Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:33](=[O:35])[CH3:34])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)Cl
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.36 g) in dimethylformamide (15 ml), acetyl chloride (0.79 g) is added, and the resultant mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water and evaporated to give 2-carbobenzoxyaminomethyl-3-acetamido-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.1 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:17]([Cl:16])=[O:19])[CH2:2]1
Reactant: OC1CCNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cl)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled 0° C. To the resulting mixture was added triphosgene (0.127 g, 0.429 mmol) and the mixture was stirred for 2 h at an ambient temperature.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CN1CCc2ccccc21
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cn1ccc2ccccc21
Yield: 57 %

Procedure:
The N-methyl indoline product in Example 47 (70 mg, 0.22 mmol) was dissolved in toluene (9 mL) in a 50-mL flask under N2 fitted with a condenser. MnO2 (199 mg, 2.3 mmol) was added, and the mixture was heated to reflux for 1.5 h. The mixture was cooled to rit, Celite, and the pad was washed several times with liberal amounts of MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (gradient 25-35% EtOAc/hexane) to provide the N-methyl indole product (39 mg, 57%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 6.93-7.11 (m, 5H), 6.72 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.84-3.96 (m, 2H), 3.77 (s, 3H), 2.99 (dd, J=11.3, 5.0 Hz, 1H), 2.67 (dd, J=11.3, 6.7 Hz, 1H), 2.49 (s, 3H); ESI MS m/z=313[C19H18F2N2+H]+.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH3:18])(=[O:9])=[O:8].[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][N:25]=[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:20])(=[O:9])=[O:8])[CH3:18]
Reactant: COC(CN)OC
Reactant: CC(=O)c1ccccc1NS(=O)(=O)c1ccccc1C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CN=C(C)c1ccccc1NS(=O)(=O)c1ccccc1C)OC

Procedure:
33.8 g of o-tolylsulfonylaminoacetophenone, 13.7 g of aminoacetaldehyde dimethylacetal and 0.4 g of toluenesulfonic acid in 400 ml of toluene are boiled for 4 hours in a water separator and concentrated to dryness in vacuo.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5].[CH2:34]([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH2:36].C(#N)C>C1(C)C=CC=CC=1>[CH:34]([C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5])=[CH:35][CH3:36]
Reactant: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)cc2)c2ccc3ccccc3c2N1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
5-[4-(2-Iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (70 mg, 0.128 mmol), allyltributyltin (98 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium(0) (15 mg, 12.8 μmol) were dissolved in anhydrous toluene (0.6 mL), and the solution was stirred at 110° C. for 16 hours. The reaction mixture was left to cool, and then added with acetonitrile, the mixture was washed with petroleum ether, and the solvent of the acetonitrile layer was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (40 mg, yield 68%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH:15]2[CH2:16][O:17]2)=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)ccc1O
Reactant: ClCC1CO1
Product: Cc1cc(C(C)(C)C)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-tert-butyl-2-methyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH:32]([CH3:34])[CH3:33])[N:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:49]=[N+:50]=[N-:51])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH:32]([CH3:34])[CH3:33])[N:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:51][N:50]=[N:49][N:26]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Solvent: Cc1ccccc1C
Product: CCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
10.0 g of N-carboethoxy-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 9.2 g of tributyltin azide in 150 ml of xylene are heated to reflux for 18 hours. The reaction mixture is concentrated and the residue is stirred in 5M etherial hydrochloric acid for 15 minutes. The mixture is concentrated again, and the residue is dissolved in ether and extracted with cold 4M potassium hydroxide solution. The aqueous phase is rendered acidic and extracted with ethyl acetate. This ethyl acetate phase is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by means of flash chromatography (250 g of silica gel, eluent N6). Amorphous product, TLC (system N6) Rf : 0.22.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)=[O:4].[C:16]([C@H:20]1[CH2:25][CH2:24][C@H:23](O)[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:16]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13]3)[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)C1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2C1
Reaction time: 0.33 h

Procedure:
To a mixture of 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (0.280 g, 1.36 mmol), trans-4-tert-butylcyclohexanol (0.2338 g, 1.496 mmol) and triphenylphosphine (0.7122 g, 2.715 mmol) in toluene (5 mL, 50 mmol) was stirred for 20 min, then, diisopropyl azodicarboxylate (0.34 mL, 1.6 mmol) was added dropwise at 0° C. The solution was stirred at reflux overnight. The reaction was added silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give the product as a white precipitate (73 mg, 16%). LCMS Rt=1.50 min, m/z=450.10 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>CCOCC>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][S:11]([C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: NCc1ccccc1Cl
Solvent: CCOCC
Product: COc1ccc(OC)c(S(=O)(=O)NCc2ccccc2Cl)c1

