Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].N1C2C(=CC=CC=2)[C:23]2([CH2:33][O:32][C:31]3[CH:34]=C4C(=C[C:30]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:34][C@H:31]1[CH2:30][CH2:23][CH2:33][O:32]1)[C:10]3=[O:18]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.61 (d, J=8.1 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=8.1, 2.1 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.00-3.66 (m, 4H), 3.77 (s, 3H), 2.10-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.9, 162.0, 161.4, 142.9, 142.8, 132.4, 132.3, 128.7, 128.6, 123.6, 123.5 (2C), 123.4, 123.2, 121.0, 120.9, 109.6, 109.3, 107.4 (2C), 96.5, 80.5, 80.4, 76.8, 76.7, 68.2, 68.1, 57.5, 55.5, 44.5 (2C), 29.2, 28.9, 25.6, 25.5; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].Cl>CO>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNCCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl ethyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (410 mg, 0.918 mmol) in methanol (6 mL) was added a 3N HCl solution (3.06 mL, 9.18 mmol). The resulting mixture was stirred at 90° C. for 30 minutes. The mixture was then passed through a 0.45 μM syringe filter, and the filtrate was concentrated in vacuo to dry foam. The residue was then partitioned between 1:1 water:saturated sodium carbonate and dichloromethane. The organic layer was separated, and the aqueous phase was extracted again with dichloromethane. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane giving the desired product 24 (135 mg, 42.4%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.6 Hz, 1H), 7.58 (d, 5.1 Hz, 1H), 7.08 (t, J=4.4 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.33 (brs, 2H), 6.21 (s, 1H), 6.07 (dd, J=8.1, 1.5 Hz, 1H), 3.63-3.57 (m, 2H), 3.33-3.28 (m, 2H), 3.01-2.96 (m, 2H), 2.71-2.65 (m, 2H), 2.53 (q, J=7.0 Hz, 2H), 1.66 (brs, 1H), 1.17 (t, J=7.0 Hz, 3H); ESI-MS (m/z, %): 347 (MH+, 83), 276 (100); HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1346; HPLC purity: 97% by area.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[C@@H:15]([OH:23])[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10].FC1C=CC(O)=CC=1>>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=2)[C@H:15]([O:23][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]
Reactant: CC(=O)N1c2ccc(F)cc2[C@@H](O)C[C@@H]1C
Reactant: Nc1ccc(F)cc1
Agent: Oc1ccc(F)cc1
Product: CC(=O)N1c2ccc(F)cc2[C@H](Oc2ccc(F)cc2)C[C@@H]1C
Yield: 61 %

Procedure:
Trans-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was obtained in the same manner as in Example 17, using 4-fluoroaniline. A compound was produced in the same manner as in Example 17, using 60 mg of trans-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 4-fluorophenol, and thus 58 mg (61%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC>O1CCCC1.CO.C(OCC)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCCC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
4-(Piperidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (121 mg) was dissolved in tetrahydrofuran (3 ml)-methanol (3 ml), and then 10% palladium carbon (61 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then suspended in diethyl ether (2 ml)-hexane (2 ml). The solid was filtered off and dried under aeration to provide the titled compound (84.8 mg, 75.2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:15][C:16]1[N:17]=[C:18]([NH:21][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]4[C:13](=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[S:19][CH:20]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Oc2ccccc2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)ccn2)n1
Yield: 79.8 %

