Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH:4]1(Br)[CH2:6][CH2:5]1.C1([Mg]Br)CC1.[Cl:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19](Cl)=[N:18][N:17]2[C:23]=1[S:24]([N:27]=[CH:28][N:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:26])=[O:25].Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([CH:4]3[CH2:5][CH2:6]3)=[N:18][N:17]2[C:23]=1[S:24]([N:27]=[CH:28][N:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:30][CH:31]([CH3:32])[CH3:33])(=[O:25])=[O:26]
Reactant: BrC1CC1
Reactant: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12)CC(C)C
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(C3CC3)nn12)CC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Magnesium metal powder (0.27 g, 11.1 mmol) was mixed with iodine (5 mg), heated with a dryer under a nitrogen atmosphere and cooled to room temperature, and anhydrous tetrahydrofuran (15.0 mL) was added thereto. Cyclopropyl bromide (1.33 g, 1.10 mmol), while being kept at 28 to 33° C., was added dropwise to the mixture under stirring at room temperature, and then the mixture was stirred at room temperature for 30 minutes to prepare a pale yellowish gray solution of cyclopropylmagnesium bromide in tetrahydrofuran. Separately, zinc chloride (1.50 g, 11.0 mmol) dried at 180° C. for 4 hours under vacuum was dissolved in anhydrous tetrahydrofuran (10.0 mL) under a nitrogen atmosphere and then kept at 0° C. or less in an ice-sodium chloride bath, during which the previously prepared solution of cyclopropylmagnesium bromide in tetrahydrofuran was added dropwise thereto. The mixture was stirred at about −10° C. for 15 minutes, and [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (0.27 g, 0.50 mmol) was added as powder to the resulting suspension, and then a solution of N′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (2.03 g, 5.00 mmol) dissolved in anhydrous tetrahydrofuran (10.0 mL) was added dropwise thereto. The mixture was stirred at −10° C. for 2 hours, then at room temperature for 16 hours, poured into an aqueous saturated saline solution, adjusted to pH 2 with dilute hydrochloric acid and extracted 4 times with chloroform. The extracts were combined, dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:1), whereby 0.64 g (31.5%) of the starting material N′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine was recovered and simultaneously the title compound was obtained as pale yellow crystals. The yield was 0.94 g (45.7%).
Reaction SMILES: C(N)(=O)C.C([O:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]3=[O:38])=[CH:24][C:23]=2[F:39])C[CH2:17]1)=[O:15])C1C=CC=CC=1>>[F:39][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:26]=[CH:27][C:22]=1[CH:19]1[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][OH:12])[CH2:17]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: CC(N)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)CO)C3)c(F)c2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 22, and making non-critical variations but substituting (5S)-N-[[3-[3-fluoro-4-[1-(benzyloxy)acetyl]-3-pyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 43) for (S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, the title compound is obtained, FAB-HRMS calculated for C18H22N3O5F+H: 380.1622. Found: 380.1625.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>>[C:1]1([C:7]2[C:8]3[C:9](=[N:25][N:26]([CH2:29][CH2:30][N:31]4[C:35](=[O:36])[C:34]5=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]5[C:32]4=[O:41])[CH:27]=3)[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCn1cc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc2n1
Yield: 31 %

Procedure:
Following a similar procedure to that described in examples 6 and 7, but using 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 2) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and N-(2-bromoethyl)phthalimide instead of iodoethane, the title compound was obtained (yield: 31%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH:12]=[CH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=CCC(C=Cc1cccnc1)CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCC(CCO)CCc1cccnc1

Procedure:
A solution of 1.75 g of methyl 7-hydroxy-5-[2-(3pyridyl)ethenyl]-hept-2-enoate in 50 mL ethanol is hydrogenated with 0.35 g 10% palladium on charcoal at 3 atmospheres pressure of hydrogen and room temperature for 21 hours. The catalyst is filtered off and washed with ethanol (4×10 mL). The filtrate is evaporated to give a yellow oil which is chromatographed to yield methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:32]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 417.22 g/mol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([S:12](=[O:15])(=[O:14])N)[CH:6]=1)=[O:4].NC1C=C(C(=O)C)C=CC=1Br.N([O-])=O.[Na+].S(=O)=O.[ClH:34]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[S:12]([Cl:34])(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Br
Reactant: Cl
Agent: CC(=O)c1ccc(Br)c(N)c1
Agent: O=N[O-]
Agent: O=S=O
Solvent: O
Product: CC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1

