Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13](OC)=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:20][NH2:21])=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 65 °C
Yield: 46.3 %

Procedure:
Methyl 3-(piperidin-1-ylsulfonyl)benzoate (150 mg, 0.529 mmol) was added to the hydrazine (50.9 mg, 1.588 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 3-(piperidin-1-ylsulfonyl)benzohydrazide (70 mg, 0.245 mmol, 46.2% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.17 (t, 1H, J=1.2 Hz), 8.05 (dt, 1H, J=1.2 & 8.0 Hz), 7.90 (dt, 1H, J=1.2 & 8.0 Hz), 7.69 (t, 1H, J=7.6 Hz), 2.99 (m, 4H), 1.62 (m, 4H), 1.43 (m, 2H). Mass [M+H]+:284.1
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>>[C:1]([C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C#CC1(O)CN2CCC1CC2
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: C#C[C@]1(O)CN2CCC1CC2

Procedure:
The title compound was synthesized from 3-ethynyl-3-quinuclidinol in the same manner as in Production Example 29 using D-(−)-tartaric acid was used as an optical resolution agent.
Reaction SMILES: [Na].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:9](\[C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)/[C:10]#[N:11])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#CCc1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#C/C(=C/c1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL), 4-pyridylacetonitrile hydrochloride (10 g, 65 mmol) was added thereto, and then the mixture was stirred at room temperature. After 10 minutes, 3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto, followed by stirring as it was for 30 minutes. The resulting precipitates were collected by filtration and washed with a small portion of water, to give the title compound (8.2 g, 56%) as a colorless solid.
Reaction SMILES: Br[C:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[C:8]([CH3:11])([CH3:10])C.[CH3:16][C:17]1[CH:22]=CC([Sn](C)(C)C)=C[CH:18]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:10][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:12]([NH:15][C:17]([CH3:16])([CH3:18])[CH3:22])(=[O:13])=[O:14])=[CH:11][CH:2]=1
Reactant: CC(C)(C)C1C=CC=CC1(Br)S(N)(=O)=O
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 90 °C
Yield: 116.8 %

Procedure:
1-Bromo-2-t-butylbenzenesulfonamide (22.4 g, 77 mmol) (Step A) and 4-methylphenyltrimethylstannane (39.35 g, 154 mmol 2eq.) were dissolved in 221 mL of dry dimethylformamide and the resulting solution treated with 2.71 g (38.6 mmol, 0.5eq) of bis(triphenylphosphine)palladium(II) chloride. The mixture was heated at 90° C. for 6 hours. The mixture was filtered through Celite and the filter cake was washed with ether. The combined organics were washed twice with water. The aqueous washings were combined and extracted with ether. The combined organics were washed with saturated aqueous sodium chloride then dried over magnesium sulfate, filtered and concentrated to dryness to yield the product which solidified on standing. Purification by preparative HPLC on silica, eluting with 10% ethyl acetate/hexane, gave 13.63 g (44.98 mmol, 58%) of the product as a yellow powder. 1H NMR (200 MHz, CDCl3): δ 1.09 (s, 9H), 2.50 (s, 3H), 3.64 (br s, 1H), 7.3-7.7 (m,7H), 8.13 (dd; 2, 8 Hz; 1H). FAB-MS: calculated for C17H21NO2S 303; found 304 (M+H, 3%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>ClCCCl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:16])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-indole-3-carboxylic acid (3.00 g, 18.6 mmol) was suspended in 1,2-dichloroethane (15 mL), and oxalyl chloride (2.42 mL, 25.38 mmol) was added dropwise. To this reaction liquor, a catalytic amount of DMF (one drop) was added, and the reaction liquor was stirred for one hour at room temperature. The solvent of the reaction mixture was distilled off under reduced pressure, to obtain 1H-indole-3-carboxylic acid chloride as a solid. The obtained acid chloride was suspended in 1,2-dichloroethane (20 mL), and (4-amino-2,5-dichlorophenyl)acetic acid ethyl ester hydrochloride (4.82 g, 16.92 mmol) was added thereto. The mixture was heated to ref lux for 18 hours with stirring. The reaction mixture was left to cool naturally to room temperature, and then the solvent was distilled off under reduced pressure. The obtained solids were dissolved in chloroform (100 mL), washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained solids were collected by filtration using hexane, to obtain [2,5-d]chloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid ethyl ester (5.95 g, 90%) as a solid. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].O.ON1C2C=CC=CC=2N=N1>O1CCCC1.O1CCCC1.O>[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44]
Reactant: CC(C)(C)CN
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CNC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 67 h
Yield: 72.1 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.16 mL), 2,2-dimethylpropyl amine (0.174 g, 2.00 mmol), 1-hydroxybenzotriazole hydrate (0.270 g, 2.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodihydrochloride (0.384 g, 2.00 mmol). This reaction mixture was stirred for 67 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with an aqueous saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–60% ethyl acetate/hexanes gave the title compound (0.337 g, 72% yield). ES-MS (m/z) 459 [M+1(−Tr)]+
Reaction SMILES: C1SC=CC=1CNC1C=C(C(O)=[O:15])C=C(S(=O)(=O)N)C=1C1C=CC=CC=1.ClC1C=C(C2C=CC=CC=2)C(S(=O)(=O)N)=CC=1C(O)=O.C1(CN)SC=CC=1.[CH2:54]([NH:61][C:62]1[CH:63]=[C:64]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[C:65]([S:71](=[O:74])(=[O:73])[NH2:72])=[CH:66][C:67]=1[C:68]([OH:70])=[O:69])[C:55]1[CH:60]=[CH:59][CH:58]=CC=1.C(N)C1C=CC=CC=1>>[CH2:54]([NH:61][C:62]1[CH:63]=[C:64]([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:65]([S:71](=[O:73])(=[O:74])[NH2:72])=[CH:66][C:67]=1[C:68]([OH:70])=[O:69])[C:55]1[O:15][CH:58]=[CH:59][CH:60]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccsc2)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccccc2)cc1-c1ccccc1
Agent: NCc1cccs1
Agent: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1-c1ccccc1
Solvent: NCc1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1-c1ccccc1

