Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9](=[O:14])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a mixture of 95% dry sodium hydride (834 mg, 33.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at room temperature was added a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (confirmed by LCMS). The reaction mixture was quenched with methanol (40 mL), the mixture concentrated under reduced pressure, then diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), 30% ammonium chloride (100 mL) and brine (100 mL), dried, and concentrated under reduced pressure. Ethyl ether (20 mL) was added, and the mixture sonicated, filtered, washed with ether (20 mL), and dried to afford tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6 mmol, 72%). LCMS mz 285.9 (M−56+H), 363.9 (M+Na), anal HPLC>97% in purity. 1H NMR (400 MHz; CDCl3) δ 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H); 4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9 H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[C:12]([C:19](=O)[CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[ClH:27].[C:22]([NH:25][N:26]=[C:16]([C:14]1[CH:13]=[C:12]([C:19](=[N:26][NH:25][C:22](=[NH:23])[NH2:24])[CH3:20])[CH:11]=[C:10]([CH:15]=1)[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17])(=[NH:24])[NH2:23]
Reactant: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc(NC(=O)c2ccccc2)cc(C(C)=NNC(=N)N)c1
Yield: 97 %

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with I mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetylaniline bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268-72° C.
Reaction SMILES: B.C1COCC1.[CH3:7][NH:8][S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C1COCC1.Cl>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH3:7])(=[O:11])=[O:10])=[CH:20][CH:19]=1
Reactant: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CO)cc1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
At 0° C., borane-THF complex (66.8 mL, 1 M in THF) is carefully added to a solution of 4-methylsulfamoyl-benzoic acid (3.56 g, 16.5 mmol) in THF (90 mL). The mixture is refluxed for 1.5 h, cooled to rt and diluted with 1 N aq. HCl (175 mL). The mixture is extracted with EA and the organic extract is washed with sat. aq. NaHCO3, dried over MgSO4 and filtered. The filtrate is concentrated and the crude product is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 4-hydroxymethyl-N-methyl-benzenesulfonamide (1.61 g) as a colourless oil; LC-MS: tR=0.56 min, [M+1+CH3CN]+=243.14.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][N:37]4C(=O)[O:41][CH2:42][C@H:36]4[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:5][CH2:4]1.C(O)(=O)C>CO>[CH:3]1([NH:6][C:7](=[O:46])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH:18]=[C:17]4[S:31]([N:34]3[CH2:39][CH2:38][NH:37][C@@H:36]([CH2:42][OH:41])[CH2:35]3)(=[O:33])=[O:32])[C:11]([CH3:44])=[C:10]([F:45])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN4C(=O)OC[C@H]4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCN[C@@H](CO)C3)c2c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 21.2 %

Procedure:
2 N aqueous NaOH solution (2 mL) was added to a solution of N-cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-{[(8aR)-3-oxotetrahydro[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl]sulfonyl}-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide (Example 49d, 0.291 g) in methanol (2 mL) and the mixture stirred at 90° C. for 45 min. The reaction was neutralised with acetic acid and the volatiles removed under reduced pressure before partitioning between water and DCM. The organic layer was separated and the aqueous extracted further (2×) and the combined organics dried (MgSO4), filtered and evaporated. The residue was purified by SCX (eluting with methanol to remove impurities, then flushing with methanolic ammonia to elute product). Further purification by preparative HPLC (Xbridge column using a 95-5% gradient of 0.3% aqueous ammonia in acetonitrile), solvent evaporation under reduced pressure and trituration with diethyl ether gave the title compound (0.059 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[C:8]1([C@@H:14]([CH2:16][OH:17])[NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:18][CH2:19][O:20]C(C)=O.CC(O)=O>C1COCC1>[C:19]([O:17][CH2:16][C@@H:14]([N:15]1[C:1](=[O:7])[CH:2]=[CH:3][C:4]1=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:20])[CH3:18]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H](c1ccccc1)N1C(=O)C=CC1=O