Procedure:
(Preparation of 2,4'-dibromo-3'-sulfamoylacetophenone: 5.35 g of 3'-amino-4'-bromoacetophenone, melting point: 113° C, were diazotized in 50 ml of semi-concentrated hydrochloric acid with 1.75 g of sodium nitrite at 0° - 5° C and then decomposed according to Meerwein with 62 ml of sulfur-dioxide-saturated glacial acetic acid solution and 2 g of copper-II-chloride-dihydrate. After the addition of 62 ml of water, the 4'-bromo-3'-chlorosulfonylacetophenone was obtained which melted at 107° C and could be introduced without further purification into about 50 ml of liquid ammonia. After evaporation of the ammonia and treatment with water, 4'-bromo-3'-sulfamoylacetophenone were obtained which melted at 161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16].[Li]CCCC.CN([CH:25]=[O:26])C>C1COCC1>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[C:4]([O:15][CH3:16])[C:5]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: COc1cc(OC)c2ccccc2c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)c(OC)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
According to the procedure by Syper et al.,38 100 (1.07 g, 4.90 mmol) was dissolved in THF (20.0 mL) at 0° C. under Argon, and then nBuLi (1.6 M in hexanes, 4.0 mL, 10.0 mmol) was added at 0° C. The reaction was stirred at 0° C. for 5 hours before DMF (0.850 mL, 11.0 mmol) was added at 0° C. The reaction was stirred for another 30 minutes at room temperature before quenching with water. The reaction was diluted with ethyl ether and washed with saturated brine. The organic layer was dried over MgSO4, filtered, and condensed. Crude product was used as a 5:1 mixture of product:starting material, affording 54 (1.07 g, 4.35 mmol, 89%) as a yellow oil. Following purification via column chromatography (CH2Cl2 to 1:9 EtOAc:CH2Cl2) pure aldehyde 54 was obtained as a yellow solid.
Reaction SMILES: C(=O)([O-])OC(C)(C)C[N:5](C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[ClH:26].[O:27]1CCOCC1>>[ClH:26].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][OH:27])=[CH:8][CH:9]=1
Reactant: COc1ccc(CN(CC(C)(C)OC(=O)[O-])C(=O)OC(C)(C)C)cc1
Reactant: C1COCCO1
Agent: Cl
Product: COc1ccc(CNO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[tert-Butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]tert-butyl carbonate (1.125 Kg, 3.1 mol) is dissolved in 1,4-dioxane (2.8 L) and a hydrogen chloride solution (4 M in dioxane, 3.15 L, 12.4 mol) is added drop wise over 1 hour 30 minutes. The solution is stirred at room temperature overnight. The title product is collected by filtration as white solid (488.0 g, 81%). 1H NMR (d6-DMSO) δ 11.71 (s, 2H), 10.94 (s, 1H), 7.44 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.22 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19]Br)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)c(CN2CCCCC2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
4',5,7-Trihydroxy-2-bromomethylisoflavone (160 mg) was dissolved in 2 ml, N,N-dimethylformamide, 100 mg piperidine was added to the solution, and the mixture was stirred at room temperature for three hours. The solvent was distilled off under reduced pressure, the residue was purified by silca gel column chromatography (chlorofrom: methanol=96:4), and the solid thus obtained was recrystallized from ethanol, giving 150 mg of 4',5,7-trihydroxy-2-piperidinomethylisoflavone.
Reaction SMILES: [CH:1](O)=O.[N:4]1[C:11]([NH2:12])=[N:10][C:8]([NH2:9])=[N:7][C:5]=1[NH2:6]>O.[NH4+].[O-][Mo]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>[CH4:1].[C:5]1([NH2:6])[N:7]=[C:8]([NH2:9])[N:10]=[C:11]([NH2:12])[N:4]=1.[C:5]1([NH2:6])[N:7]=[C:8]([NH2:9])[N:10]=[C:11]([NH2:12])[N:4]=1
Reactant: O=CO
Agent: O=[Mo](=O)([O-])[O-]
Agent: Nc1nc(N)nc(N)n1
Agent: [NH4+]
Solvent: O
Product: C

Procedure:
Melamine molybdate was prepared in the presence of formic acid as follows. 10 grams of melamine, 7.30 grams of formic acid, and 250 ml water were dissolved together by refluxing in a 500 ml. round-bottomed flask equipped with a stirrer and water-cooled condenser. 26.95 grams of ammonium dimolybdate was dissolved in 50 ml hot water and then added to the first solution. A white precipitate formed immediately.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]6[CH2:34]CC[CH:30]6[CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:37])[C:8]2=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].IC.CC(C)=[O:45].C(OCC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:37][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[C:30](=[O:45])[CH2:29]3)=[O:27])=[CH:22][CH:21]=2)[CH:17]=[C:18]([Cl:19])[C:13]=1[CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:38]
Reactant: CC(C)=O
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN2CCCC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: CN1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
Treat a solution of racemic 1-cyclohexyl-3-[3,5-dichloro-4′-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-on (0.245 g, 0.46 mmol) in dimethylformamide (6 mL) with 60% sodium hydride (0.037 g, 0.93 mmol) and stir for 15 minutes at room temperature under a nitrogen atmosphere. Cool the reaction to 0° C., treat with iodomethane (0.25 g, 1.76 mmol) and then stir at room temperature for 16 hours under a nitrogen atmosphere. Quench the reaction with 1N hydrochloric acid, dilute with ethyl acetate and wash with water. Dry the organic layer with sodium sulfate and purify by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford product. Re-crystallize from acetone/diethyl ether to afford 81 mg (32%) of the title compound: MS (m/z) 542 (M+).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].[C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH:23](Cl)[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:13]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH:23]([O:22][C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C:12]#[N:13])[CH2:15][CH2:16]2)=[O:21])[CH3:24])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(Cl)OC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CC(OC(=O)[C@H]1CC[C@H](C#N)CC1)OC(=O)[C@H]1CC[C@H](C#N)CC1

