Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][OH:17])=[CH:28][CH:27]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(OCCO)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4(2-hydroxyethoxy)benzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C21 was scraped and collected. (100 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:22][CH2:21][C:18]2[CH:19]=[N:20][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]=1[CH3:12]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: COc1cc([N+](=O)[O-])ccc1C
Product: COc1cc(NCCc2ccc(C(F)(F)F)nc2)ccc1C
Yield: 31.3 %

Procedure:
In analogy to example 6, step 1, 2-methoxy-1-methyl-4-nitro-benzene (988 mg, 5.91 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.0 g, 5.37 mmol, prepared in example 1, step 1) to give the title compound (521 mg, 31%) as an orange oil MS m/e: 311.1 [M+H]+.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O:14]C)=[O:13])(=O)=O.O1CCCC1.[OH-].[Na+:22]>O>[OH:5][C@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13].[Na+:22]
Reactant: COC(=O)C[C@@H]1C=CC[C@H]1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])C[C@@H]1C=CC[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.290 g. (0.00124 mole) of racemic methyl trans-2-methylsulfonyloxy-4-cyclopentene-1-acetate in 10 ml. of tetrahydrofuran and 4 ml. of water at 0° C. was added dropwise, 1.00 ml. (0.0020 mole) of 2 N sodium hydroxide solution. The two-phased solution was vigorously stirred at 0° C. for 1 hr. and at room temperature for 16 hrs. to form racemic sodium cis-2-hydroxy-4-cyclopentene-1-acetate in admixture with racemic cis-2-hydroxy-4-cyclopentene-1-acetic acid lactone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][CH:16](O)[CH3:17].[OH2:19]>>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([N:15]([CH2:16][CH2:17][OH:19])[CH3:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: O
Reactant: CNC(C)O
Product: CN(CCO)[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are reacted with 17 g (0.1 mol) of methylaminoethanol in 200 ml of water analogously to Example D a).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (64.1 mg, 0.17 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.15 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (32.8 mg, 0.15 mmol) and DIEA (0.030 mL, 0.17 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (60.0 mg, 0.102 mmol, 66.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:20])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:11]([CH3:28])[CH2:10]2)[C:38](=[O:40])[CH3:39])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of (2S, 4R)-[4-(4-chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone (250 mg, 0.636 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol) followed by acetyl chloride (90 uL, 1.27 mmol). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>CO.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)cc(-c2cccc(F)c2)c1
Temperature: 70 °C
Yield: 88 %

Procedure:
A suspension of methyl 3-bromo-5-methoxy-benzoate (3.2 g, 13.1 mmol, 1.0 eq), 3-fluorophenylboronic acid (2.0 g, 14.4 mmol, 1.1 eq) K2CO3 (7.2 g, 52.2 mmol, 4.0 eq) and Pd(PPh3)4 (754 mg, 0.65 mmol, 0.05 eq) in a mixture of methanol (10 mL) and dioxane (50 mL) was heated at 70° C. for 4 h under N2. After cooling, the resulting mixture was concentrated and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound as an oil (3.0 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.C.[CH2:16]([NH:19][C:20]([NH:22][CH2:23][CH:24]=[CH2:25])=[S:21])[CH:17]=[CH2:18]>CC(C)=O>[ClH:1].[CH3:12][C:11]1[C:2]([S:21][C:20](=[N:19][CH2:16][CH:17]=[CH2:18])[NH:22][CH2:23][CH:24]=[CH2:25])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=CCNC(=S)NCC=C
Reactant: Cc1nc2ccccc2nc1Cl
Agent: C
Solvent: CO
Solvent: CC(C)=O
Product: C=CCN=C(NCC=C)Sc1nc2ccccc2nc1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-Chloro-3-methylquinoxaline (3.56 g., 0.02 mole) was dissolved in 50 ml. of methanol, treated with Norit and filtered. The filtrate was added to 3.125 g. (0.02 mole) of 1,3-diallylthiourea in 50 ml. of methanol. The mixture was stirred at room temperature for 31/2 hours, then freed of solvent. Acetone was added to the residue and the solution again freed of solvent. The residue was triturated with ether and with acetone, filtered, washed and dried to give 4.12 g. (61.5% yield), m.p. 90°-93° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:49]([N:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([NH:63][CH3:64])=[CH:59][CH:58]=1)[CH2:53][CH2:54][CH3:55])[CH2:50][CH3:51]>CN(C=O)C>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:63]([C:60]2[CH:61]=[CH:62][C:57]([CH2:56][N:52]([CH2:49][CH2:50][CH3:51])[CH2:53][CH2:54][CH3:55])=[CH:58][CH:59]=2)[CH3:64])=[O:20])=[CH:22][CH:23]=1)[CH2:6][C:2]1[NH:3][CH:4]=[CH:5][N:1]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)Cc1ccc(NC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(N(C)C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The compound (278 mg) obtained in Example 2-2, HOBt (95.9 mg), and DCC (147 mg) were dissolved in anhydrous DMF (11.0 ml), followed by stirring at room temperature for 19 hours. Then, the solution was added with a solution (1.2 ml) of the compound (128 mg) obtained in Example 68-1 in DMF and stirred at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and added with 1 mol/l hydrochloric acid to separate the solution into layers. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to adjust the solution to pH 11. The aqueous layer was extracted with chloroform and the organic layer was then dried with anhydrous magnesium sulfate. After having been treated with hydrochloric acid, the product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (10.2 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:21]=[CH:20][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[C:22]1([C:28]2[O:32][C:31]([C:33](OCC)=[O:34])=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:22]1([C:28]2[O:32][C:31]([C:33]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:21]=[CH:20][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:34])=[N:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: CC(=O)N1CCN(Cc2ccc(OC3CNC3)cc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)CC1
Temperature: 140 °C
Yield: 10.4 %