Procedure:
3-thenylamino-6-sulfamoyl-biphenyl-4-carboxylic acid from 3-chloro-6-sulfamoyl-biphenyl-4-carboxylic acid and thenylamine; m.p. 214° - 216°C. (decomp.); yield 37% of theory; and 3-benzylamino-6-sulfamoyl-biphenyl-4-carboxylic acid from 3-chloro-6-sulfamoyl-biphenyl-4-carboxylic acid and benzylamine: m.p. 225° - 227°C. (decomp.); yield 53% of theory.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([F:13])([F:12])[S:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[S:3][C:4]([C:7]([F:13])([F:12])[S:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: CC(C)SC(F)(F)c1nnc(N)s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)SC(F)(F)c1nnc(Cl)s1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
2-Amino-5-[difluoro(isopropylthio)methyl]-1,3,4-thiadiazole (190 g) was dissolved in a mixture of acetic acid (880 ml) and concentrated hydrochloric acid (216.5 ml) at 60° C. A solution of sodium nitrite (171.3 g) in water (300 ml) was then added dropwise over 30 minutes at 65°-70° C. The mixture was stirred at 65° C. for 15 minutes and then allowed to cool. It was then poured onto water (3 L) and extracted with ether, the combined extracts being washed with water, dried (MgSO4) and evaporated to give an orange liquid, which was distilled under vacuum to give 150 g of 2-chloro-5-[difluoro(isopropylthio)methyl]-1,3,4-thiadiazole, bp 75°-77° C. at 0.7 mmHg.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCNCC1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 43.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (120 mg) as colorless prisms, mp 217°-219° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cnc2ccccc2c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2cnc3ccccc3c2)[nH]c1-c1ccc(C)cc1
Yield: 43.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.6 g) and 3-aminomethylquinoline (8.5 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(3-quinolyl)imidazole-4-carboxylate (7.0 g). 6.7 g therefrom was dissolved in ethyl alcohol (135 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(3-quinolyl)imidazole-4-carboxylic acid (2.5 g), melting point 224° C. (decomposition).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([NH:11][C:12](=[NH:33])[C:13](=[NH:32])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:20]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.[S:37](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O>C(N(CC)CC)C>[CH2:4]([NH:11][C:12]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:32][S:37][N:33]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N=C(NCCCOc1cccc(CN2CCCCC2)c1)C(=N)NCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNc2nsnc2NCCCOc2cccc(CN3CCCCC3)c2)cc1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of N-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml of CH2Cl2 and 3.8 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmoles) and stirred for one hour. The mixture was washed with 44 ml of 10% KOH, dried (MgSO4) filtered, diluted with toluene and concentrated. The residue was chromatographed by flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCl in 2-propanol gave the hydrochloride salt of the title compound, mp 138°-141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C)c(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)c(CCCBr)c1
Yield: 86.9 %

