Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]2[CH2:33][O:32]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1>C(O)(C)C.CCO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]([OH:32])[CH2:33][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1OCC1CO1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Solvent: CCO
Solvent: CC(C)O
Product: CC(=O)Nc1cc(Cl)ccc1OCC(O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Yield: 100.6 %

Procedure:
A solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (480 mg, 2.0 mmol) and N-(5-chloro-2-oxiranylmethoxy-phenyl)-acetamide (490 mg, 2.0 mmol) in isopropanol (i-PrOH) (10 mL) and EtOH (10 mL) were stirred at 80° C. for 17 h, after which the solvent was removed in vacuo. The residue was purified using gradient flash chromatography (CH2Cl2 to MeOH), yielding the desired product as a white solid (960 mg, 99%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([C:13]([N:19]=[N+:20]=[N-:21])=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
oxalyl chloride (460 mg, 3.62 mmol) followed by N,N-dimethylformide (0.05 mL) was added to a solution of 5-chloro-4-nitrothiophene-2-carboxylic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 4 hours. TLC analysis showed no acid remaining so the mixture was allowed to be concentrated in vacuo. The resulting acid chloride was dissolved in dry tetrahydrofuran (10 mL). Sodium azide (190 mg, 2.89 mmol) was added to the above solution. The resulting mixture was stirred at ambient temperature for 10 hours. After this time, TLC analysis showed no acid chloride remaining so the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford the title product as a brown solid (400 mg, 59% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.23 (2H, s).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([NH:23][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (50 mmol), Et3N (100 mmol) and DMF (80 mL) was added dropwise a solution of n-butylamine (51 mmol) in DMF (20 mL) at rt, and the mixture was stirred at rt for 5 h. The reaction was quenched by cold H2O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Cl.[N:24]1([C:29](N)=[NH:30])C=CC=N1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:29]([NH2:30])=[NH:24])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol) was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO3 solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H2O (50 ml). The filter cake was then washed with minimum quantities of cold H2O and ether to give 12.32 g white crystalline solid intermediate 1 (77% yield, M+1: 208 on MS).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:18])(=O)=[O:16])=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:2][CH:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:22])(=[O:18])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(S(=O)(=O)Cl)cc1

Procedure:
A mixture of sodium 4-(2-cyclopentylethoxy)-benzenesulfonate (2.5 grams, 8.6 mmole), thionyl chloride (15 mL), and a few drops of N,N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as an oil, 2.24 grams (90%).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5].[F:19][C:20]([F:31])([F:30])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[OH:22]>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[N:12]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]([OH:22])[C:20]([F:30])([F:31])[F:19])=[CH:24][CH:25]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Reactant: CC(C)(C)CC(=O)N1CCC2(CCNC2=O)CC1
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(3,3-dimethyl-butyryl)-2,8-diaza-spiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. Light yellow crystalline solid. MS (ESI): 427.3 MH+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NCCCCSc1ccccc1)P(=O)(O)O
Yield: 58.6 %

Procedure:
Tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (11.1 g) was dissolved in concentrated hydrochloric acid (!50 ml) and the mixture was refluxed For 2.5 hours. After the reaction mixture was concentrated under reduced pressure, water was poured and separated crystals were collected by filtration to obtain 4-(phenylthio)butylaminomethylenebisphosphonic acid (4.94 g) as a white powder. Sodium methylate (28% methanol solution, 13.3 g) was added to the suspension of this powder (4.08 g) in methanol (50 ml), and the resultant was stirred at room temperature for one hour and then concentrated under reduced pressure. Methanol was added to the residue, the separated white crystals were collected by filtration and recrystallized from water-methanol to obtain tetrasodium 4-(phenylthio)butylaminomethylenebisphosphonate as a white powder (3.90 g, 43% ).
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:14][C:12]([C:9]1[NH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:2]2)=[N:11][N:10]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1nnc(N2CCNCC2)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 5-(piperazin-1-yl)-4H-1,2,4-triazole-3-carboxylate (1.0 g, 4.44 mmols) in DCM (10 mL) was added (BOC)2O (0.970 g, 4.44 mmol), DMAP (0.050 g, 0.41 mmol), DIEA (3.9 mL, 22.4 mmol). The reaction was stirred at RT overnight. Reaction concentrated and ISCO purification (0-5% MeOH in DCM) to obtain tert-butyl 4-(5-(methoxycarbonyl)-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (0.580 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)CCN
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Product: CN(C)CCNc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
7-Chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (1 g) and N,N-dimethylethylenediamine (30 ml) were heated in a sealed tube at 180° C. for 10 days. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated potassium carbonate solution. The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was dissolved in HCl, washed with diethyl ether (2×), then basified with sodium hydroxide, extracted into ethyl acetate, dried (MgSO4), and concentrated in vacuo, to give 0.248 g of the title compound; mp 230° C. (ethyl acetate); Found: C, 63.76; H, 5.64; N, 11.75.C19H2O ClN3O.0.9H2O requires C, 63.37; H, 6.14; N, 11.76%. δ (360 MHz, DMSO-d6) 1.94 (6H, s, (CH3)2N), 2.17 (2H, m, NCH2CH2N), 2.69 (2H, m, NCH2CH2N), 5.82 (1H, br s, NH), 7.17-7.95 (8H, m, aromatics), 11.23 (1H, br s, NH); m/z (CI+) 341 (M+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([OH:17])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Br[CH2:19][C:20]([NH2:22])=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:4]1[N:5]([O:17][CH2:19][C:20]([NH2:22])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1O
Reactant: NC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1nc2cnc3ccccc3c2n1OCC(N)=O
Yield: 83.9 %

