Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:19]1[CH:23]=[N:22][N:21]=[N:20]1
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Cn1c(Cn2cnnn2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 45 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.33 mmol) and 1H-tetrazole (0.65 mmol) are dissolved in DMF (3 ml). To the solution, K2CO3 (0.98 mmol) is added and the mixture is stirred at room temperature under nitrogen atmosphere for 23 h. The reaction mixture is diluted with water and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give A in 45% yield and B in 48% yield in the order of elution.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][C@H:7]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:8]([C:15](=[O:25])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[C@H:9]2[CH3:14])(=[O:3])[CH3:2].[CH3:35][Mg]Cl>C1COCC1>[Si:28]([O:27][CH2:26][C@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[C:1]([OH:3])([CH3:35])[CH3:2])[C@H:9]([CH3:14])[N:8]1[C:15](=[O:25])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:30])[CH3:29]
Reactant: CC(=O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(C(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Dissolve 1-((1S,3R)-5-acetyl-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (68 mg, 130 μmol) in THF (1.3 mL). Cool to 0° C., add MeMgCl (87 μL, 261 μmol, 3M in Et2O). Stir 30 min at 0° C. and 30 min at room temperature. Add MeMgCl (87 μL, 261 μmol, 3M in Et2O) at rt. Stir 60 min. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound as a white foam (0.054 g, 100 μmol). MS (m/z): 536.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=1)[CH2:8]2.Br[CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:24]3)[N:14]=1)[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCN(CCO)CC2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
After N-(adamantan-2-yl)-6-(piperazin-1-yl)picolinamide (34 mg, 0.100 mmol) was dissolved in DMF (2 ml), 2-bromoethanol (19 mg, 0.150 mmol) and potassium carbonate (41 mg, 0.300 mmol) were added thereto, and then the resulting mixture was stirred at 100° C. under nitrogen stream for 18 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 37 mg of colorless oil (96%). MS (ESI): 385 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][N:7]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:36][CH:37]=3)[C:11]=2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1
Reactant: O=Cc1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(N)c2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(NCc3ccc(OCCCCc4ccccc4)cc3)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 8-amino-4-(4-methoxy-4-oxobutyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (80 mg; prepared by subjecting the compound prepared in Example 3 to the same procedure as described in Example 29) and 4-(4-phenylbutoxy)benzaldehyde (60 mg) were dissolved in 1,2-dichloroethane (4 mL), and to this solution was added sodium triacetoxyborohydride (96 mg) with ice cooling, and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=8:2) to give the title compound (121 mg) having the following physical data.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[CH2:4][O:5][C@H:6]([CH2:8][CH:9]=[CH2:10])[CH3:7].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[CH3:7][C@@H:6]1[O:5][CH2:4][C:3]2=[N:2][O:1][CH2:10][C@@H:9]2[CH2:8]1
Reactant: C=CC[C@H](C)OC/C=N/O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@H]2CON=C2CO1

Procedure:
To a solution of C5 (8.6 g, 0.06 mol) and triethylamine (0.455 g, 4.50 mmol) in dichloromethane (150 mL) at room temperature was slowly added a 6% aqueous solution of sodium hypochlorite (90 mL) while maintaining the internal temperature between 20° C. and 25° C. After the addition, the organic phase was separated, dried and concentrated in vacuo Silica gel chromatography (petroleum ether/ethyl acetate=10:1) provided the product as a yellow oil. Yield: 5.70 g, 40.4 mmol, 67%. LCMS m/z 142.1 [M+H+], 1H NMR (400 MHz, CDCl3), δ 4.68 (d, J=13.2 Hz, 1H), 4.59 (dd, J=10, 8 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.76 (dd, J=12, 8 Hz, 1H), 3.59-3.66 (m, 1H), 3.39-3.50 (m, 1H), 2.14-2.19 (m, 1H). 1.42-1.51 (m, 1H), 1.25 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: O=C(CCI)CCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