Procedure:
23B (0.16 g, 0.53 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.11 g, 0.50 mmol) were mixed together in a microwave vial together with toluene (3 mL). The mixture was heated in a microwave oven at 140° C. for 30 min. The solvent was removed by evaporation. The product was purified by preparative chromatography on a Kromasil C8 column eluting with acetonitrile and 0.1 M NH4OAc. The combined fractions were concentrated and the aqueous solution was pH adjusted to pH 9 with 1M NaOH. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4. The solvent was removed by evaporation. There was obtained 24 mg (10%) of the product as a foam. 1H NMR (400 MHz, CDCl3): δ 2.08 (s, 3H), 2.32-2.47 (m, 4H), 3.37-3.54 (m, 4H), 3.62 (s, 2H), 4.29-4.40 (m, 1H), 4.59-4.70 (m, 1H), 4.71-4.82 (m, 1H), 5.02-5.19 (m, 2H), 6.74 (d, 2H), 7.26 (d, 2H), 7.49-7.64 (m, 3H), 8.16 (d, 2H), MS (APCI+) m/z 462 [M+H]+, LC purity: 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][C:26]=2[CH:34]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:28]1[S:29][C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:34][C:26]=3[CH:27]=1)(=[O:31])=[O:32])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cc3cc(C)ccc3s2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 5-methyl-1-benzothiophene-2-sulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (8 mg, 27%) as a white solid. MS (ESI+) for C21H22N2O3S2 m/z 415 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:30]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:66])[C:51]3[CH:56]=[CH:55][C:54](B4OC(C)(C)C(C)(C)O4)=[CH:53][CH:52]=3)=[CH:45][CH:44]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH2:31][CH3:32].C([O-])(O)=O.[Na+]>COCCOC.O>[CH2:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([C:54]4[CH:55]=[CH:56][C:51]([C:50]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([CH2:42][N:39]6[CH2:40][CH2:41][N:36]([S:33]([CH2:30][CH2:31][CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]6)=[CH:44][CH:45]=5)=[O:66])=[CH:52][CH:53]=4)=[CH:3][CH:4]=3)=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23])[CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(Br)cc3)cc2)CC1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5ccc(CN6CCN(S(=O)(=O)CCC)CC6)cc5)cc4)cc3)cc2)CC1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture containing 5 (88.8 mg, 0.18 mmol), 6 (101.4 mg, 0.19 mmol), Pd(TPP)4 (9.1 mg, 0.008 mmol), and NaHCO3 (57.1 mg, 0.68 mmol) in DME/H2O (4.5:1 v/v, 7 mL) was heated at 80° C. for 19 h, allowed to cool to rt, and evaporated to dryness. The remaining crude product was washed with H2O (3×10 mL) and dried, then a portion (60.5 mg of the 178.1 mg isolated) was purified by PTLC to give the title product (21.9 mg). Rf 0.38 (100:10:1 v/v CHCl3/MeOH/NH4OH (28%)). HPLC: tR 1.68 min (method 1). LC-MS m/z calcd for C42H52N6O6S2 ([M]+), 800. found, 801 ([M+H]+). 1H NMR (DMSO-d6): δ 0.92 (t, J=7.5 Hz, 3H), 1.62 (m, 2H), 2.38 (m, 4H), 2.95 (m, 2H), 3.10 (m, 4H), 3.44 (br s, 2H), 7.23 (m, 2H), 7.70 (m, 2H), 7.87 (m, 2H), 8.03 (m, 2H), 10.25 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)/[CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].ClC[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)/[CH:12]([CH2:16][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[C:13]([OH:15])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(C)C(=O)O)n1Cc1ccccc1Cl
Reactant: ClCc1cccs1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
This compound is prepared according to the procedure of Example 14(i, ii) using less than one equivalent of 2-chloromethylthiophene in place of methyl iodide.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[C:37](O)(=[O:40])[CH2:38][CH3:39].S(=O)(=O)(O)O>>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][C:37](=[O:40])[CH2:38][CH3:39])[C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Yield: 32 %

