc(SCCC(F)(F)F)nc32)C(O)C1O
Solvent: ClCCl
Product: CCCSc1nc(NC2CC2c2ccc(F)cc2)c2nnn(C3CC(CO)C4OC(C)(C)OC43)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (1.29 g) was added to a solution of [3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml). The reaction mixture was stirred at room temperature for 3 hours, then washed with water, dried and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane 1:1 as eluent) to afford the subtitle compound (1.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([F:28])[C:23]([C:25](O)=[O:26])=[CH:24][C:18]=4[N:17]=3)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].FC1C(C([NH:57][CH2:58][CH2:59][C:60]2[N:61]=[CH:62][NH:63][CH:64]=2)=O)=CC2N=C(C3C=C(C4C(OC)=NC=CC=4)C=CC=3O)NC=2C=1>>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([F:28])[C:23]([C:25]([NH:57][CH2:58][CH2:59][C:60]5[NH:61][CH:62]=[N:63][CH:64]=5)=[O:26])=[CH:24][C:18]=4[N:17]=3)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4c[nH]cn4)c(F)cc3[nH]2)c1
Product: CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4cnc[nH]4)c(F)cc3[nH]2)c1

Procedure:
was synthesized using aldehyde 9b in a similar manner as the methoxy derivative 10a in 16% overall yield. 1H NMR (MeOD) δ 8.45-8.16-8.06 (m, 2H), 7.96 (d, J=6.36 Hz, 1H), 7.91 (s, 1H), 7.76 (dd, J=7.32 Hz, 1.83 Hz 1H), 7.66-7.59 (m, 2H), 7.39 (d, J=11.31 Hz, 1H), 7.09-7.01 (m, 2H), 6.93 (br s, 1H), 4.45-4.36 (m, 2H), 3.68 (t, J=6.96 Hz, 2H), 2.93 (t, J=6.96 Hz, 2H) 2.93 (t, J=7.02 Hz, 3H). ES-MS MH+ 487.5.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CC(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([O:1][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reaction time: 48 h

Procedure:
29.1 g of 4-hydroxy-4'-methoxybenzophenone (R. Martin et al., Monatsh, Chemie 110, 1057-1066 (1979)) are dissolved in 400 ml of dry acetone. Then, while stirring, 19.3 g of finely powdered K2CO3 and 16 ml of methyl bromoacetate are added, and the mixture is stirred at room temperature. The reaction is complete after 2 days. The precipitated mixture of salt and substance is filtered off with suction, and the filtrate is concentrated. Both residues are suspended in water, and the pH is adjusted to 3 with 2N HCl. The solid is filtered off with suction, washed with water and dried under high vacuum in a desiccator.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Br:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][NH:38][C:37]5[CH:39]=[CH:40][CH:41]=[C:35]([Br:34])[CH:36]=5)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:22][CH:23]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1ccc(C=O)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(CNc2cccc(Br)c2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
5′-Formyl-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (40 mg) and 3-bromo-aniline (18 mg) were stirred together in dry dichloromethane (10 ml) containing 3 A molecular sieves. The mixture was then heated to 40 C for 4 h. Sodium (triacetoxy)borohydride (50 mg) and glacial acetic acid (1 ml) were then added and stirring continued at 20 C for 18 h. The sieves were then removed by filtration and the mother liquor evaporated. The residue was purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave the title compound as a pale yellow solid (32 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:7]2[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:19][CH2:18]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 80 °C
Yield: 105.1 %

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (which may be prepared according to Example 22, step A) (1 g, 5.8 mmol) in 15 mL of DMSO was added, 1-[2-(methyloxy)ethyl]piperazine (0.92 g, 6.4 mmol), and K2CO3 (2.4 g, 17.4 mmol). The mixture was heated to 80° C. overnight. The mixture was then poured into 100 mL of H2O and extracted with EtOAc, washed with a saturated NaCl solution, dried over Na2SO4, filtered and rotovapped to dryness to give 1.8 g of crude 1-[2-(methyloxy)ethyl]-4-[3-(methyloxy)-4-nitrophenyl]piperazine. MS (ESI): 296 [M+H]+. This material was dissolved in 15 mL EtOH and 1 mL DMF in a 100 mL round bottom flask. Platinum on Carbon (5% by weight) (0.2 g) was added and the flask was flushed with N2. After about 15 min, a balloon containing H2 was added and the N2 was removed. H2 was bubbled through the solution for a few minutes. The reaction mixture was let stir overnight under balloon pressure. In the morning the balloon was removed and the flask flushed with N2 to remove all H2. The solution was filtered through celite and evaporated to afford the title compound of step A (1.49 g, 5.62 mmol, 92%); MS (ESI): 266 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:11][C:12]=2[C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH3:19])[C:14]=2[CH:20]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:18][C:16]1[N:15]([CH3:19])[C:14]2[CH:20]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3[CH2:8][CH2:9][CH:10]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:11][C:12]=3[C:13]=2[N:17]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a suspension of 3.4 g (9.6 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid ethyl ester in 100 ml dioxane and 25 ml water were added 1.4 g (57.7 mmol) lithium hydroxide and the reaction refluxed for 6 h. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 2 M HCl solution. The precipitate was filtered off and crystallized with n-butanol to afford 3.0 g (96%) of the title compound as a beige solid of m.p. 323°-326° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH:15][CH3:16])=[O:14].CO.Cl.[O:26]([NH2:28])[CH3:27]>O>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:28][O:26][CH3:27])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CON
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1cc(C)ccc1C
Yield: 95.3 %