Procedure:
2,5-dimethoxyphenyl-sulfonyl chloride is reacted with 2-chlorobenzylamine in ether at about 25° C. to provide N-(2-chlorobenzyl)-2,5-dimethoxy-phenylsulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)/[CH:5]=[CH:6]/[C:7]1[NH:15][C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH3:21])[C:9]=2[N:8]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:25])[C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH3:21])[C:9]=2[N:8]=1
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(Br)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
Compound g (2.5 g, 6.43 mmol) obtained in Reference Example 7 was dissolved in 20 ml of dimethylformamide. To the solution were added 2.22 g (16.1 mmol) of potassium carbonate and subsequently 0.8 ml (12.9 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 70 minutes. After cooling, insoluble matters were filtered off and water was added to the filtrate. The mixture was extracted three times with chloroform. The extract was washed three times with water and subsequently twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave 2.37 g (yield 92%) of crude Compound h as a yellow solid, which was further recrystallized from cyctohexane/toluene to give Compound h as a yellow powder.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[NH:9][C:10](=[O:12])[CH3:11])([O-:5])=[O:4].I[CH3:17].Cl>CN(C)C=O>[CH3:17][N:9]([C:10](=[O:12])[CH3:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1
Reactant: CI
Reactant: CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 5.19 g) in N,N-dimethylformamide (30 ml) was added a solution of 3′-nitroacetanilide (214 mg) in N,N-dimethylformamide (30 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, then iodomethane (3.59 ml) was added. After 30 minutes, 1N hydrochloric acid was poured into the mixture and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-methyl-3′-nitroacetanilide (4.64 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([OH:34])[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[CH:17]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Yield: 98.6 %

Procedure:
Using 1.34 g (2.79 mmol) of {4-[3-hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzyl}carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.84 g, 6.97 mmol) and following the procedure of Example 42(b) afforded 1.6 g of the required product. 1H NMR (DMSO-d6): δ 1.30 (8H, m), 1.40 (9H, s), 1.8 (8H, m), 4.1 (2H, d), 6.68 (1H, s), 6.82 (2H, s), 7.08 (2H, d), 7.22 (2H, d), 7.28 (2H, d), 7.4 (1H, t), 7.88 (2H, d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[CH2:11].[Li]CCCC.CN(C)[CH:19]=[O:20]>C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]=[O:20])[CH2:9][CH:10]=[CH2:11]
Reactant: CN(C)C=O
Reactant: C=CCCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of 1-bromo-2-(but-3-en-1-yl)benzene (1 g, 4.74 mmol) in THF (15 mL) at −78° C. was added BuLi (2.274 mL, 5.68 mmol) dropwise. It was stirred at this temperature for 1 h, then N,N-dimethylformamide (0.416 g, 5.68 mmol) was added and stirred at −78° C. for 30 min. then warmed up to rt and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was then dried over MgSO4, filtered and concentrated to obtain 2-(but-3-en-1-yl)benzaldehyde (0.7 g, 92%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.35-10.26 (m, 1H), 7.86 (dd, J=7.6, 1.5 Hz, 1H), 7.54 (td, J=7.5, 1.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.95-5.83 (m, 1H), 5.09-5.00 (m, 2H),), 3.20-3.12 (m, 2H), 2.44-2.36 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:23][NH2:24])(=O)[CH2:19][CH2:20][CH3:21]>C(O)CCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:24][N:23]=1)[CH2:20][CH3:21]
Reactant: CCCC(=O)NN
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CCCc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
A mixture of 5.0 g of 3-chloro-6-(α,α, α-trifluoro-p-tolyl)pyridazine, 3.94 g. of butyric acid hydrazide and 100 ml. of n-butanol is refluxed for 48 hr. The solvent is removed under vacuum and the residue dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate and the eluent concentrated to give 3.2 g. of product Recrystallization from CHCl3 -hexane gives crystals, m.p. 173°-175° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.O>[Cl-].[NH+]1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
trans-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (2 g) was dissolved in melted pyridinium chloride, prepared from a mixture of pyridine (10 ml) and conc. hydrochloric acid where the water has been removed by distillation at 140° C. The mixture was heated for 75 min. Cooled down to room temperature. Water was added (15 ml) and pH adjusted to 12 with sodium hydroxide (32.5%). The mixture was extracted with toluene (15 ml). The organic phase was separated, dried over potassium carbonate and evaporated.
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:19](=[O:21])=[O:20]>CCOCC>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:19]([OH:21])=[O:20])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: O=C=O
Reactant: Cc1sc2cc(CO)ccc2c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1sc2cc(CO)ccc2c1C(=O)O
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromo-6-hydroxymethyl-2-methylbenzo[b]thiophene (2.11 g.) in dry ether (150 ml.) was added dropwise over 20 minutes to a stirred solution of n-butyl lithium (25 ml. of 1.5M solution in hexane) in dry ether (150 ml.) at -70° C. under an atmosphere of dry nitrogen. The mixture was stirred at -70° C. for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water and the aqueous layer was separated and acidified with concentrated hydrochloric acid. The solid was filtered off, washed well with water and dried to give 6-hydroxymethyl-2-methylbenzo[b]thiophene-3-carboxylic acid (1.26 g.), m.p. 195°-196° C., raised to 196°-197° C. on crystallization from ethanol/water.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:12]1[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Yield: 90.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (1.07 g, 3.45 mmol) prepared in Example 161a, triethylamine (2.88 mL, 20.7 mmol), benzoyl chloride (2.00 mL, 17.2 mmol) and dichloromethane (10 mL), to yield the title compound (1.30 g, 91%) as a colorless oil.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([NH2:26])[N:18]=2)=[CH:9][C:8]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].[Br:35][CH2:36][C:37](Cl)=[O:38]>CCOC(C)=O>[NH2:26][C:19]1[N:18]=[C:17]([NH:16][CH2:15][CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:37](=[O:38])[CH2:36][Br:35])=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[CH:9]=2)[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1ccc(NCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1nc(NCCNc2ccc(NC(=O)CBr)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Aqueous NaHCO3 (8 eq) was added to the stirred solution of [4-amino-3-(2,4-dichlorophenyl)phenyl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine (1 eq) in EtOAc at room temperature. 2-bromoacetyl chloride (1.5 eq) in minimal EtOAc was added slowly to the vigorously stirred reaction solution. The reaction was monitored by LC/MS and determined to be complete within 30 min. The organic layer was separated and washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-bromoacetamide as a dark yellow glass in 76% yield (˜90% pure, LC/MS m/z 555.2 MH+). The product was stored at −4° C. to avoid decomposition.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[C:26]1([CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([OH:35])=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:42][O:43][C:44]([C@H:46]1[NH:51][CH2:50][C:49]2[N:52]=[CH:53][N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[C:58]([CH3:65])[CH:57]=3)[C:48]=2[CH2:47]1)=[O:45]>C(#N)C>[CH3:42][O:43][C:44]([C@H:46]1[N:51]([C:33](=[O:35])[CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:50][C:49]2[N:52]=[CH:53][N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[C:58]([CH3:65])[CH:57]=3)[C:48]=2[CH2:47]1)=[O:45]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)[C@@H]1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.5 %