Procedure:
Substantially the same manner as that in Example 123 was repeated except that 1.06 g (2.10 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4), 32 mL of propionic acid and 8 mL of concentrated sulfuric acid were used, and the resulting compound was purified by silica gel column chromatography (chloroform:acetonitrile=20:1) and high performance liquid chromatography, to give 261 mg of Compound 124 (yield: 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][OH:33])[C:6]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]=2[CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCOS(C)(=O)=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in pyridine (5 ml) is added with stirring methanesulfonyl chloride (0.11 ml) under ice-cooling, and the mixture is stirred at room temperature for two hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as colorless amorphous.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CCOCCO>[C:16]([NH:24][N:25]=[C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(O)nc2ccccc2c1O
Reactant: NNC(=O)c1ccncc1
Solvent: CCOCCO
Product: CC(=NNC(=O)c1ccncc1)c1c(O)nc2ccccc2c1O
Yield: 84.5 %

Procedure:
20.3 g of 3-acetyl-2,4-dihydroxyquinoline and 13.8 g of isonicotinic acid hydrazide are condensed in 180 ml of ethyl cellosolve analogously to Example 1, yielding 27.2 g of 3-acetyl-2,4-dihydroxyquinoline isonicotinoylhydrazone. 3.2 g of this product are suspended in 25 ml of dimethylformamide and treated with a solution of 2.4 g of zinc(II) acetate·2H2O in 35 ml of dimethylformamide. The resulting mixture is stirred for 2 hours at 90°-100° C. and the product is then isolated by filtration and subsequently washed with isopropanol and then with water. After the product has been dried under vacuum at 70°-80° C., 3.2 g of a yellow powder of the following formula: ##STR86## as the 1:1 zinc complex are obtained.
Reaction SMILES: ClC1C=CC(O)=CC=1.BrCC(SC1C(Cl)=CC=CC=1Cl)C[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Br[CH2:28][CH2:29][C:30]([OH:32])=[O:31].N1C=CN=C1>>[N:13]1([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(O)CCBr
Reactant: Clc1cccc(Cl)c1SC(CBr)Cn1ccnc1
Agent: Oc1ccc(Cl)cc1
Agent: c1c[nH]cn1
Product: O=C(O)CCn1ccnc1

Procedure:
A mixture of 12.9 g of p-chlorophenol, 36.6 g of 1-bromo-2-(2,6-dichlorophenylthio)-3-(1-imidazolyl)propane [obtainable by reaction of 3-bromopropionic acid with imidazole to give 3-(1-imidazolyl)propionic acid, bromination to give 2-bromo-3-(1-imidazolyl)propionic acid, reaction with Na 2,6-dichlorothiophenolate to give 2-(2,6-dichlorophenylthio)-3-(1-imidazolyl)propionic acid, reduction with LiAlH4 to give the corresponding alcohol, and reaction with PBr3 ], 8 g of NaOH and 400 ml of ethanol is heated at 100° for 10 hours. The mixture is evaporated, worked up as usual and Ia of m.p. 175°-177° is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:38]1[C:43](=[O:44])[C:42](COS(C)(=O)=O)=[CH:41][C:40]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)=[N:39]1)[CH:35]([CH3:37])[CH3:36].N1(C(OC(C)(C)C)=O)CCNC[CH2:62]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:42]2[C:43](=[O:44])[N:38]([CH2:34][CH:35]([CH3:36])[CH3:37])[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:53][CH:52]=3)[C:41]=2[CH3:62])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.5 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH3:34]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:34])=[O:14])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) ammonia in THF, gave the title compound.