Procedure:
Compound 62-2 (1.64 g) was dissolved in methylene chloride (33 ml), triphenylphosphine (2.90 g) and N-bromosuccinimide (1.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.97 g) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:32])=[C:8]2[C:16]([C:17]#[N:18])=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+].CO>>[C:17]([C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:3])[C:7]=2[OH:32])[N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)#[N:18]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2ccc(F)cc2)n(-c2ccccc2)c2c(C#N)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3,7-dicyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 454 (M−1)−.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(C(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(F)(F)F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC(F)(F)c1cccc(NCC2CCCC2)c1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:28]([NH2:30])=O.C(O)(=O)C>C(Cl)Cl.O>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][CH:28]=[N:30][C:20]=4[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccccc2)c1N
Reactant: NC=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccccc3)ncnc21
Temperature: 200 °C
Yield: 59 %

Procedure:
The mixture of 3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (33 mg, 0.09 mmol), formamide (0.5 mL, excess), and acetic acid (0.1 mL) was heated in the microwave at 200° C. for 20 min. After cooling, the mixture was diluted with CH2Cl2 and water, and the CH2Cl2 layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparatory HPLC to provide the title compound (20 mg, 59%) as a white solid: HPLC tR=2.20 min; MS m/z 370.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH2:35]>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH:30]4[CH2:31][CH2:32][CH2:33][N:29]4[CH3:28])=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CN1CCCC1CN
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CN1CCCC1CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (1-methylpyrrolidin-2-yl)methylamine similar to as described in Example 2 to afford 7.6 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-[(1-methylpyrrolidin-2-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.27 (s, 1H), 7.01 (d, J=10.4, 4.6 Hz, 1H), 4.67-4.44 (m, 2H), 4.44-4.14 (m, 2H), 2.96 (s, 2H), 2.36 (s, 1H), 2.02-1.86 (m, 2H), 1.83 (s, 1H), 1.78-1.62 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:30][C:31]1[C:32]([O:46][CH3:47])=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1>CN(C=O)C>[C:37]([C:35]1[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:32]([O:46][CH3:47])=[C:31]([NH:30][C:13]([C:11]2[S:10][C:9]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[CH:12]=2)=[O:15])[CH:36]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc([N+](=O)[O-])c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of the above carboxylic acid (900 mg) in DMF was added EDC (1.2 eq) and HOBT (1.2 eq). After stirring for 10 min, N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (1.0 eq) was added. The suspension was stirred at room temperature for 48 h. The DMF was removed in vacuo and the resulting oil was dissolved in EtOAc, washed with water three times, followed by saturated NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude yellow solid which was triturated with 30% EtOAc/hex (small amount) and filtered to provide 7-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a bright yellow solid (1.4 g, 72%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:23])[CH:10]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2COc3cc(OC(C)=O)ccc3C2O)cc1
Temperature: 25 °C
Reaction time: 55 h
Yield: 101.4 %

Procedure:
Palladium-on-charcoal (5%, 0.08 g) was added to a suspension of 7-acetoxy-4′-methoxyisoflavone (0.5 g, 1.6 mmol) in absolute ethanol (400 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 55 hours. The catalyst was removed by filtration through Celite and the filtrate was evaporated in vacuo to yield 7-acetoxy-4′-methoxyisoflavan-4-ol (0.51 g, 100%) in quantitative yield. A nuclear magnetic resonance spectrum revealed the product to be a clean 1:1 mixture of cis- and trans-7-acetoxy-4′-methoxyisoflavan-4-ol.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:8](=[O:21])[N:9]([CH3:20])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][CH:11]=2)=[O:6])C>C(OC(=O)C)(=O)C>[OH:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][CH3:19])[N:9]([CH3:20])[C:8](=[O:21])[C:7]=1[C:5]([OH:6])=[O:4]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2c1c(O)c(C(=O)O)c(=O)n2C
Temperature: 80 °C
Yield: 76 %

Procedure:
While cooling, 10 ml of conc. hydrochloric acid was added to 30 ml of acetic anhydride. To this solution 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (10.5 g, 38 mmol) was added and the mixture heated at 80° C. for 14 hours. The mixture was cooled to room temperature and the crystalline product was filtered off, washed with cold methanol and dried to give the title compound (7.2 g), yield 77%.