To a solution of 36 g (0.17 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 300 mL of dry tetrahydrofuran was added 71 g (0.17 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 55.3 g (0.19 mole) of 1-iodo-5-phenyl-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 30 min, at 50° C. for 3 hr., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh Mg SO4, and concentrated at reduced pressure to give 71.5 g of crude oil. This crude material was passed through HPLC to give 46.4 g. of purified material.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CO)nc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(C=O)cc2)nc2cccnc21
Yield: 45.2 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 500 mg of 3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 374 mg of 4-hydroxybenzaldehyde, 0.76 ml of tributylphosphine, 773 mg of 1,1'-(azodicarbonyl)dipiperidine and 12 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.37 g of the title compound, melting at 124-125° C.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].CCCCCC>C(O)(=O)C>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc2c1OCC2(C)C
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Temperature: 24 °C
Reaction time: 4 h

Procedure:
A solution of 7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan (10.0 g, 49.0 mmol) in glacial acetic acid 80 mL) is treated with 70% nitric acid (4.0 mL, 63.7 mmol) dropwise, and allowed to stir at 24° C. for 4 h. TLC (hexane) is used to monitor reaction progress. The reaction mixture is partitioned between Et2O (100 mL) and H2O (100 mL). The Et2O layer is washed with H2O (50 mL) and saturated Na2 CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid (9.12 g). Crystallization from hexane provides 7-tert-butyl-3,3-dimethyl-5-nitro-2,3-dihydrobenzo[b]furan as an orange solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCC.C[O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:19]2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[OH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCS
Solvent: ClCCl
Product: Oc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Temperature: 0 °C
Yield: 101.8 %

Procedure:
In 400 ml of dichloromethane was suspended 45.1 g of anhydrous aluminium chloride. While stirring, 45.1 ml of butylmercaptan was added thereto. After the mixture was stirred at room temperature for 1 hour, 34 g of 1-(3-methoxy- phenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine was added under ice-cooling. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into about 2 l of ice-water. The resulting crystals were collected by filtration, and washed with water to give 33.0 g of 1-(3-hydroxy- phenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 142°-144° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: C=CCN
Reactant: Cc1ccc2c(c1)NCC(C(=O)O)O2
Agent: Cl
Solvent: CCO
Product: C=CCNC(=O)C1CNc2cc(C)ccc2O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
42.4 g of 4A and 38 g of 2-propenamine were mixed in 165 ml of ethanol and the mixture was stirred at room temperature for 90 hours. The solvent was removed under reduced pressure. The residue was partitioned between ether and water. The ether solution was dried (MgSO4), about half the solvent was evaporated, and solid which formed was filtered, then dried under reduced pressure to give 4, mp: 113°-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH3:28])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(N(C)C(=O)OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 34.2 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 5.8 g. of sodium hydride (50% dispersion in oil) in 300 ml. of absolute dimethylformamide was stirred at room temperature for 4 hours. The resulting solution was treated with 17 g. of methyl iodide with stirring and ice-cooling. After stirring at room temperature for 1 hour, the dimethylformamide was removed under vacuum at 60° C. Then, 1 liter of water was added to the residue and the emulsion was extracted with two 2 liter portions of ethyl acetate. The organic phases were washed with two 1 liter portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained 2,6-dimethoxy-4-(methoxy-carbonyl)-N-methyl-carbanilic acid benzyl ester having a melting point of 130°-131° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[N+:2]=[N-:3].NN.O>C(O)C>[N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1N
