Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18]([OH:20])=O)[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]1([CH2:64][CH2:65][CH2:66][CH2:67][NH2:68])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][CH:17]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])[C:18]([NH:68][CH2:67][CH2:66][CH2:65][CH2:64][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Reactant: NCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CC(c2ccc(CC(NS(=O)(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2Cl)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.4 %

Procedure:
(2S)-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]propanoic acid (15.0 mg, 0.0317 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.8 mg, 0.0381 mmol) and stirred at rt for 5 minutes. A solution of 4-phenylbutan-1-amine (10 μL, 0.0634 mmol) and N,N-diisopropylethylamine (28 μL, 0.16 mmol) in DMF (1 mL) was added and the reaction stirred at rt for 1 h. Purification by preparative LCMS afforded product as a white solid (12.9 mg, 67%). 1H NMR (400 MHz, CD3OD): δ 7.68–7.64 (m, 2H), 7.54–7.34 (m, 4H), 7.27–7.11 (m, 7H), 5.59–5.57 (m, 1H), 3.92–3.87 (m, 1H), 3.42–3.35 (m, 1H), 3.35–3.28 (m, 1H), 2.99–2.84 (m, 3H), 2.79–2.74 (m, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.53–1.47 (m, 2H), 1.33–1.29 (m, 2H); LCMS found for C28H31ClN3O6S2 (M+H)+: m/z=604.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl-].[NH2:16][C:17]1[CH:39]=[CH:38][C:20]([NH:21][C:22]([C:24]2[CH:37]=[CH:36][C:27]([NH:28][C:29]3[CH:34]=[CH:33][N+:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:18]=1.Cl.CO.CCOC(C)=O>CO.CCOC(C)=O>[Cl-:1].[CH3:35][N+:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]([NH:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:38]=3)=[O:23])=[CH:37][CH:36]=2)=[CH:34][CH:33]=1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-6-nitroquinoline (70 mg, 0.33 mmol) in MeOH (10 mL) was added compound D5 (100 mg, 0.28 mmol), and the mixture was stirred at 20° C. for 1 h (until a clear solution obtained). A drop of c.HCl was then added, and refluxing was continued for a further 20 h. TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) showed some D5 remained, so more 4-chloro-6-nitroquinoline (35 mg, 0.16 mmol) was added and refluxing was continued for a further 4 h. The reaction mixture was then diluted with EtOAc and the resulted precipitate was filtered and washed sequentially with EtOAc, CH2Cl2 and diisopropylether, and finally crystallized from MeOH EtOAc to give Cpd. N1 (111 mg, 75%), mp (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ14.50 (br, 1 H, N+H); 11,42, (br s, 1 H, NH), 11.10 (s, 1 H, NH), 10.58 (s, 1 H, NH), 9.82 (d, J=2.1 Hz, 1 H, ArH), 8.72 (dd, J=9.3, 2.2 Hz, 1 H, ArH), 8.60 (d, J=7.0 Hz, 1 H, ArH), 8.42 (d, J=7.4 Hz, 2 H, ArH), 8.24 (d, J=8.6 Hz, 1 H, ArH), 8.15 (d, J=8.6 Hz, 2 H, ArH), 8.04 (d, J=8.8 Hz, 2 H, ArH), 7.51 (t, J=8.3 Hz, 4 H, ArH), 7.34 (d, J=7.5 Hz, 2 H, ArH), 6.91 (d, J=7.0 Hz, 1 H, ArH), 4.01 (s, 3 H, N+CH3); LCMS 489+ve.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[CH:34]([C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40])=O.CO.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:34][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41][CH3:42])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(CN2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (100 mg, 0.21 mmol, 1.00 equip), methyl 3-formylbenzoate (68 mg, 0.41 mmol, 2.00 equip), methanol (10 mL), NaBH3CN (66 mg, 1.03 mmol, 5.00 equip), and acetic acid (0.1 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate as a yellow solid. LCMS (ES, m/z) 626 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[CH3:9][NH:10][O:11][CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:12][O:11][N:10]([CH3:9])[C:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:8]
Reactant: O=C(O)c1cscn1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cscn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of thiazole-4-carboxylic acid (1 g, 7.74 mmol), N,O-dimethylhydroxylamine (1.51 g, 15.5 mmol), and HATU (3.83 g, 10.07 mmol) in CH2Cl2 (25 mL) was added TEA (4.84 mL, 34.85 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The organics were concentrated and purified by chromatography (60-70% EtOAc/hexanes) to yield N-methoxy-N-methylthiazole-4-carboxamide as a clear oil. 1H NMR (CDCl3) δ: 8.83 (s, 1H), 8.10 (s, 1H), 3.79 (s, 3H), 3.46 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:5][C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[CH2:11][OH:12].[CH2:29](I)[CH3:30]>[Ag-]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:5][C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C:10]=1[CH2:11][O:12][CH2:29][CH3:30]
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CCI
Agent: O=[Ag-]
Product: CCOCc1c(Oc2cc(Cl)cc(Cl)c2)c(CC)nn1CCNC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
Silver(I)oxide (210 mg, 0.900 mmol) was added in one portion to a stirred solution of the alcohol of Example 135 (129 mg, 0.300 mmol) in ethyl iodide (1.75 ml) at room temperature under nitrogen. The reaction was heated at 40° C. for 1 day and then cooled to room temperature. The mixture was filtered and the residual solid was washed with dichloromethane (10 ml). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to provide the title compound (60 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[N:28]([CH3:29])[N:27]=[CH:26][C:25]=1[C:30]#[N:31]>ClCCl.CN(C)C=O>[C:30]([C:25]1[CH:26]=[N:27][N:28]([CH3:29])[C:24]=1[NH:23][C:12]([C:11]1[C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1)=[O:14])#[N:31]
Reactant: Cn1ncc(C#N)c1N
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C#N)cnn3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (1.0 ml) and dimethylformamide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (0.1 g) was taken up in dichloromethane (10 ml) and sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.84 ml) was added. After 5 minutes the acid chloride was added and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent 50% ethyl acetatethexane-75% ethyl acetate/hexane) to yield the title compound as an off-white solid (0.088 g). TLC Rf 0.13 (50% ethyl acetate/hexane); Mpt 190-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:6][C:21](=[O:22])[C:13]3[N:9]2[C:10]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[N:11][C:12]=3[CH3:14])=[CH:7][CH:8]=1
Reactant: Cc1cn(-c2cc(Cl)ccc2N)c(C2CCCCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C2CCCCC2)n2c1c(=O)[nH]c1ccc(Cl)cc12

