Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:17])C>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1cccc(Oc2ccccc2)c1
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
Experiments were carried out under such conditions that the mixing ratio of m-phenoxytoluene to acetic acid was varied. Using as catalysts 3 mol% of cobalt acetate tetrahydrate and 3 mol% of sodium bromide to m-phenoxytoluene and limiting the total volume of the reaction liquid to 150 ml, the experiments were carried out in the same manner as described in Example 17. The results obtained are shown in Table 21. No substantial intermediate oxidation product was obtained when the amount of acetic acide was zero. When the amount of acetic acid was 0.5 mol per mol of m-phenoxytoluene, m-phenoxybenzaldehyde was obtained at a rate of selection of 20 mol% at a conversion rate of 30%. However, this experiment showed bad reproducibility.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]=[N+:9]=[N-:10])[CH2:5]1)(O)=[O:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:8]([C@@H:6]1[CH2:7][C@H:4]([C:1]([Cl:14])=[O:2])[CH2:5]1)=[N+:9]=[N-:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
A solution of cis-3-carboxycyclobutyl azide (1.86 g, 13.2 mmol) in dichloromethane (30 ml) was treated with oxalyl chloride (1.5 ml, 17.2 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (0.5-1 h) and the solvent was evaporated in vacuo leaving a yellow oil; 2.0 g, 95% ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C=O of acylchloride).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([OH:20])=[O:19])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:23])=[N-]>CCOC(C)=O.CCOCC>[C:1]1([C:7]2[S:8][C:9]([C:18]([O:20][CH3:23])=[O:19])=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1sc(-c2ccccc2)nc1-c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a pre-cooled (0° C.) solution of 2,4-Diphenyl-1,3-thiazole-5-carboxylic acid 72 (400 mg, 1.422 mmol) in EtOAc (7.109 ml) was added a 0.5 M solution of diazomethane (5.69 ml, 2.84 mmol) in Et2O (freshly prepared) (c.a. 5 mL) and the resulting white suspension was stirred at 0° C. for 1 h. TLC showed completion. Then, the small amount of white solid left was filtered off and the filtrate was concentrated in vacuo to afford methyl 2,4-diphenylthiazole-5-carboxylate 73 (0.449 g, 107% yield).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
In a volumetric flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0° C. 4-Fluorobenzoyl chloride (34.59 g, 218.2 mmol) was added followed by the slow addition of triethylamine (48.13 g, 475.6 mmol). The reaction was stirred for 30 min at 5° C. and allowed to reach room temperature. It was washed with 5% aqueous citric acid (180 mL) and with 5% aqueous NaHCO3 (180 mL). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 20.23 g of the desired compound (yield: 88%).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])=[CH:30][C:29]=1[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Reactant: [N-]=[N+]=Nc1ccccc1-c1nc2ccccc2s1
Product: Nc1ccc(OS(=O)(=O)C(F)(F)F)cc1-c1nc2ccccc2s1

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(2-azidophenyl)benzothiazole (Found: M+ 374. C14H9F3N2O3S2 requires MW 374).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7](N2CCCCC2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31]Cl>>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:8]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: CCCCn1cc(N2CCCCC2)c2ccncc21
Product: CCCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccncc21
Yield: 96.2 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 1.35 g (5.25 mmol) of 1-butyl-3-piperidin yl-1H-pyrrolo[2,3-c]pyridine and 1.35 g (6.3 mmol) of 2-(2-chloroethoxy)benzoic acid methyl ester. After standard work-up and purification, 1.1 g (49% yield) of 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester were obtained.
Reaction SMILES: [C:1]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)([C:3](OC)=[O:4])=[O:2].[BH4-].[Li+].O>O1CCCC1>[OH:4][CH2:3][C:1]([CH:7]1[CH2:8][CH2:9][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:11][CH2:12]1)=[O:2]
Reactant: COC(=O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CO)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a suspension of the compound (100 mg) obtained in Example 157 in anhydrous tetrahydrofuran (THF; 20 ml) was added lithium borohydride (5.5 mg) under cooling with ice. The mixture was stirred for 5 minutes. After adding another lithium borohydride (5.5 mg), the mixture was stirred for further 5 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride=1:1) to yield 45 mg (48%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:42]([NH:45][C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:45]([C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH:42]([CH3:44])[CH3:43])=[O:8])=[CH:9][CH:10]=1
Reactant: CCC[C@@H](CN1CC(O)C1)NC(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(O)C1)N(C(=O)c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a mixture of 4-chlorobenzoic acid (0.067 g, 0.43 mmol) and TBTU (0.137 g, 0.43 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 1.28 mmol). The suspension was stirred at rt for 30 min. A solution of (S)-1-(2-(isopropylamino)pentyl)azetidin-3-ol (Compound O2.1) (0.142 g, 0.43 mmol) in DCM (1 mL) was added and the reaction mixture was stirred at rt overnight. The reaction was washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge. The residue was dissolved in MeOH (2 ml) and 1M NaOH (aq., 0.5 ml) was added. The mixture was stirred at rt for 1.5 h. Acetic acid (110 mg) was added and the mixture was concentrated. The residue was dissolved in DCM (3.5 ml) and washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge and the residue purified by preparative HPLC affording the title compound (20 mg, 14%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.62-0.78, 0.76-0.93, 0.93-1.14, 1.14-1.54, 1.67-1.93, 2.24-2.40, 2.41-2.77, 2.76-2.97, 2.96-3.15, 3.16-3.45, 3.45-3.75, 3.96-4.20, 5.12-5.31, 7.17-7.35, 7.38-7.52. Number of protons: 27. HRMS (M+H)+: calculated 339.1839. found 339.1866
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(C#Cc2cccc(C=O)c2)cc1