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a suspension of the of 2-(2-azido-phenyl)-isoindole-1,3-dione (373 mg, 1.4 mmol) in ethanol (10 mL) was added hydrazine (140 μL, 4.24 mmol) followed by stirring for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue which was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes to 33% ethyl acetate/hexanes gradient elution) to give 48 mg (25%) of 2-azidophenylamine as a solid: 1H NMR (300 MHz, DMSO-d6) δ 6.98 (m, 1H), 6.86 (m, 1H), 6.66–6.55 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: Fc1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22.0 g of piperazine in 20 ml of o-xylene, a solution of 7.47 g of 1-bromo-4-fluorobenzene in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/1-bromo-4-fluorobenzene=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.25 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate. Gas chromatographic analysis of the obtained product by the internal standard method revealed that the intended arylamine, i.e., N-(4-fluorophenyl)piperazine was obtained in a yield of 95% by mole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCN1CCOCC1
Reaction time: 10 h
Yield: 68.2 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.22 ml (0.01525 mol) of N-(3-aminopropyl)-morpholine were added thereto and the mixture was boiled for 43 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with ethyl acetate/methanol 5:1, dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.58 g (68%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 65°-67° and 0.93 g (18%) of oily material from the mother liquors.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4]C=1C.OS(O)(=O)=O.[OH-].[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:20]=1[C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][OH:22]>>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][O:22][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cccc(F)c1F
Reactant: CN1CCn2c1cc(Cl)nc2=O
Product: CN1CCn2c1cc(OCc1cccc(F)c1F)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([NH:37][NH2:38])=[CH:29][CH:28]=1>>[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)=[CH:29][CH:28]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=464.2 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][N:16]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)c1ccc(NC(=O)C2(O)CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(O)CCN(Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 25.6 mg (0.09 mmol) 4-Hydroxy-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide, 19.9 mg (0.1 mmol) 4-fluorobenzyl bromide and 27 mg (0.27 mmol) NEt3 in 2 ml DCM was stirred for 3 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 5.4 mg (17%) of the title compound as off-white solid. MS (m/e): 371.3 [(M+H)+].
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[NH:6]1[CH:10]=[N:9][C:8]([S:11](F)(=[O:13])=[O:12])=[N:7]1>C(O)(=O)C>[CH2:1]([NH:3][S:11]([C:8]1[N:9]=[CH:10][NH:6][N:7]=1)(=[O:13])=[O:12])[CH3:2]
Reactant: CCN
Reactant: O=S(=O)(F)c1nc[nH]n1
Solvent: CO
Solvent: CC(=O)O
Product: CCNS(=O)(=O)c1nc[nH]n1
Temperature: 0 °C

Procedure:
To a solution of ethylamine in methanol (2 M, 2.4 mmol, 4.8 mmol) was added 1H-1,2,4-triazole-3-sulfonyl fluoride (200 mg, 1.18 mmol, J. Heterocycl. Chem. 1988, 25, 1857). After ten minutes the reaction was concentrated in vacuo to give a yellow oil. Ice-cold water (2-3 mL) was added and the resulting solution was sonicated for approximately one minute. Several drops of acetic acid were added which immediately caused precipitation of the title compound which was obtained as a white solid after filtration (57 mg).
Reaction SMILES: [N:1]([C@@:4]1([OH:19])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].C(OC(=O)C)(=O)C.[Br:27]Br>C(O)(=O)C>[N:1]([C@@:4]1([OH:19])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Br:27])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: [N-]=[N+]=N[C@]1(O)C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@]1(O)C[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3'-Azido-5-bromo-2'-doxyuridine was prepared from the known 3'-azido-2'-deoxyuridine (T. A. Krenitsky, et al., J. Med. Chem., 26, 891, (1983)) (0.827 g, 3.3 mMol) by first acetylating the 5'-hydroxyl with acetic anhydride (15 mL) then by brominating the 5 position by the addition of acetic acid (0.5 mL) and bromine (0.566 g). The red-brown solution was stirred at room temperature for two hours. The reaction was taken to an oil in vacuo and triturated with ethyl ether. The oil was dissolved in methanol ammonia to remove the acetyl group. The desired product was isolated by chromatography on silica gel by elution with CHCl3 :MeOH (95:5 v/v). The yield as 32%.