Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[CH:7](Cl)[C:8]([CH2:10]Cl)=[O:9]>CO.[Zn].[Pd]>[CH:5]12[O:1][CH:2]([CH:3]=[CH:4]1)[CH2:10][C:8](=[O:9])[CH2:7]2.[CH:5]12[O:1][CH:2]([CH2:3][CH2:4]1)[CH2:10][C:8](=[O:9])[CH2:7]2
Reactant: c1ccoc1
Reactant: O=C(CCl)C(Cl)Cl
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: O=C1CC2C=CC(C1)O2
Product: O=C1CC2CCC(C1)O2

Procedure:
8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3]cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999,64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsaturated ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C1COCC1>[C:31]([C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1)#[N:30]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(C#N)ccc12
Temperature: -75 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (54.6 g, 160.5 mmol) in THF (500 mL) at −75° C. was added chlorosulfonyl isocyanate (17.5 mL, 200.6 mmol) in THF (100 mL) dropwise over a 30 minutes period keeping the temperature below −70° C. and the mixture was stirred at −75° C. for 1 hr. To this mixture was added DMF (37.3 mL, 481.5 mmol) dropwise at −75° C. and the mixture was warmed to ambient temperature, stirring for a total of 2 h. The mixture was quenched with 1 L of 1N NaOH and transferred to a separatory funnel with 500 mL of methyl-tert-butyl ether. The aqueous phase was separated and extracted with an additional 500 mL of methyl-tert-butyl ether. The combined organic phases were washed twice with 500 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to yield a crude mixture that was purified by column chromatography with a 0-100% EtOAc/hexane gradient to yield tert-butyl 1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (45 g, 76%) as an oil that crystallized upon standing. ESI-MS m/z calc. 365.2, found 266.2 (M-Boc+1)+. Retention time: 2.43 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 74.8 %

Procedure:
A suspension of 3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.51 g, 13.2 mmol), (S)-(+)-2-methylpyrrolidine (1.35 g, 15.84 mmol), and K2CO3 (4.01 g, 29.04 mmol) in acetonitrile (44 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-Methylpyrrolidine (834 mg, 9.79 mmol), and continued heating for 20 h. Removed from heating and concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). Dried the organics over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.51 g (75% yield) of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH2:16].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:18]1[CH:23]=[CH:22][C:21]([CH2:3][CH2:2][CH3:11])=[CH:20][C:19]=1[C:9](=[O:12])[CH3:8]
Reactant: Clc1ccccc1Cl
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O
Agent: CN(C)c1ccncc1
Product: CCCc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
2-Hydroxy-5-n-propylacetophenone (276 mg), 4-chloro-6,7-dimethoxyquinoline (117 mg), and 4-dimethylaminopyridine (191 mg) were suspended in o-dichlorobenzene (6.5 ml), and the suspension was stirred at 130° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (50 mg, yield 26%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([OH:32])=[CH:9][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:32][CH2:3][C:2]#[CH:1])=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)NS(C)(=O)=O)c12
Reaction time: 8 h
Yield: 24.7 %

Procedure:
Propargyl bromide (1.30 g, 9.19 mmol) was added to a mixture of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (2.5 g, 6.13 mmol) and cesium carbonate (5.00 g, 12.3 mmol) in DMF. The mixture was stirred overnight and then was poured into water (600 mL). The mixture was stirred overnight and a gummy solid was isolated by filtration. The solid was dissolved in dichloromethane and the resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-30% of a 1:5-methanol/dichloromethane solution in dichloromethane) to provide 675 mg of N-{2-[4-amino-2-(ethoxymethyl)-7-(prop-2-ynyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as an off-white solid. A small portion was recrystallized from methanol to yield an off-white solid, mp 175.0-176.0° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][C:13]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][C:22](NCOC)=[O:23])([CH3:15])[CH3:14]>O1CCCC1.CCCCCC>[CH3:15][C:13]([O:16][C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:14]
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCCC(=O)c1nccs1
Temperature: -70 °C
Yield: 33.3 %