Procedure:
4-Methoxyphenylacetylene was reacted with 3-bromobenzaldehyde in the manner described in Example 1a to yield the title compound in form of white crystals melting at 52°-53° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1([S:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>[OH-].[Na+]>[C:11]1([S:17][CH2:18][C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CSc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CSc1ccccc1)Nc1ccccc1C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 6.3 g of anthranilic acid in aqueous NaOH (4 g of NaOH in 40 mL of water) which was cooled using an ice-bath was added 8.6 g (0.046 mol) of phenylmercaptoacetylchloride from Example 46. The reaction mixture was stirred for 1 h. The reaction mixture was neutralized with 5% HCl, water (50 mL) was added, and then the mixture was extracted with EtOAc (3×100 mL). The EtOAc solution was dried, filtered, and then concentrated to give after drying under high vacuum, 7.0 g (53%) of the title compound, mp 166°-167° C. (lit. 164°-166° C. (Gorlitzer, K.; Weber, J. Arch. Pharm (Weinheim) 1980, 314, 76)); 1H NMR (DMSO-d6) δ11.82 (s, 1H, COOH), 8.51 (s, 1H, J=8.4),7.96 (dd, 1H, J=1.2, J=8), 7.58 (t, 1H, J=8), 7.38 (d,1H, J=7.2), 7.13 (m, 5H), 4.01 (s, 2H); 13C NMR (DMSO-d6) δ169.17, 167.42, 140.31, 135.00, 134.07, 133.72, 131.12, 129.18, 128.07, 126.33, 123.01, 119.77, 116.58, 116.31, 114.54; MS (EI, m/z) 287 (M+). HRMS (EI) calcd for C15H13N2 O3S 287.0616, found 287.0617.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:19])[C:13]=2[CH2:15][N:16]([CH3:18])[CH3:17])[N:8]([CH3:20])[C:7]=1[CH2:21][CH2:22][CH3:23])=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)C=NC[CH2:29]2>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2=[C:13]3[C:12](=[CH:11][CH:10]=[C:9]2[N:8]([CH3:20])[C:7]=1[CH2:21][CH2:22][CH3:23])[O:19][CH:17]1[N:16]([CH2:18][CH2:29][C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:35]=[CH:34][C:33]=21)[CH2:15]3)=[O:5])[CH3:2]
Reactant: COc1ccc2c(c1)CCN=C2
Reactant: CCCc1c(C(=O)OCC)c2c(CN(C)C)c(O)ccc2n1C
Product: CCCc1c(C(=O)OCC)c2c3c(ccc2n1C)OC1c2ccc(OC)cc2CCN1C3
Yield: 7.7 %

Procedure:
By following the general procedure of Example 2 for the preparation of 9-methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylic acid ethyl ester, 4-(dimethylamino-methyl)-5-hydroxy-1-methyl-2-propyl-1H-indole-3-carboxylic acid ethyl ester (2.1 g, 6.6 mmol) was reacted with 6-methoxy-3,4-dihydro-isoquinoline (1.005 g, 6.6 mmol) to give the desired product (0.22 g, 8%). MP 150-151° C. MS: 435.2 (M+1+).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:31][CH:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrCC1CCOCC1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Product: O=c1c2ccc(OCC3CCOCC3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 4-Bromomethyl-tetrahydro-pyran by method K. The product with the molecular weight of 491.61 (C29H34FN3O3) was obtained in this way; MS (ESI): 492 (M+H+).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[C:6]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:9]([O:8][C:6](=[O:7])[NH:13][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22](=[O:23])[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSC1