Procedure:
Acetonitrile (16 ml) was added to a mixture of N,N'-dicyclohexylcarbodiimide (DCCI) (2.1080 g, 0.01022 mol), 1-hydroxybenzotriazole (HBTA) (1.3806 g, 0.01022 mol), and diphenylacetic acid (2.1685 g, 0.01022 mol), followed by stirring at room temperature for 20 minutes. A solution of (S)-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (VI-2) (2.7000 g, 0.00817 mol) in acetonitrile (14 ml) was added to the suspension, and the mixture was stirred at room temperature for 21 hours. An insoluble portion in the reaction mixture was filtered out and washed with acetonitrile, and then the filtrate and washings were joined and concentrated. The residue was dissolved in methylene chloride (40 ml), washed with a 10% sodium carbonate solution and a saturated brine, then dried over sodium sulfate and concentrated to obtain an orange oily material (4.5203 g). This crude oily material was purified by silica gel column chromatography (Kieselgel 60, 270 g, chloroform/methanol=60/11) to obtain the objective compound (V-2) (2.8250 g; yield: 65.9%) as colorless crystals (top: 174.5°-177° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC([O-])(C)C.[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21](F)[CH:20]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:21]2[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[C:19]([F:18])[CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2cc(F)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 19.5 mmol) in DMSO (30 ml) was added t-BuOK (2.56 g, 21.5 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes under N2 flow. 1,3-Difluoro-5-nitrobenzene (2.34 ml, 20.5 mmol) was added dropwise at room temperature. The mixture was heated at 90° C. for 2 hours under N2 flow. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as a dark brown oil, which was crystallized with i-Pr2O. The crystals were collected by filtration to give the desired product as pale yellow crystal (1.92 g, 40%). The filtrate gave additional product (1.46 g, 30%) as pale yellow crystal by silica gel column chromatography eluting with 4:1 EtOAc/hexane.