Procedure:
A solution of 2-bromothiazole (3.6 g) in dry tetrahydrofuran (100 ml) was cooled to −78° C. under an atmosphere of nitrogen. A 2.5M solution of n-butyllithium in hexane (8.8 ml) was added dropwise over 15 minutes maintaining the temperature below −60° C. The product from step (a) (2.46 g) in tetrahydrofuran (20 ml) was then added over 15 minutes again keeping the temperature below −60° C. The reaction mixture was then maintained at −70° C. for 1 h, then allowed to warm to −10° C. over 1.5 h. The reaction mixture was then partitioned between 10% ammonium chloride solution and ethyl acetate and the resulting colloid was filtered through celite. The organic extracts were dried over magnesium sulfate, filtered and the filtrate evaporated. The resulting dark brown oil was purified by flash chromatography, eluting with hexane:ethyl acetate (2:1) to give the subtitle compound as a pale yellow oil (0.9 g, 15%).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](=O)[NH:14][C:15]3[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=3[NH2:21])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(O)(C)C.[OH-].[K+].O>C1(C)C=CC=CC=1>[O:25]=[C:18]1[N:19]([CH2:22][CH2:23][CH3:24])[C:20]2[N:21]=[C:13]([C:8]34[CH2:11][CH2:12][C:5]([C:3]([OH:2])=[O:4])([CH2:10][CH2:9]3)[CH2:6][CH2:7]4)[NH:14][C:15]=2[C:16](=[O:29])[N:17]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(N)c(NC(=O)C23CCC(C(=O)OC)(CC2)CC3)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 17.5 °C

Procedure:
4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (VII, Example 83b, 0.760 kg) and isopropanol (3.62 l) are combined. The mixture is stirred under nitrogen and potassium hydroxide (2 M, 3.62 l) is added. The contents are heated at reflux for 3 hr (test for reaction completion by NMR). The mixture is then allowed to cool to 10 to 25° C. Water (8.48 l) is added followed by toluene (0.95 l) and the contents are stirred vigorously for 5 to 15 minutes. The layers are separated. Extraction with toluene (0.95 l) is performed two additional times. The aqueous phase is then cooled to between 0 and 10° C. and acidified with concentrated hydrochloric acid (0.562 l). The mixture is stirred at between 0 and 10° C. for 60 minutes. Solid product is collected by filtration and dried under reduced pressure at 50 to 60° C. to give the title compound.
Reaction SMILES: [Na].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11]([O-:14])(=O)=[O:12])=[CH:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][S:11]([C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:2][CH:3]=1)(=[O:14])=[O:12]
Reactant: O=S(=O)([O-])c1csc2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1csc2ccccc12

Procedure:
180 g of sodium-benzothiophene-3-sulphonate are placed in 650 ml of phosphorus oxychloride and then combined with 156 g of phosphorus pentachloride. The reaction mixture is refluxed for 3.5 hours before the excess phosphorus oxychloride is eliminated by distillation in vacuo. The residue is taken up in 800 ml of chloroform and the precipitate formed is separated off by filtering. The filtrate is concentrated by evaporation and stirred into 800 ml of petroleum ether with heating. The crystalline substance thus precipitated is filtered off, washed with petroleum ether and dried at 35° C. Yield: 113 g. M.p.: 88-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]2N(C)CCN2C)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[OH2:22]>C(OCC)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=[O:22])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C)C1c1ccc(C(=O)OC(C)(C)C)s1
Reactant: O
Solvent: CCOCC
Solvent: CI
Product: CC(C)(C)OC(=O)c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.54 g (9 mmol) of 5-(1,3-dimethyl-imidazolidin-2-yl)-thiophene-2-carboxylic acid tert-butyl ester wered dissolved in 15 ml of diethyl ether, and after addition of 5 ml of methyl iodide the solution was stirred overnight at room temperature. The resulting crystalline suspension was vigourously stirred for 1 hour with 100 ml water. Then 100 ml diethyl ether were added, and after separation of the phases the organic phase was dried with anhydrous magnesium sulfate. After filtration, the solvents were removed in vacuo. 1.7 g of a light brown oil were isolated which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([Cl:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[Cl:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: CC(Cl)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-chloro-ethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)=[O:18].[CH3:25][C:26](C)=[O:27]>>[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)=[O:18])(=[O:27])[CH3:25]
Reactant: CC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2cnccn2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cnccn2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(pyrazine-2-carbonyl)indole (step 1). tlc: Rf=0.4 (50% acetone in hexanes)
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22](OC1C=CC=CC=1)=[O:23])[CH3:17]>C1(C)C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[CH2:1][N:10]2[CH2:15][CH2:14][N:13]([C:22]([O:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:31])=[O:23])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\CN1CCNCC1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCN(C/C=C/c2ccccc2)CC1
Yield: 35.3 %