Procedure:
Maleic anhydride (358 mg, 3.65 mM) was added to (S)-(+)-2-phenylglycinol (500 mg, 3.65 mM) dissolved in 5 ml THF stirred under Ar. A precipitate formed immediately but redissolved after 1 hr. The mixture was stirred overnight. TLC (silica gel, EtOAc/HOAc 95:5) showed two spots, the product Rf 0.34, and a lower Rf spot, Rf 0.09. The THF was evaporated, and the residue was dissolved in 6 ml hot CH2Cl2. Crystals formed almost immediately in the hot mixture which was let stand at 5° for 2 hrs. The crystals were filtered, washed with cold CH2Cl2, and dried under vacuum to give the title compound: 600 mg (70%), mp. 131°-2°. ##STR48##
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cc2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (6-(4-fluoro-benzyloxy)-pyridin-3-yl)acetohydroximoyl chloride (133 mg, 0.450 mmol) described in Manufacturing Example 58-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol), which was stirred for 3 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1) to obtain the title compound (67.4 mg, 76.5%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].C1(C)C=CC=CC=1.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18].C(N(CC)CC)C>O>[C:4]([O:6][CH2:21][C:20](=[O:23])[N:19]([CH2:24][CH3:25])[CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CCN(CC)C(=O)CCl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(=O)/C=C/C(=O)OC
Temperature: 15 °C

Procedure:
At a temperature of about 50-70° C., under a nitrogen atmosphere, a slurry of mono-methyl fumarate (130 g), toluene (800 mL) and N,N-diethylchloroacetamide (157 g) is added to triethylamine (1.07 g). The temperature is adjusted to 85-95° C. and maintained there for 4 hours. Then the temperature is then adjusted to 15-25° C. and the mixture is subjected to vigorous agitation. After 30 minutes of vigorous agitation in 200 mL of water, the agitation is stopped and the phases are allowed to separate for 30 minutes. The upper organic phase is washed with additional deionized water (75 mL) with vigorous agitation for 30 minutes. The agitation is then stopped and the phases are allowed to separate for 30 minutes. The organic layer is dried over anhydrous sodium sulfate (25 g) for 2 hours. The reaction is filtered and the solution is cooled to 10-20° C. Heptane (1600 mL), at −5 to −20° C. is added over 5 minutes. The reaction is cooled to −5° C. to −10° C. for 24 to 48 hours. The resulting product is air dried for 12 hours. XRPD analysis confirms product is form 4.
Reaction SMILES: [N:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=O)[N:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.Cl.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:11]([C:8]2[N:7]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[NH:10][N:9]=2)=[O:13])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]c(-n2cccc2)n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2n[nH]c(-n3cccc3)n2)CC1
Reaction time: 16 h

Procedure:
To 100 mg 5-Pyrrol-1-yl-1H-[1,2,4]triazole-3-carboxylic acid in 1 ml DMF and 0.3 ml NEt3, 121 mg 1-Isopropyl-piperidin-4-ylamine dihydrochloride and 142 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After addition of 5 ml of water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The obtained crude product was used without further purification in the next reaction step. Yield: 170 mg.
Reaction SMILES: [Br-].[C:2]([CH2:5][NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(O)=O.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=C.C(N(CC)CC)C>C1(C)C=CC=CC=1.O=[Mn]=O>[C:13]1([C:12]([O:16][CH3:17])=[O:15])[CH:2]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)C[NH+]1C=CC=CC1
Reactant: C=CC(=O)OC
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2ccccc12
Temperature: 90 °C

Procedure:
To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmol) in 240 mL of toluene there are added in succession 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine (30 mmol) and then, in portions, 20.9 g of MnO2 (240 mmol). The whole is subsequently heated at 90° C. for 3 hours. After cooling, the reaction mixture is filtered over a Celite cake and concentrated to dryness. The title product is then isolated by purification on silica gel (heptane/AcOEt gradient: 0-10%) in the form of an oil, which crystallises when cold.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])=[O:21].O1CCOCC1>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:31][C:32]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)=[O:33])(=[O:29])=[O:30])=[O:21]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(CSc2ccccn2)nc(N)n1
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSc2ccccn2)cc(OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidine and 6.8 g of 2-methoxycarbonylphenylsulfonylisocyanate are stirred in 50 ml of abs. acetonitrile for 2 hours at 20°-25° C. The turbid solution is filtered, and the solvent evaporated off in vacuo. The residue is crystallised from dioxane to thus obtain 5.5 g (37% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidin-2yl]-urea, which crystallises with 0.5 mol of dioxane, m.p. 175°-181° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Product: COc1ccc(N2CCN(C(=O)Cc3ccccn3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using pyridin-2-yl-acetic acid and (S)3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 2.56 min, [M+1]+ 468. Potency class ND.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]([C:10]2[NH:9][CH:13]=[CH:12][CH:11]=2)[C:13]2[NH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc[nH]c1
Product: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1