Procedure:
To 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-N-methyl-2-oxoacetamide (0.27 g, 0.9 mmol), added were methanol (2.0 ml) and methoxylamine hydrochloride (0.15 g, 1.8 mmol), and the reaction mixture was heated under reflux for 4 hours. After completion of the reaction, water (100 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl] -2-methoxyimino-N-methylacetamide (0.28 g; yield, 98.9%) as a mixture of E-form and Z-form.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:24]([NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1)([CH3:26])[CH3:25]
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)NC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A solution of compound 119 (0.75 g, 2.926 mmol) in 1,2-dichloroethane (20 mL) was treated with AcOH (0.16 mL, 2.926 mmol), isopropyl amine (0.25 mL, 2.926 mmol), NaBH(OAc)3 (0.93 g, 4.390 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 139 (0.636 g, 73%) as a semi-solid. 1H NMR (DMSO-d6) δ 0.99 (d, 6H, J=6.0 Hz), 1.36-1.47 (m, 1H), 1.89-1.97 (m, 2H), 2.45-2.56 (m, 2H), 2.81-2.89 (m, 1H), 2.91-2.99 (m, 1H), 3.16 (brs, 1H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.88 (dd, 1H, J=2.1, 9.0 Hz), 7.95 (d, 1H, J=9.0 Hz), 8.30 (d, 1H, J=2.1 Hz), 11.83 (brs, 1H); ESI-MS (m/z, %) 300 (MH+, 100), 241 (35).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH3:41][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O:31][CH3:41])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (4.23 g, 10 mmol) in a mixture of CH2Cl2 (50 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.00 ml, 10.00 mmol). The solution was stirred at rt for 2 h under nitrogen. LC/MS showed no SM left. The reaction mixture was concentrated to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (4.37 g, 100%). The compound was used in the next step without further purification. LCMS: m/e 559.4 (MH+), 3.29 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.22 (m, J=8.6 Hz, 2H), 5.22-5.39 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.49-4.67 (m, 1H), 3.94 (s, 3H), 3.87 (s, 1H), 3.38 (d, J=10.6 Hz, 1H), 2.37-2.60 (m, 1H), 2.05-2.21 (m, 1H), 1.96 (d, J=11.1 Hz, 2H), 1.90 (d, J=13.1 Hz, 1H), 1.61-1.82 (m, 7H), 1.55 (br. s., 8H), 1.37-1.52 (m, 2H), 1.18-1.37 (m, 4H), 1.08-1.18 (m, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+].O>C(#N)C.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.[Cu]I>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15]([OH:19])=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:4][CH:3]=1)#[N:21]
Reactant: Oc1cccc2occ(CCc3ccc(Br)cc3)c12
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(CCc2coc3cccc(O)c23)cc1
Yield: 33.7 %

Procedure:
A suspension of 3-[2-(4-bromophenyl)ethyl]-4-hydroxybenzofuran (0.5 g), sodium cyanide (0.23 g), tetrakis(triphenylphosphine)palladium (0) (91 mg) and copper (I) iodide (30 mg) in acetonitrile (5 mL) was heated for reflux for three days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.14 g). To a solution of hexamethyldisilazane (0.35 mL) in diethyl ether (2 mL) was added n-butyl lithium (2.46 mol/L n-hexane solution 0.7 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a solution of the 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.13 g) in diethyl ether (3 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was washed with diethyl ether twice. The aqueous layer was basified by addition of 2 mol/L aqueous sodium hydroxide solution, and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with a mixed solvent of dichlorometane and methanol (5/1) (three times), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[2-(4-carbamimidoylphenyl)ethyl]-4-hydroxybenzofuran (0.11 g). This material was dissolved in 1,4-dioxane (5 mL)-1 mol/L aqueous sodium hydroxide solution (5 mL). To the solution was added benzyl chloroformate (0.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (35 mg).