Procedure:
A solution of 1.40 g (6.93 mmol) of trans-1-cinnamylpiperazine and 1.74 g (7.76 mmol) of ethyl{[(phenoxy)carbonyl]oxy}acetate (J. Med. Chem., 1999, 42, 277-290) in 15 ml of toluene is heated at 80° C. overnight. It is evaporated to dryness and the residue is taken up in 50 ml of ethyl acetate. It is washed with 2 times 20 ml of water and 1 times 10 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 50/50 mixture of cyclohexane and ethyl acetate, then with ethyl acetate, to give 0.814 g of product in the form of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)ccc1Br
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.9 %

Procedure:
To a suspension of 4-bromo-3-fluoroaniline (10.0 g, 52.6 mmol, 1.0 eq) and K2CO3 (21.7 g, 157.8 mmol, 3.0 eq) in MeCN (10 mL) was added benzyl bromide (19.8 g, 115.8 mmol, 2.2 eq) and the mixture was stirred for 16 h at 80° C. and then filtered through celite pad, and the solvents was evaporated under vacuum and washed with PE (100 mL) to get N,N-dibenzyl-4-bromo-3-fluoroaniline (13.8 g, 55%; TLC system: EtOAc/PE (1:9), Rf: 0.6).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:17]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:18]1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: CCO
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ncccn1

Procedure:
A solution of 2.36 g of ethyl 4-chloroquinoline-3-carboxylate and 1.46 g of 2-hydrazinopyrimidine in 80 ml of ethanol is refluxed for 2 hours and 30 minutes. The resulting slurry is cooled down to 5°, then filtered and the resulting product is taken up in 20 ml of N sodium hydroxide and sufficient water to effect solution. Ammonium chloride (10 g) is added, the resulting precipitate is collected, and is washed three times with ethanol and three times with ether to yield 2-(2-pyrimidyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, m.p. above 360°; IR (KBr) 800, 817, 844, 886 cm-1.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[C:9]2[CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[C:9]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CO
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(F)ccc21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(=O)n(C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
16 ml (219 mmol) of thionyl chloride are added dropwise over approximately 30 minutes to a stirred suspension of 11.37 g (49.38 mmol) of a mixture of 6-fluoro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 120 ml of methanol. The mixture is stirred overnight (13 hours) at room temperature and the solvent is driven off under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulphate, filtration and concentration of the filtrate, 9.6 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:19].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:19])=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Yield: 86.2 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br-:14].[Al+3].[Br-].[Br-].[CH2:18]=[CH2:19]>CCCCCC>[Br:14][CH2:18][CH2:19][C:8]12[CH2:10][C:4]3([CH3:13])[CH2:3][CH:2]([CH2:11][C:6]([CH3:12])([CH2:5]3)[CH2:7]1)[CH2:9]2
Reactant: [Br-]
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: C=C
Agent: [Al+3]
Solvent: CCCCCC
Product: CC12CC3CC(C)(C1)CC(CCBr)(C3)C2
Reaction time: 0.08 h
Yield: 48 %

Procedure:
Mix 1.4 mol of 1-bromo-3,5-dimethyl adamantane (I) in hexane with 0.6 mol of aluminum bromide at -75° C. Subsequently, pass ethylene through the solution for 20-30 minutes, stir for 5 min., and pour the reaction mixture onto ice water. Extract with ether, dry the organic phase and evaporate to dryness. Recrystallize the residue from methanol. (Yield: 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]#[N:12])[N:4]=1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([CH2:11][NH2:12])[N:4]=1
Reactant: COc1ccc(C#N)nc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN)nc1OC
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dimethoxy-6-cyanopyridine (3-5, 5.1 g, 31.1 mmol) in MeOH (260 mL) was added Pearlman's Catalyst (2.18 g, 3.11 mmol, 20 wt %) and concentrated HCl (20.0 mL, 249 mmol, 12M). The system was then stirred under an atmosphere of hydrogen via a balloon for 1.5 h. The reaction contents were filtered through a pad of celite and methanol was removed in vacuo. The crude mixture was then basified using saturated Na2CO3 and then extracted using 4:1 Chloroform:Ethanol. The organic phase was washed with brine, dried over Na2SO4, filtered and purified by gradient elution on silica gel (0 to 12% MeOH(10% NH4OH) in DCM) to yield the desired product (3-6) as a bone semi-solid. ESI+MS[M+H]+C8H12N2O2: M-16 (—NH2), 152.06 found, 168.2 required.