Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(OCC)(=O)C>[Br:32][C:14]1[C:13]2[C:9](=[CH:10][N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)c(Br)c3n2)cc1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (1.31 g) in ethyl acetate (15 mL) were added N-bromosuccinimide (0.56 g) and azobisisobutyronitrile (99 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as an orange oil (1.41 g).
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[F:6][C:7]([F:19])([F:18])[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:8]([C:7]([F:6])([F:18])[F:19])=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5]2)[CH2:3][CH2:2]1
Reactant: NNC1CC1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)c1cc(C(F)(F)F)n(C2CC2)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (Hexane/EtOAc 9:1). tR: 1.10 min (LC-MS 2); ESI-MS: 249 [M+H]+ (LC-MS 2); Rf=0.17 (hexane/EtOAc 9:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2([NH2:11])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:12]C1C=CC(C#N)=CC=1>>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NC1(c2cccc(Cl)c2)CC1
Product: NC1(c2ccc(Cl)cc2)CC1

Procedure:
was prepared using the same procedure as for the preparation of 1-(3-chloro-phenyl)-cyclopropylamine starting from 4-chlorobenzonitrile. MS (UPLC-MS): 170 [M+H]+, 168 [M−H]; tR (HPLC conditions f): 1.21 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[N:16]2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:22][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[N:16]=1
Reactant: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nn(C[C@H]2CC[C@H](N)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-[4-(3,4,5-trimethyl-pyrazol-1-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (step 2) (215 mg, 0.669 mmol) in methanol (3 mL) at room temp is added a solution of 4M HCl in dioxane (3 mL). The mixture is stirred at room temp for 1 hour and then concentrated in vacuo. The resulting gum is dried under vacuum overnight to afford the title compound which is used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.16 (3H, br s), 4.10 (2H, d), 2.90 (1H, m), 2.29 (3H, s), 2.27 (3H, s), 2.01-1.90 (5H, m including 3H, s), 1.83 (1H, s), 1.54 (2H, m), 1.30 (2H, m), 1.12 (2H, m). (NMR shows contamination with side products and solvents.)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.C(N(CC)CC)C.Cl.[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH:46]=[CH2:47])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:33][C:32]2=[O:48])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:22])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH:46]=[CH2:47])=[CH:44][CH:45]=3)(=[O:38])=[O:39])[CH2:33][C:32]2=[O:48])[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=2)[CH2:28][CH2:29]1)=[O:22])[CH3:19]
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCNCC3)C(=O)C2)cc1
Reactant: OCc1cc(Cl)ccn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(CO)c4)CC3)C(=O)C2)cc1
Yield: 17.5 %

Procedure:
4-Chloro-2-(hydroxymethyl)pyridine (118 mg), triethylamine (500 mg) and ethanol (15 ml) were added to 1-{1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone hydrochloride (200 mg), to react at 150° C. for 15 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from ether to obtain the title compound (40 mg) as pale yellow crystals.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:23]1([CH2:36][O:37][C:38]([NH:40][C@H:41]([C:54](O)=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[C:35]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.[NH2:57][C:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=[CH:60][CH:59]=1>O.C(OCC)(=O)C>[C:58]1([NH:57][C:54](=[O:55])[C@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[NH:40][C:38]([O:37][CH2:36][C:23]2[C:35]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:39])[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)O
Reactant: Nc1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)Nc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Under cooling with ice water, 2.97 g (22 mmol) of 1-hydroxybenzotriazole and 4.60 g (24 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to an ethyl acetate solution (50 ml) of 9.37 g (20.0 mmol) of Nα-fluorenylmethyloxycarbonyl-Nε-t-butoxycarbonyl-L-lysine and 2.86 g (20.0 mmol) of 1-aminonaphthalene. The mixture was stirred overnight as it was. Water was added to the reaction mixture, and a solid deposited was collected by filtration, washed with ethyl acetate and dried, thereby obtaining 7.95 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 98.9 %