Procedure:
Using the method of Example 3, Step B, 2-chloro-4-phenoxypyridine (0.575 g, 2.79 mmol), 4-methylthiazol-2-amine (6.35 mL, 2.54 mmol), potassium phosphate (0.593 g, 2.79 mmol), Pd2(dba)3 (0.0582 g, 0.0635 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0404 g, 0.0699 mmol) were reacted in toluene (6 mL) and water (2 mL) to provide N-(4-methylthiazol-2-yl)-4-(naphthalen-1-yloxy)pyridin-2-amine (0.371 g, 77.8% yield) as off white solid. 1H NMR (CDCl3) δ 8.13 (d, 1H), 7.90 (m, 2H), 7.76 (d, 1H), 7.53 (m, 1H), 7.46 (m, 2H), 7.18 (d, 1H), 6.49 (dd, 1H), 6.25 (m, 2H), 2.09 (s, 3H); Mass spectrum (esi) m/z=334 (100) (N+H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(C(C)C)CC)(C)C.[CH:19]1([C:22]2[CH:26]=[C:25]([NH2:27])[NH:24][N:23]=2)[CH2:21][CH2:20]1>C1COCC1.C(O)(C)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:27][C:25]2[NH:24][N:23]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:26]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyanuric chloride (5 g, 27.1 mmol) in THF (40 mL) were added diisopropylethylamine (7.1 mL, 40.6 mmol) and 3-cyclopropyl-1H-pyrazol-5-amine (4.0 g, 32.5 mmol) in isopropyl alcohol (40 mL) at 0° C. over 30 minutes. The reaction mixture was stirred at room temperature overnight. The crude reaction solution was used for the next step without purification. A small amount was purified by Biotage (0-50% EtOAc/Hexane, 1 L). 1H NMR (DMSO, 400 MHz) δ 11.33 (s, NH), 6.19 (s, 1H), 3.83 (br s, NH), 1.88-1.95 (m, 1H), 0.93-0.96 (m, 2H), 0.68-0.70 (m, 2H). LC/MS [M+H]+: 271/273; Ret time (Method F): 3.00 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=O)[C:5](F)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][C:14]([NH2:16])=[NH:15]>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:15]=[C:14]([NH:13][CH3:12])[N:16]=[CH:9][C:4]=2[CH:3]=1
Reactant: CNC(=N)N
Reactant: O=Cc1cc(Br)cnc1F
Agent: Cl
Solvent: CC#N
Product: CNc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Yield: 23.9 %

Procedure:
Treat a solution of 5-bromo-2-fluoropyridine-3-carboxaldehyde (0.50 g, 2.451 mmol) and 1-methylguanidine hydrochloride (0.322 g, 2.94 mmol) in acetonitrile (20 mL) with TEA (0.947 mL, 7.35 mmol) and heat to 180° C. in the microwave for 15 min. Concentrate the mixture to dryness, treat the residue with DCM and wash with H2O, then brine. Dry the organic layer over Na2SO4, concentrate to dryness and purify via silica gel chromatography (20-100% EtOAc/Hexanes) to afford the title compound (140 mg, 24% yield). MS (m/z): 241.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)O)ccn1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2ccnc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Reaction time: 16 h

Procedure:
60 mg (0.21 mmol) of the compound of Example 6A and 37 mg (0.21 mmol) of 2-tert-butyliso-nicotinic acid were reacted and worked up analogously to the procedure of Example 33, except that in this case the reaction time was 16 h. This gave 13 mg (96% pure, 13% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:37][C:38]([C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[NH:47][CH:46]=[CH:45]2)=[NH:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:39]=[C:38]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:48]=3[NH:47][CH:46]=[CH:45]4)[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1cccc2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (5.2 g) in tetrahydrofuran (15 mL) stirred at room temp was added EDCI (5.8 g) and HOBT (4.6 g). The reaction mixture was stirred at room temperature for 2 h. Then N-hydroxy-1H-indole-7-carboximidamide (3.5 g) was added. The reaction mixture was stirred at 60° C. for 2 h, and then TBAF (15.7 g) was added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 130° C. for 3 h. After cooling the reaction, solvent was removed. Water (200 mL) and ethanol (50 mL) was added. The precipitate was collected, washed with acetonitrile and dried in vacuo to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (5.1 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.47 (6H, d), 4.70-4.76 (1H, m), 6.68 (1H, dd), 7.08 (1H, d), 7.29 (1H, t), 7.40 (1H, t), 7.85 (1H, d), 8.11 (1H, dd), 8.13 (1H, dd), 8.30 (1H, d), 9.86 (1H, s). MS (ES): C19H16ClN3O2 requires 353; found 354.1 (M+H+)
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=O.N1CCCCC1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (106 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL) was held in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 140 mg (83% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide as an orange solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OCC)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 13, Step C) and ethyl chloroformate, according to the procedure of Example 14. The crude product was flash chromatographed over silica gel (gradient elution using 0.3-5.0% MeOH/CH2Cl2) to afford the desired material as a white solid, mp 79°-81° C.; homogeneous by TLC (5% MeOH/CH2Cl2); mass spectrum (FAB) m/e 603 (M+1)+, 625 (M+Na)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:39])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:38])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:3]1([S:6]([NH:9][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[C:30]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:38])[CH2:12][C:11]3([CH3:39])[CH3:10])=[O:22])(=[O:8])=[O:7])[CH2:5][CH2:4]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
To a suspension of 60% sodium hydride (198 mg, 4.95 mmol) in N,N-dimethylformamide (2 mL) was added cyclopropanesulfonic acid amide (605 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A21. A solution of 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (324 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B21. Solution B21 was added to Solution A21 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-cyclopropanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (30 mg, 6%) as a white solid: MS (ESI) M+1=504.2.
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].[Cl:12]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:11][C:3]([CH2:1][CH3:2])=[N:4][C:5]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cccnc2[nH]1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Cl)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
2-Ethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 4.00 g, 27.2 mmol) was dissolved in chloroform (45 mL), and the solution was added with m-chloroperbenzoic acid (5.18 g, 29.9 mmol) followed by stirring at room temperature for 5 hr. The reaction mixture was concentrated, added with ethyl acetate and water, and partitioned between ethyl acetate and water. The aqueous layer was concentrated and the residue was dissolved in chloroform (8 mL). Phosphorus oxychloride (24 mL, 257 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured onto ice, neutralized with aqueous ammonia, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and the precipitated solid was collected by filtration to give the title compound (3.32 g, 67%).
Reaction SMILES: [K:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16][C:15]2=[O:23])=[C:5](Cl)[N:4]=1.C([O-])=O.[NH4+].C(Cl)(Cl)Cl.CO>CO>[K:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[O:18][C:17]([CH3:21])([CH3:22])[O:16][C:15]2=[O:23])=[CH:5][N:4]=1
Reactant: CC1(C)OC(=O)C(CCn2cnc3c(Cl)nc(N)nc32)C(=O)O1
Agent: O=C[O-]
Agent: [K]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)C(CCn2cnc3cnc(N)nc32)C(=O)O1