Procedure:
Thiazolidine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid then base) and the product used without further purification. Yield 5.5 g, 86%.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3ccc(C(F)(F)F)cn3)C2)C(=O)O1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-fluoro-5-trifluoromethylpyridine at 150° C. for 20 min. LC-MS Method 1 tR=1.51 min, m/z=464(M+1); 1H NMR (CD3OD) 8.26(s, 1H), 8.00(d, 1H), 7.38(m, 4H), 7.29(m, 1H), 7.01(m, 1H), 4.74(m, 1H), 3.77(m, 2H), 3.58(q, 1H), 3.47(m, 1H), 2.83(m, 1H), 2.55(m, 2H), 2.18(s, 2H), 1.24(s, 3H), 0.94(s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH2:41])[CH:39]=[CH2:40]>CO>[C@@H:6]1([NH:24][C:25]([NH:41][CH2:38][CH:39]=[CH2:40])=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C=CCN
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: C=CCNC(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine(2.204 g., 0.004 mole) was added to a solution of allylamine(2.74 g., 0.048 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 24 hours in the pressure bottle with the stopper well closed. The reaction mixture was filtered and the filtrate was evaporated to a syrupy material. The residual syrup was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky solid. The supernatant was decanted and the residue was dissolved in the minimum amount of acetone. Benzene was added to the solution to give a precipitate. The white precipitate was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel(1×20 cm) using ethyl acetate as the first solvent(60 ml.), acetone-ethyl acetate(3:7) as the second solvent(50 ml.), and acetone as the third solvent(80 ml.). The third acetone effluent was reduced to ca.25 ml. and was set aside at 5° overnight. No precipitate was formed. The solution was evaporated to dryness below 30° in vacuo. The formed solid was recrystallized from acetone to give a white precipitate. The precipitate was filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.591 g. (43.9%); m.p. 95°-97°(dec.).
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:1]([CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCOc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenoxyethylbromide (2.01 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were reacted together according tothe procedure of Example 51. The title compound as its hydrochloride (2.06 g.) had m.p. 207° C. (Found: C, 67.0; H, 7.1; N, 7.7. C20H24N2O2.HCl requires C, 67.3; H, 7.1; N, 7.85%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:15](OC)(OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[Cl:12][C:8]1[CH:9]=[C:10]2[O:11][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:1][C:2]2=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: Nc1c(O)cc(Cl)cc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A 25-mL, round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-5-chloro-3-hydroxybenzoic acid (0.931 g, 4.96 mmol), trimethyl orthobenzoate (7.23 g, 39.7 mmol), and pyridinium p-toluenesulfonate (0.062 g, 0.248 mmol). After stirring at 90° C. for 1 h, the reaction was diluted with hexanes (30 mL) filtered, and the filter cake dried in a vacuum oven at 40° C. to afford 0.455 g (33% yield) of 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 8.24 (m, 3H), 7.84 (s, 1H), 7.65 (m, 3H); MS (ESI) m/z 272 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=S)[NH:10][C:4]=2[CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>C(OCCO)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NCc1cccnc1
Reactant: O=S1(=O)c2ccc(Cl)cc2NC(=S)c2ccccc21
Solvent: CCOCCO
Product: O=S1(=O)c2ccc(Cl)cc2N=C(NCc2cccnc2)c2ccccc21

Procedure:
A solution of 0.46 g (1.5 mmol) of 8-chloro-5,5-dioxo-dibenzo[b,f]-1,4-thiazepin-11(10H)-thione in 15 mL of 2-ethoxyethanol was treated with 0.3 mL (3.0 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. An additional 0.4 mL of 3-(aminomethyl)pyridine was added and the refluxing continued another night. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (97/3) followed by precipitating the product from acetone with H2O gave an amorphous tan solid. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =384.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C:19]1([CH3:25])[O:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:21]2[CH2:22][CH2:23][O:24][C:19]([CH3:25])([CH3:18])[CH2:20]2)[C:14]2[N:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: CC1(C)CNCCO1
Reactant: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2nc(Cl)nc3c2nc2n3CCOC2(C)C)CCO1
Temperature: 140 °C
Yield: 85.4 %

Procedure:
A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), 2,2-dimethyl-morpholine (84 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane) affording 3-Chloro-1-(2,2-dimethyl-morpholin-4-yl)-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a white solid (110 mg, 85%). LCMS (method A): RT=3.51 min, [M+H]+=352.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36][OH:37])[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:34]2[N:35]=[C:24]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]4)=[O:16])[CH2:12]3)[O:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(Cl)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 57 mg (0.33 mmol, 1.5 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 86 mg (78% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[CH:3]=1.[N:22]([O-])=[O:23].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[C:3]=1[N:22]=[O:23]
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2F)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a stirred solution of the product from example 4, step (c) (10 g) in acetic acid (300 ml) at room temperature was added a solution of sodium nitrite (2.24 g) in water (30 ml). The reaction was stirred at 0° C. for 30 min, and the resultant purple precipitate isolated by filtration, washing with water, to give the subtitled compound as a dark blue solid (4.8 g).