Procedure:
A solution of 2-propyl-1H-imidazo[4,5-c]quinolin-1-ol (2.0 g, 8.8 mmol), bromoacetamide (1.9 g, 14 mmol), and triethylamine (2.8 mL, 0.020 mol) in THF (100 mL) was heated at reflux overnight. The solvent was removed under reduced pressure, and dichloromethane (75 mL) and saturated aqueous sodium bicarbonate (25 mL) were added to the residue. The resulting mixture was filtered to provide 2.1 g of 2-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]acetamide as a solid. The organic layer was separated, and methanol was added until all solids were dissolved. The solution was then dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide an additional 0.13 g of material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[N:11]1([C:17]([S:19][CH3:20])=[S:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:14]1[CH2:15][CH2:16][N:11]([C:17]([S:19][CH3:20])=[S:18])[CH2:12][CH2:13]1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN2CCN(C(=S)SC)CC2)c1
Yield: 82.8 %

Procedure:
In a nitrogen atmosphere, 1.57 g (10.0 mmol.) of 3-methoxybenzyl chloride, 2.00 g (10.0 mmol., purity 88.1% of methyl 1-piperazinecarbodithioate, 1.06 g (10.0 mmol.) of anhydrous sodium carbonate and 20 ml of ethanol. The mixtrue was refluxed under heating for 5 hours. The solvent was distilled off under reduced pressure. The residue was mixed with 15 ml of dichloromethane and 10 ml of water. The mixture was allowed to give separated layers. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was purified over a silica gel column to give 2.46 g of methyl 4-(3-methoxybenzyl)-1-piperazinecarbodithioate as a colorless crystalline product, yield 82.8%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH2:3]1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[CH:29]=[N:28]1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([NH:16][C:9]2[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:36]([C:32]4[CH:31]=[C:30]5[C:35](=[CH:34][CH:33]=4)[NH:27][N:28]=[CH:29]5)=[O:37])[CH2:3]3)[N:8]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5[nH]ncc5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
To a solution of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.27 mmol) and 1H-indazole-5-carboxylic acid (44 mg, 0.27 mmol) in dichloromethane (20 mL) were added the solution of 1-methyl-1H-imidazole (88 mg, 1.1 mmol) and EDCI (206 mg, 1.1 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid formed during the reaction was collected by filtration and washed with MeOH to afford N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-5-carboxamide (78 mg, 56.1%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 13.25 (s, 1H), 9.58 (s, 1H), 8.81 (s, 1H), 8.61 (d, 1H, J=6.3 Hz), 8.36 (s, 1H), 8.19 (s, 1H), 7.88-7.86 (m, 2H), 7.56 (d, 1H, J=8.7 Hz), 7.50 (s, 1H), 6.91 (d, 1H, J=8.4 Hz), 4.61-4.59 (m, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.62 (brs, 3H), 2.28-2.09 (m, 2H). LC-MS: 517 [M+H]+, tR=1.34 min. HPLC: 95.89% at 214 nm, 97.39% at 254 nm, tR=4.52 min
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(O[C:13]([N:15]([CH2:17][C@@:18]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:24][C@H:23]2[C@@H:19]1[CH:20]=[C:21]([CH2:25][CH3:26])[CH2:22]2)C)=O)(C)(C)C>>[ClH:1].[CH2:25]([C:21]1[CH2:22][C@@H:23]2[C@H:19]([CH:20]=1)[C@@:18]([CH2:27][C:28]([OH:30])=[O:29])([CH2:17][NH:15][CH3:13])[CH2:24]2)[CH3:26]
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate (13 mL) was added to [(1S,5R,6R)-6-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (0.90 g, 2.78 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from hexane-isopropanol to obtain the compound of interest as a white solid (0.34 g, 47%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19]Br>C(O)=O.CCOC(C)=O.[Fe]>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OCC2CCCCC2)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COC(=O)c1ccc(OCC2CCCCC2)c(Br)c1
Reaction time: 1 h