Procedure:
A suspension of morpholine (3.30 mL, 3.30 g, 37.8 mmol), 6-bromo-1-hexanol (6.72 g, 72.3 mmol), ethanol (20 mL), and potassium carbonate (6.23 g, 45.1 mmol) was stirred for 36 hours at 25° C., after a slight exotherm at the beginning. The reaction mixture was diluted with ethyl acetate (30 mL), filtered and concentrated. The residue was taken up in ethyl acetate, filtered and concentrated. The 7.0 g of 4-(6-hydroxyhexyl)morpholine was isolated as a yellow oil and used as is.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:3]1=[O:32].[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1.C(N(CC)CC)C>C1COCC1>[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:22])[CH:38]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25 ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5 ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester. This ester (885mg, 1.94mmol) was dissolved in THF (5 ml) and treated with a solution of lithium hydroxide (815 mg, 19.4 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 3 hours, diluted with water (100 ml), acidified with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, filterate, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with chloroform followed by 9:1 chloroform:methanol. The product fractions were combined and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate to provide the title compound: (mp 167°-170° C.).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:29](=[O:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 4-(benzylamino)piperidine-1-carboxylate (8.1 g, 28.0 mmol) and Et3N (7.8 mL, 56.0 mmol) in CH2Cl2 (100 mL) was added acetyl chloride (2.4 mL, 33.5 mmol) and the reaction was stirred at room temperature overnight, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 30% to 60% EtOAc/CH2Cl2, afforded tert-butyl 4-(N-benzylacetamido)piperidine-1-carboxylate (9.3 g, 99%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH3:22]>CC(=O)CC>[OH:13][CH2:12][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:20][CH2:21][CH3:22])[CH:4]=1
Reactant: CCCBr
Reactant: OCc1cnc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCn1cc(CO)c(=O)c2ccccc21

Procedure:
A mixture of 4-hydroxy-3-hydroxymethylquinoline (5.0 g.), anhydrous potassium carbonate (1.6 g.), propyl bromide (2.6 ml.) and 2-butanone (500 ml.) was stirred and boiled under reflux for 18 hours. Additional propyl bromide (2 ml.) was added and the mixture boiled under reflux for 23 hours. The solvent was evaporated and the residue treated with water (100 ml.) and basified with 5 N aqueous sodium hydroxide. The solution was extracted with dichloromethane (4×100 ml.). The extract was dried and evaporated to give an oil. This oil was triturated with petroleum ether:ethyl acetate:industrial methylated spirit 12:1:1 to give the novel compound 3-hydroxymethyl-1-propyl-4-quinolone, m.p. 88°-91°.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:27])([F:26])[C:18]([F:29])([F:28])[C:17]2[CH:30]=[CH:31][CH:32]=[CH:33][C:16]1=2>>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH:15]1[C:16]2[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=2[C:18]([F:29])([F:28])[C:19]([F:26])([F:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC1(F)c2ccccc2C(Cl)c2ccccc2C1(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reaction time: 1 h

Procedure:
Diethyl malonate, 90 ml., is stirred, cooled in an ice bath, and treated with 1.51 g. of 55.7% sodium hydride in mineral oil in several portions. The mixture is stirred approximately 5 minutes at room temperature and then treated with 10.03 g. (0.0334 mole) of 5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene. Stirring is continued for 16 hours at approximately 40°C., 1 hour at 50°C., 1 hour at 60°C. and 1 hour at 70°C. The excess diethyl malonate is distilled at 70°-75°C. and 0.1 mm. and the residue is triturated with hexane. The insoluble mixture of product and sodium chloride is collected, washed with hexane and petroleum ether, and dried at 80°C. and 0.1 mm. The mixture is triturated with benzene and the insoluble sodium chloride is removed by filtration. Evaporation of the benzene solution under reduced pressure and recrystallization of the residual white solid from absolute ethanol affords purified product, m.p. 144° -146°C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:10]=2[CH2:11][N:12]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:52]([O:54][CH2:55][CH3:56])=[O:53]>C(Cl)Cl>[F:29][C:26]([F:28])([F:27])[C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1)[CH2:19][N:12]([CH2:11][C:10]1[CH:34]=[C:35]([C:38]([F:41])([F:39])[F:40])[CH:36]=[CH:37][C:9]=1[C:3]1([O:2][CH3:1])[CH2:4][CH2:5][N:6]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:7][CH2:8]1)[C:13]1[N:14]=[N:15][N:16]([CH3:18])[N:17]=1
Reactant: CCOC(=O)Cl
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(OC)(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a suspension of N-(2-(4-methoxypiperidin-4-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (31 mg; 0.049 mmol) in methylene chloride (0.5 mL) was added diisopropylethylamine (0.05 mL; 0.287 mmol). Ethyl chloroformate (10uL; 0.104 mmol) was then added. The resulting reaction was stirred at room temperature for 16 hours. The reaction was filtered over a column of silica/sodium sulfate and concentrated under reduced pressure. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (30-85% ethyl acetate in heptane) to give 32 mg (98%) of a gum. MS (ES+): Calc: 668.5, Found: 669.6 (M+H), 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.73 (s, 2H), 7.51 (d, J=6.64 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J=8.71 Hz, 1H), 5.10 (s, 2H), 4.82 (s, 2H), 4.2 (s, 3H), 4.14 (q, J=7.05, 2H), 4.02 (bm, 2H), 3.16 (t, J=12.45 Hz, 2H), 2.95 (s, 3H), 2.14 (m, 2H), 1.9-1.63 (m, 2H), 1.27 (t, J=7.05 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+].Cl>O.CC#N>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-bromophenyl)phenol (3.74 g, 15.0 mmol), MeCN (20 ml), ethyl 4-bromobutyrate (4.42 g, 22.7 mmol), and K2CO3 (3.12 g, 22.6 mmol) was stirred at 80° C. After 16 h water (100 ml) and 1N HCl (40 ml) were added, and the product was extracted (3×AcOEt), the combined extracts were washed with brine (2×), dried (MgSO4), and concentrated. The residue was recrystallized from EtOH (40 ml) to yield 4.35 g (80%) of 4-(4′-bromobiphenyl-4-yloxy)butyric acid ethyl ester as colorless plates.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].C(O)=O.CS(O)(=O)=O>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: O=CO
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(C(=O)O)nn12
Reaction time: 1 h