Procedure:
1.45 g 4-Chloro-2-(2-cyclohexyl-4-methyl-imidazol-1-yl)-aniline were stirred in 25 ml toluene. 1.0 g Carbonyldiimidazole was added and the mixture was refluxed for 6 hours. After cooling 25 ml water was added, the product was filtered off, washed with 20 ml water and 25 ml toluene and dried.
Reaction SMILES: [O:1]=[C:2]([N:5]1[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])[CH2:3][CH3:4].CCN(C(C)C)C(C)C.[CH:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:10]([C@@H:9]1[CH2:8][O:7][C:6](=[O:17])[N:5]1[C:2](=[O:1])[C@H:3]([CH3:4])[C@H:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[OH:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of (R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone (Aldrich, 2.0 g, 8.6 mmol) in DCM (60 mL) at −40° C., a solution of TiCl4 in DCM (1.0 M, 10.0 mL, 10.0 mmol) was added. The mixture was stirred at −40° C. for 10 min., then DIPEA (3.7 mL, 21 mmol) was added. The reaction mixture was allowed to warm to 0° C. and stirred for 20 min. A solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Aldrich, 2.0 g, 8.7 mmol) in DCM (20 mL) was then added dropwise and the resulting mixture was stirred for 1.5 h. The reaction was quenched by the addition of a saturated aq. NH4Cl and the mixture was extracted with EtOAc. The separated organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-40% EtOAc in hexanes) to give the sub-title compound as the major product (5:2) in 87% yield (3.44 g). LCMS calc. for C24H34N2NaO7 (M+Na)+: m/z=485.2. found 485.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(=O)Nc1cccc(-c2ccc([C@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)c1
Yield: 41.6 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (200 mg, 0.51 mmol, prepared in example 17) and 3-acetamidophenylboronic acid (109 mg, 0.61 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with 2% methanol/methylene chloride to afford 85 mg (42%) of the title compound as a white solid when concentrated from ether.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.5 g (1.87 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 25 mL of dichloromethane and 0.72 g (9.16 mmol) of pyridine was treated with 0.57 g (5.61 mmol) of acetic anhydride. The resulting mixture was stirred at room temperature overnight and then diluted with 10 mL of dichloromethane. The organic phase was extracted with 20 mL of 1M aqueous HCl, a saturated solution of NaHCO3 and brine, then dried by sodium sulphate. The solvent was then removed by evaporation under reduced pressure and the crude product was crystallised from a mixture of dichloromethane and ethyl acetate to give the desired product as white crystals of m.p. 175.8°-176.9° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][C@@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Reactant: C[C@@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (95 mg, 0.30 mmole), D-Alanine (529 mg, 5.94 mmole) and 0.5 M sodium methoxide/methanol (11.3 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted with dichloromethane (3×30 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (8 mL). The white suspension was extracted with ethyl acetate (30 mL) and dichloromethane (30 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (90 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.52 (bs, 1H), 9.15 (br s, 1H), 8.30 (d, 1H), 8.10 (m, 1H), 7.67 (t, J=8 Hz, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 4.83 (q, 1H), 1.68 (d, J=7.0 Hz, 3H)); MS: (+) m/z 378.29 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][O:20][CH2:21][CH3:22].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:30][CH2:31][CH2:32][C:33](ON2C(=O)CCC2=O)=[O:34])C=CC=CC=1.CO>ClCCl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][O:20][CH2:21][CH3:22])[N:5]([O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][SH:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1OCCN
Solvent: ClCCl
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1OCCNC(=O)CCS
Temperature: 0 °C
Reaction time: 120 h
Yield: 46.7 %