Procedure:
A solution of 23-2 (26.3 g, 106 mmol) was warmed on a steam bath in 110 mL of HCOOH with 592 mg (10.6 mmol) of Fe powder. Bromine (7.6 mL, 147.4 mmol) in 50 mL of HCOOH was added by dropping funnel over a period of 10 min. The reaction mixture was stirred an additional 1 h , cooled and poured onto ice. The resulting gum was taken up in 500 mL of EtOAc and washed with sat'd Na2S2O3 (2×150 mL), water (5×100 mL), sat'd NaHCO3 (3×100 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 23-3 as a white solid.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][N:23]=1)=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:17]=4[CH3:16])=[N:23][CH:24]=3)=[O:29])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)cn1

Procedure:
As described for Example 46, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (1 mmol) with 2-[(2-methyl-5-fluorobenzoyl)amino]-5-pyridinylcarbonyl chloride (1.0 mmol) in dichloromethane in the presence of N,N-diisopropylethylamine (3 mmol) gives the product as a glass.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]#[N:26].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([F:16])([F:27])[F:28])[C:25]#[N:26]
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1C(F)(F)F)c1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 1.0 g, 4.01 mmol) in tetrahydrofuran (16.7 mL, 0.24M) was treated with (2-trifluoromethyl-phenyl)-acetonitrile (743 mg, 4.01 mmol) followed by potassium tert-butoxide (676 mg, 6.02 mmol). The reaction was heated at 80° C. for 2 h. After this time, the reaction was cooled to 25° C. where it stirred overnight. The reaction mixture was then partitioned between water (100 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 20-40% ethyl acetate/hexanes) afforded [5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yl]-(2-trifluoromethyl-phenyl)-acetonitrile (0.73 g, 45%) as a yellow solid; ES+-HRMS m/e calcd for C18H15N3O2F3Cl [M+H+] 398.0878, found 398.0878.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[CH:10][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(COC(C)=O)c(COC(C)=O)c1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(COC(C)=O)c(COC(C)=O)c3)cc3ccccc23)CC1
Yield: 94.4 %

Procedure:
3,4-Bis(acetoxymethyl)tributylstannylbenzene (1.91 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.00 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.14 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.36 g) of 1-(4-ethylpiperazin-1-yl)-3-[3,4-bis(acetoxymethyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Br:16][CH:3]([C:2](=[O:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCC(=O)c1ccccc1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CCC(Br)C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of methyl 5-oxo-5-phenylpentanoate (16.1 g) in diethyl ether (100 ml) was added bromine (4.01 ml) at room temperature over 30 min. and the mixture was stirred for 30 min. An aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine, dried (MgSO4) and concentrated to give methyl 4-bromo-5-oxo-5-phenylpentanoate (22.1 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH3:15]>C(OCC)(=O)C.CCCCCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH:16]([N:14]([CH3:15])[CH3:13])[CH2:17][CH2:18][NH2:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN(C)CCCN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)C(CCN)c1ccnc2cc(Cl)ccc12

Procedure:
From 4,7-dichloroquinoline and 3-(N,N-dimethylamino)-propylamine; colourless crystals from ethyl acetate-hexane, m.p.: 111°-113° C.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1
Reactant: N#Cc1n[nH]c2c1CCC2
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.320 g (77.50 mmol) of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile were dissolved in 100 ml of DMF, 30.304 g (93.01 mmol) of caesium carbonate and 16.116 g (85.26 mmol) of 2-fluorobenzyl bromide were added, and the mixture was stirred at RT overnight. The mixture was concentrated and taken up in dichloromethane, and water was added. The organic phase was removed and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, filtered through a silicone filter and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate, gradient). 11.37 g (60% of theory) of the target compound were obtained.