Procedure:
Conclusion. The one-flask solventless reaction of an aldehyde with excess pyrrole provides a simple means of preparing the corresponding dipyrromethane. A wide variety of Brønsted or Lewis acids can be employed as catalyst. The Brønsted acids that afford product also give a dark reaction mixture, while the Lewis acids give less discoloration. Excellent results were obtained with InCl3 (for benzaldehyde and other aryl aldehydes) and MgBr2 (for mesitaldehyde). The workup procedure entails quenching with NaOH, filtration, removal of pyrrole, and crystallization. The simplicity of this procedure (no aqueous/organic extraction, distillation, or chromatography) minimizes waste and enables scalability. The absence of any reaction solvent other than pyrrole enables facile recovery of the excess pyrrole from the crude reaction mixture; the recovered pyrrole can be reused. Indeed, the reaction of 0.75 mmol of benzaldehyde in 5.2 L of pyrrole gave 116 g of 5-phenyldipyrromethane and recovery of 90% of the excess pyrrole in a form suitable for reuse. Characterization of the purity of dipyrromethanes is best accomplished using a combination of analytical techniques, including gas chromatography. Given that the N-confused dipyrromethane(s) and the tripyrrane(s) are dominant byproducts of the reaction, and the former is an isomer while the latter is an oligomer of the dipyrromethane, a satisfactory elemental analysis is a necessary but insufficient criterion of purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH2:12][CH3:13].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1)[CH2:12][CH3:13]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(F)cc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(F)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 from 7-chloro-3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C(=O)C>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (25.4 g) in N,N-dimethylacetamide (420 mL) were added potassium carbonate (23.1 g) and benzyl bromide (19.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 90 minutes. An insoluble was filtered, and then diluted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=20/1), and then triturated with ethyl acetate to give 1-[4-(benzyloxy)-3-hydroxyphenyl]ethanone [REx(26-1)] (11.0 g) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18](=[O:20])[CH2:17][C:16]3=[O:21])[C:7]=2[CH:22]=1)#[N:2].[BH4-].[Na+].O>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH:18]([OH:20])[CH2:17][C:16]3=[O:21])[C:7]=2[CH:22]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(=O)CC2=O)[C@@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(O)CC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,4-dioxo-1-pyrrolidinyl)-2H-1-benzopyran -3-ol (0. g) in dry DMSO under N2, was added NaBH4 (0.11 g). The reaction was stirred for 3 h at room temperature. Water (100 mL) was added add the aqueous phase extracted with EtOAc. The organic layer was washed with H2O add brine, dried over MgSO4, filtered and evaporated to give the crude product (0.5 g) as an orange solid. This mixture was chromatographed (chromatotron CHCl3 →CHCl3 -10% MeOH gradient elution; 2 mm silica gel) to give two fractions.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6](Br)=[CH:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C=CCn1cc(Br)c2ncnc(Cl)c21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a chilled (−78° C.) solution of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (570 mg, 2.1 mmol) in 10 mL of THF was added n-BuLi (2.5 M in THF, 1.5 mL, 2.5 mmol) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (708 mg, 2.3 mmol) in 3 mL of THF was added in one portion. After 15 minutes, the mixture was diluted with water and warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (15-60% gradient) to provide 245 mg (23%) of the title compound as a beige solid. MS m/z 502.23 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[B](F)F.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21](F)[C:22]=3[O:24][CH:25]([F:27])[F:26])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:13][CH2:12]1.O>CS(C)=O>[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21]([N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)[C:22]=3[O:24][CH:25]([F:26])[F:27])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:12][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Reactant: CC1CNCCN1
Agent: F[B]F
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1.63 g (0.016 moles) of 2-methylpiperazine was added to a solution of 2.58 g (0.0068 mole) of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate (prepared as described in Preparation 8) in 20 ml of dimethyl sulfoxide, and the mixture was allowed to stand at room temperature overnight, the reaction mixture was then poured into 100 ml of water, and the crystals which precipitated were collected by filtration and washed with water. The crystals were then dissolved in 500 ml of 80% v/v aqueous methanol containing 15 ml of triethylamine, and the solution was heated under reflux for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was washed with ethanol, to give 2.30 g of a pale yellow powder. The whole of this powder was dissolved in 50 ml of water, insoluble materials were removed by filtration, and the filtrate was adjusted to a pH value of 7.5 by the addition of a 1N aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with water and with ethanol, in that order, to give 1.74 g of the title compound as fine pale yellow needles, melting at 223°-225° C.