Procedure:
A mixture of 2-amino-6-Chloro-9-[1-(2,2-dimethyl-1,3-dioxane-4,6-dione-5-yl)eth-2-yl]purine potassium salt (200 mg, 0.53 mmol), ammonium formate (148 mg, 2.34 mmol) and 10% palladuim on charcoal (80 mg) in methanol (15 ml) was heated under reflux under dry nitrogen for 3 h. T.1.c. [chloroform/methanol (2:1)] showed one spot, rf=0.15. The mixture was filtered and the filtrate evaporated to leave a gum. The material was not purified further.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>ClCCl>[CH:1]1([NH:6][S:7]([C:10]2[CH:19]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[N+:15]3[O-:35])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2nccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ncc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoxaline-5-sulfonamide (0.069 g, 0.18 mmol) and mCPBA (max 77% by weight, 0.083 g, 0.37 mM) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. Additional mCPBA (0.166 g, 0.74 mM) was added and the reaction stirred for 16 hours at room temperature. Volatiles were removed under reduced pressure and the crude product purified by preparatory HPLC (5-95% MeCN/H2O, 0.1% TFA) to afford the product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][N:19]=1>>[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][N:19]=1)[CH3:14]
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1
Yield: 56.9 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (0.98 g) and 2-(methylthio)-5-[(3-pyridinyl)methyl]-4(3H)-pyrimidinone (1 g) were heated at 140° for 16 h. The residue, after column chromatography (silica/methanol -0.88 ammonia, 79:1) gave the title compound as a yellow gum (0.96 g).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=O)([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>CCO.O>[OH:36][N:35]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)[CH2:18][CH2:17][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: NO
Reactant: COC(=O)CCc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CCc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NO)cc1C
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of methyl 3-[4-[3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-2-methylphenyl]propionate [Example 12 (7)] (70 mg, 0.15 mmol) in EtOH (1.5 ml) was added a solution of hydroxylamine hydrochloride (11 mg, 0.15 mmol) and sodium acetate (14.5 mg, 0.176 mmol) in water (1 mL). The mixture was heated under reflux for 1 hour, cooled at room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a pale yellow crystal (55 mg, 57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][C:43]#[N:44]>>[C:43]([CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:44]
Reactant: N#CCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCC#N)cc3)cc21

Procedure:
Analogously to Method I, 0.615 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.176 ml of 4-bromobutyronitrile are reacted. The title compound is obtained as a yellowish oil. Rf=0.16 (2:1 EtOAc-heptane); Rt=5.00.