Procedure:
Trans-4-cyanocyclohexanecarboxylic acid (11.5 g; 0.075 mol) and tetrabutylammonium hydrogen sulfate (25.5 g; 0.075 mol) was dissolved in 2M sodium hydroxide and extracted with ethanolfree chloroform. The chloroform solution was dried and the solvent evaporated. The residue was dissolved in trichloroethylene (600 ml) and 1-(trans-4-cyanocyclohexanoyloxy)ethyl chloride (10.8 g; 0.05 mol) was added. The solution was refluxed for 8 h. It was then washed, dried and evaporated. Yield 17.1 g, m.p. 75°-76° C.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]([F:63])([F:62])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:42][CH2:43][NH:44][CH:45]3[CH2:54][CH2:53][CH2:52][C:51]4[N:50]=[C:49]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:48]=[CH:47][C:46]3=4)=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]([CH2:3][CH2:2][N:44]([CH2:43][CH2:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:63])([F:20])[F:62])=[CH:23][CH:24]=3)=[CH:61][CH:60]=2)[CH:45]2[CH2:54][CH2:53][CH2:52][C:51]3[N:50]=[C:49]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:48]=[CH:47][C:46]2=3)=[CH:5][CH:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
300 mg (1.04 mmol) of methyl 4-(2-iodoethyl)benzoate and 55 mg (0.52 mmol) of anhydrous sodium carbonate were added to a solution of 208 mg (0.35 mmol) of ethyl 5-[(2-{2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 155A) in 3 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 102 mg (0.13 mmol, 39% of theory) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:25][C:26](=[O:36])[NH:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:25][C:26](=[O:36])[NH:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:45])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)NOCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-])NOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a stirring solution of (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (140 mg, 0.28 mmol) in dichloromethane (DCM) (5 mL) under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (147 mg, 0.85 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. aq. NaHCO3 and then extracted with DCM. The organics were dried over Na2SO4, filtered, and concentrated to provide the crude product which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (90 mg, 0.18 mmol, 62% yield) as a white solid. MS: 512 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O-:29])=[O:28])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS, 2RS, 3SR)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (43 mg, 0.10 mmol) in EtOH (1 ml) was added 6M KOH (0.10 mL, 0.60 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from Et2O/hexanes. The title compound was obtained as a solid; m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([OH:25])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:26]1([CH:36]([NH2:38])[CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:38][CH:36]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][N:27]=3)[CH3:37])=[O:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(N)c1nccc2ccccc12
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Product: CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1nccc2ccccc12
Yield: 70 %

Procedure:
The title compound is prepared analogously to Example 264 from the carboxylic acid from Example 156A (40 mg, 0.11 mmol) and 26.7 mg (0.16 mmol) of 1-isoquinolin-1-ylethylamine [preparation: see Chem. Ber. 108, 3771-3778 (1975)]. Yield: 70% of theory
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(F)cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(F)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)(4-fluoro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si](C)(C)[C:21]#[C:22][CH2:23][CH2:24][N:25]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[N:26]1.C[Si](C)(C)C#CCCN1C2C(=CC=CC=2)C=N1.C(N1C2C(=CC=CC=2)C=N1)CC#C>C1COCC1.O>[CH2:24]([N:25]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)=[N:26]1)[CH2:23][C:22]#[CH:21]
Reactant: C[Si](C)(C)C#CCCn1cc2ccccc2n1
Agent: C#CCCn1ncc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CCCn1ncc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C#CCCn1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
TBAF (1.24 mL, 1.24 mmol) was added to a solution of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole (250 mg, 1.03 mmol) in THF (5 mL) and the reaction mixture was stirred for 2 hours at room temperature. After the addition of water, the solvent was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by bulb-to-bulb distillation (0.2 mbar, 100-120° C.) to yield 160 mg (0.94 mmol, 91%) of 2-(but-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole.
Reaction SMILES: COC1C=C(F)C=CC=1C(Cl)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([OH:48])=[C:18]([C:20]2[NH:29][CH:28]([NH:30][C@@H:31]3[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][C@H:32]3[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:19]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([OH:48])=[C:18]([C:20]2[N:29]=[C:28]([NH:30][C@@H:31]3[CH2:35][NH:34][CH2:33][C@H:32]3[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:19]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC1NC(c2cc(F)ccc2O)=Nc2ccccc21
Agent: COc1cc(F)ccc1C(=O)Cl
Product: CCOC(=O)[C@@H]1CNC[C@H]1Nc1nc(-c2cc(F)ccc2O)nc2ccccc12

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 1-A, 1-B, 1-D and 2, replacing 2-methoxybenzoyl chloride with 2-methoxy-4-fluorobenzoyl chloride in Synthesis 1A, and replacing (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester with trans-1-tert-butyl 3-ethyl 4-(2-(5-fluoro-2-hydroxyphenyl)-3,4-dihydroquinazolin-4-ylamino)pyrrolidine-1,3-dicarboxylate in Synthesis 2-A.