Procedure:
5.8 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carbethoxy-s-triazolo[4,3-b]pyridazine were heated under reflux with 18.3 ml. 90% aqueous formic acid and 2.75 ml. methane-sulfonic acid for 3 hours at a bath temperature of 130° C. 80 ml. water were then added thereto and the precipitated crystals were filtered off with suction, after having stood for 1 hour, and washed with water. There were thus obtained 4.85 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-carboxy-s-triazolo[4,3-b]pyridazine, which has a melting point of 257° - 260° C. 1 g. of the product was recrystallized from 15 ml. dioxan with the addition of charcoal, to give 0.6 g. of pure product which melts, with foaming up, at 260° - 262° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:22](O)=[O:23])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C1CCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCC4)cc23)CC1
Yield: 96.3 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol) cyclobutanecarboxylic acid, 15.0 mg (96%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[C:3]2[C:10](=[CH:28][C:14]3[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.3 %

Procedure:
To a mixture of 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (85 mg, 0.5 mmol) and 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (125 mg, 0.5 mmol) in ethanol (4 mL) was added 0.1 to 0.2 mL of piperidine. The mixture was stirred at room temperature for 20 hours. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol, and dried to give 89 mg (45%) of 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([F:24])=[C:22](F)[N:21]=[C:20]([F:26])[C:19]=1[F:27]>C(OCC)C>[CH3:17][C:18]1[C:23]([F:24])=[C:22]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:21]=[C:20]([F:26])[C:19]=1[F:27]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(F)c(F)nc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Butyl lithium (2.7 ml, 6.7 mmol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-trifluoromethyl benzene (1.0 ml, 7.3 mmol) in anhydrous diethyl ether (10 ml) at −20° C. The mixture is stirred for 60 min at −20° C. and for 60 min at 10° C. After cooling to −40° C. 4-methyl-2,3,5,6-tetrafluoropyridine (1.1 g, 6.6 mmol) is added. The resulting mixture is stirred for 120 min at −30° C. and then is allowed to warm to ambient temperature. After 2 days at ambient temperature the mixture is washed twice with saturated aqueous ammonium chloride. The layers are separated and the organic layer is dried with anhydrous magnesium sulfate and filtered. After removal of the solvents in vacuo, the crude product is purified by flash column chromatography (silica gel, pentane/ethyl acetate=9/1 by volume) yielding colorless crystals of 4-methyl-2,3,5-trifluoro-6-(4-trifluoromethylphenyl)pyridine (0.5 g, 1.7 mmol) of mp. 52° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[NH:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:19])=[O:18])=O)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[NH2:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:40])[CH3:41])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:18])=[O:19]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(=O)(=O)NOC(=O)OC(C)(C)C)c3)c(CF)c2cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(N)(=O)=O)c3)c(CF)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of dimethylcarbamic acid 3-{3-((tert-butoxycarbonyloxy)aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1j-1-3-1F-other) (23 mg, 0.039 mmol) in anhydrous dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was then obtained by vacuum concentration, and purified by preparative TLC (ethyl acetate:hexane=1:1) to yield the title compound (19 mg, 100%) as a pale yellow powder.