Procedure:
A solution of 1-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 0.10 mmol) and succinimido 3-(triphenylmethylthio)propanoate (54 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred for 24 hours at room temperature. Methanol (1 mL) was added and stirring was continued for another 5 days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (2 mL) and triethylsilane (0.16 mL) and cooled to 0° C. Trifluoroacetic acid (0.4 mL) was added. The solution was stirred for 30 min; then it was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to provide 18.2 mg of N-(2-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethyl)-3-mercaptopropanamide as a solid. HRMS (ESI) calcd for C18H24N5O3S+H 390.1600, found 390.1579.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O.O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (200 g, 2.66 mol) in purified water (400 mL) was added sodium bicarbonate (246 g, 2.93 mol). To this mixture was added benzyl chloroformate (500 g, 2.93 mol) in tetrahydrofuran (800 mL) at an internal temperature of 20° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was crystallized from petroleum ether to give the target product as a white solid (403 g, yield 72.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](=[N:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[NH2:6].Cl[CH2:18][CH:19]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]=[CH:19][N:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=CCCl
Reactant: N/C(=N/c1ccccc1)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Brc1cccc(-c2nccn2-c2ccccc2)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
(E)-3-bromo-N′-phenylbenzimidamide (6.95 g, 25.3 mmol), 2-chloroacetaldehyde (6.94 g, 44.2 mmol) and sodium bicarbonate (5.30 g, 63.1 mmol) were charged into the reaction flask with 200 mL of 2-propanol. This reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature, was diluted with 200 mL of water then was extracted with ethyl acetate. The extracts were washed with aqueous lithium chloride then were dried over magnesium sulfate. These dried extracts were then filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 30-35% ethyl acetate/hexanes yielding 2-(3-bromophenyl)-1-phenyl-1H-imidazole (2.8 g, 9.36 mmol, 37% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccccn1

Procedure:
A solution of pyridin-2-ol (1 g), tert-butyl bromoacetate (2.33 mL) and cesium carbonate (6.85 g) in DMF (20 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(c(N3CCCCC3)n1)C(=O)OCC2
Yield: 95 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) was suspended in 8 mL of anhydrous acetonitrile and then dropwisely added with 1.0 mL of triethylamine and piperidine (0.19 mL, 1.898 mmol) in this order and heated to reflux for about 3 hours under the nitrogen atmosphere. The mixture was concentrated under reduced pressure, added with 10 mL of a saturated solution of ammonium chloride and 10 mL of distilled water and then extracted twice with 30 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (10% EtOAc/MC) was performed on the resulting residue and 296 mg (95%)of 6-methyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: CC(=O)N1CCc2c(sc(CCCl)c2C)C1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(CCN3CCC(c4csc5cc(F)ccc45)CC3)c2C)C1

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine.