Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:16][CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:11](=[O:15])[CH:12](Br)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:3]([N:10]1[CH2:16][CH:17]([C:18]([F:21])([F:20])[F:19])[O:22][CH:12]([CH3:13])[C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)C(=O)N(Cc1ccccc1)CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC1OC(C(F)(F)F)CN(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
A solution of 3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (2.68 g, 12.3 mmol) and triethylamine (1.7 mL, 12.2 mmol) in CH2Cl2 is cooled to 0° C. The solution is treated drop wise with 2-bromopropanoyl chloride (1.2 mL, 12 mmol, Aldrich) and stirred for 5 minutes. The solution is diluted to 100 mL with CH2Cl2 and washed sequentially with 1.0 M HCl, saturated NaHCO3, and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation yielding (N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide as a golden oil. Dry NaH is suspended in dry, inhibitor free THF (25 ml) in a flame dried flask and the mixture is cooled to 0° C. with stirring on an ice bath. The N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.25 g, 12 mmol) is added as a solution in dry, inhibitor free THF (25 ml) and the resultant suspension is warmed to RT. After stirring for one hour the reaction is quenched with MeOH over an ice bath until no more gas evolved and the mixture is poured into 1.0 M HCl (200 mL). The aqueous mixture is extracted into MTBE (200 mL) and the organic layer is washed with saturated NaHCO3 and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered, and the solvent is removed by rotary evaporation yielding an amber oil.
Reaction SMILES: [I:1]Cl.[F:3][S:4]([OH:7])(=[O:6])=[O:5].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>>[S:4]([F:3])([O:7][C:10]([F:12])([F:11])[C:9]([I:1])([F:13])[F:8])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)F
Reactant: FC(F)=C(F)F
Reactant: ClI
Product: O=S(=O)(F)OC(F)(F)C(F)(F)I
Temperature: 100 °C
Yield: 66 %

Procedure:
Into a 1-liter pressure reactor was charged a mixture of iodine monochloride (162.5 g, 1.0 mol) and fluorosulfonic acid (110 g, 1.1 mol). The reactor was cooled and tetrafluoroethylene (120 g, 1.2 mol) was added. After the addition of TFE was complete, the reaction mixture was heated at 100° C. for 10 hr. The cooled mixture was then slowly poured into a large amount of ice with stirring. The lower layer was separated, washed with dilute NaHSO3 solution and water and dried over MgSO4. Distillation afforded the desired product as a clear liquid (215 g, 66% yield), bp. 87-88° C. 19F NMR (188.24 MHz, CDCl3): -85.4 (dt, J=8.4 Hz, J=5.2 Hz, 2F), -65.7 (t, J=5.2 Hz, 2F), +49.6 (t, J=8.3 Hz, 1F).
Reaction SMILES: [Cl-].[Cl-].[NH3+]C1C=CC(C(N[C:11]2[CH:24]=[CH:23][C:14]([NH:15][C:16]3[CH:21]=[CH:20][N+](C)=CC=3)=[CH:13][CH:12]=2)=O)=CC=1.ClC1C2C(=CC=C([N+:38]([O-:40])=[O:39])C=2)N=CC=1>CO.Cl>[N+:38]([C:16]1[CH:21]=[CH:20][C:13]2[C:14](=[CH:23][CH:24]=[CH:11][CH:12]=2)[N:15]=1)([O-:40])=[O:39]
Reactant: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc([NH3+])cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=[N+]([O-])c1ccc2ccccc2n1

Procedure:
To a suspension of amide B7 (2.09 g, 5.32 mmol) in dry MeOH (100 mL) were sequentially added 4-chloro-6-nitroquinoline (F1) [1.11g, 5.32 mmol] and a few drops of concentrated HCl, and the resultant mixture was refluxed for 12 h. After this time, solvent was removed under reduced pressure, and the residue was re-suspended in 1:1 MeOH:EtOAc. This mixture was heated to remove MeOH, and then cooled, and the resulting precipitate collected by filtration. This solid was recrystallized from MeOH:EtOH to give nitroquinoline Cpd. G (2.48 g, 89%) as an amorphous yellow solid; 1H NMR [CD3)2SO]: δ 3.96 (s, 3H, R2N+−CH3), 7.12 (m, 3H, ArH), 7.35 (d, J=8.81 Hz, 2H, ArH), 7.68 (d, J=8.51 Hz, 2H, ArH), 7.96 (d, J=8.81 Hz, 2H ArH), 8.24 (m, 5H, ArH), 8.72 (m, 2H, ArH), 9.83 (d, J=1.69 Hz, 1H, ArH), 10.56 (s, 1H, ArNHAr), 10.67 (s, 1H, ArNHAr), 11.48 (br s, 1H, ArNHAr). LCMS (APCI+): 492 (20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:22])[N:12]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.O>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])[N:12]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2ccccc2C=O)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2ccccc2CO)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
tert-Butyl{[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (218 mg) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (24 mg) and methanol (1 mL) were added at 0° C. After stirring at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:3) to give the title compound as a colorless oil (yield 132 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].[I-].[K+]>O1CCCC1>[CH2:22]([O:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH:21]=[CH2:20]
Reactant: C=CCCl
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1cc(OC)ccc1C(=O)c1ccccc1

Procedure:
2-Hydroxy-4-methoxybenzophenone (114 parts) was dissolved in tetrahydrofuran (100 parts). Potassium hydroxide (30.9 parts) was added. By heating and stirring, complete dissolution was achieved. Allyl chloride (46.4 parts) and potassium iodide (4.2 parts) were added to this solution, which was then heated and refluxed for 8 hours. After cooling, it was washed with water and the solvent was removed by distillation. A crude product of the desired 2-allyloxy-4-methoxybenzophenone was obtained. It was recrystallized in n-hexane to obtain 125 parts of 2-allyloxy-4-methoxybenzophenone (melting point 40° C.) at 93% yield.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][N:10]2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.25 g (7.8 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 1.5 g (7.76 mmol) of 6-fluoro-3-methoxycarbonyl-1H-indole in 40 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.5 hour, 1.29 g (7.8 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 6 hours, the reaction mixture is poured into 150 cm3 of water and extracted with 150 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a brown solid which is purified by silica gel chromatography [eluent: dichloromethane and then dichloromethane/ethyl acetate (90/10 by volume)]. After concentrating the fractions under reduced pressure, 1.5 g of 6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 186° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:6][C@@H:7]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]([CH3:20])([CH3:19])[C@H:8]1[OH:21])[CH3:5])#[N:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C@H:8]1[C@H:7]([NH:6][C:4](=[N:3][C:1]#[N:2])[CH3:5])[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1([CH3:20])[CH3:19])(=[O:24])[CH3:23]
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(C)=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A mixture of trans-4-[N-[1-(cyanoimino)ethyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (0.53 g) and acetic anhydride (0.38 g) in dry pyridine (2.65 ml) was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, successively. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether and collected by filtration to give trans-3-acetoxy-4-[N-[1-(cyanoimino)-ethyl]amino]-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.55 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:16][NH2:17].O>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: NNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1.49 g, 10.0 mmol) in ethanol (25 mL) was added triethylamine (2.02 g, 2.78 mL, 20.0 mmol) and hydrazine (321 mg, 0.321 mL, 10.0 mmol). The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with methanol:dichloromethane (2 to 5% methanol) to give (2-chloro-pyrimidin-4-yl)-hydrazine (330 mg, 23%) as a white solid. MS (ES+): m/z=144.9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH3:7].CS(C)=O.O.Cl.[CH3:34][CH2:35]OCC>>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][C:34]#[CH:35])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOCC
Reactant: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: C#CCCC(CCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of 32.2 g. (85 moles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30° C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH3:17]N(C=O)C.[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O>[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH2:2][CH3:17])[C:9]=4[C:10]=3[CH3:16])=[O:15])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: CN(C)C=O
Reactant: CCOc1cccc2oc(C(=O)O)c(C)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 110 mg (0.47 mmol) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid in 4 mL of oxalyl chloride was refluxed for 4 h in the presence of a catalytic amount of DMF. The excess oxalyl chloride was then removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 204 mg (0.56 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 152 mg (57% yield) of (S)-2-{4′-[(3-methyl-4-propoxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C([O:16][C@H:17]([CH3:36])[C@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=O)=CC=1)([O-])=O.C1COCC1.C(OCC)(=O)C>CO>[OH:16][C@H:17]([CH3:36])[C@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1
Reactant: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Potassium carbonate powder (6.43 g) was added to a mixed solution of (1R,2R)-2-tert-butoxycarbonylamino-1-methyl-2-(3,4,5-trifluorophenyl)ethyl 4-nitrobenzoate (7.03 g) in methanol (90 ml)-THF (10 ml), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine (twice). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the resulting residue, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate=6:1) to obtain 4.49 g of the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])([CH3:15])([CH3:14])[CH3:13].Cl[CH2:23][CH2:24][S:25][CH2:26][CH2:27]Cl>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([C:18]1([C:19]#[N:20])[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: ClCCSCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1(C#N)CCSCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-hydroxy-ethylsulfanyl)-ethanol (13.17 g), thionyl chloride (24 mL) in DCM (250 mL) was stirred in an ice/water bath overnight. Then the reaction mixture was concentrated to give crude product 1-chloro-2-(2-chloro-ethylsulfanyl)-ethane (100%), which was used directly in the next step. DBU (42.04 mL) was added slowly to a solution of cyano-acetic acid tert-butyl ester (13.23 g) and 1-chloro-2-(2-chloro-ethylsulfanyl)-ethane (all the crude from previous step) in DMF (200 mL) at rt and then the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated; the residue was column purified to give title compound (7.961 g). 1H NMR in CDCl3, δ in ppm: 3.1-2.9 (m, 2H), 2.7-2.5 (m, 2H), 2.45-2.35 (m, 2H), 2.2-2.1 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1.[CH:18](O)=O>CO.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:18][N:8]([CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Reactant: O=CO
Agent: [Fe]
Solvent: CO
Product: Brc1ccc2ncn(C3CCOCC3)c2c1
Reaction time: 4 h

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (600 mg, 1.99 mmol) in HCOOH (10 mL) was added Fe powder (1.3 g, 23.2 mmol). After stirring for 4 h at reflux temperature, the mixture was diluted with MeOH (100 mL) and filtered over a Celite pad. The filtrate was concentrated to give the title compound which was directly used for next step without further purification.
Reaction SMILES: [S:1](=[O:3])=[O:2].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17](N)[CH:18]=[CH:19][CH:20]=1)[CH2:9][C:8]2([CH3:23])[CH3:22].N([O-])=O.[Na+].[ClH:28]>C(O)(=O)C.O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([S:1]([Cl:28])(=[O:3])=[O:2])[CH:18]=[CH:19][CH:20]=1)[CH2:9][C:8]2([CH3:23])[CH3:22]
Reactant: O=S=O
Reactant: Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(c2cccc(S(=O)(=O)Cl)c2)Nc2ccc(Cl)cc21
Temperature: -10 °C

Procedure:
Sulphur dioxide was bubbled into a flask with acetic acid (10 mL) and cupric chloride (62 mg 0.63 mmol) until the green solution turned into blue. 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (600 mg 2.09 mmol) was dissolved in a aceticacid (27 mL) and hydrochloric acid (3 mL) solution, and cooled to −10° C., sodium nitrite (213 mg, 3.09 mmol) in water (2 mL) solution was added and the mixture was stirred for 45 min. sulphur dioxide solution was added dropwise to the diazonium salt solution and stirred at −10° C. After the addition, the solution was warmed to room temperature and stirred for 24 h. The mixture was poured to 100 mL water and extracted with dichloromethane. The combined organic layers was washed with sodium bicarbonate and dried. Removal of the solvent afforded 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzenesulfonyl chloride as yellow solid (crude 98 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C.[I-].ClCC1C=CC=C[NH+]=1>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: ClCc1cccc[nH+]1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 1.13 g of benzoic acid (9.3 mmol), in 33 ml of methylene chloride at 0° C., was added N,O-dimethylhydroxylamine hydrochloride (906.7 mg; 10.23 mmol), 4.26 ml of triethylamine (3.09 g; 30.6 mmol) and 2-chloromethylpyridinium iodide (2.6 g; 10.23 mmol). After stirring at 25° C. for 12 hours, the reaction mixture was poured into 250 ml of methylene chloride, then this solution was extracted with 150 ml of 1N hydrochloric acid, 150 ml saturated, aqueous solution of sodium bicarbonate, and 150 ml of brine. The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to give a oil, which was purified by flash chromatography (SiO2; 50% ethyl acetate/hexane) to give 0.872 of N-methoxy-N-methyl-benzenecarboxamide as an oil: Anal. Calc'd. for C9H11NO2+0.25 H2O: C, 63.70; H, 6.29; N 8.14. Found: C, 63.73; H, 6.83; N, 8.25
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:14][CH:15]=1>O.Cl>[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cc3cc(C#N)ccc3o2)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a melted pyridine hydrochloride (15.0 g) at 160-180° C. was added 2-(3-methoxyphenyl)benzofuran-5-carbonitrile (120) in one portion and the stirring continued at 180° C. for 2.5 h. The mixture was cooled down, diluted with water (100 mL) and 1 M HCl (50 mL) and stirred at room temperature for 30 min. A precipitate formed was separated, washed with 1 M HCl (150 mL) and water (150 mL) and dried. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes 1/3) followed by recrystallization to give 125 as white solid (1.50 g, 69%): mp 222-224° C. (EtOAc/hexanes). 1H NMR (DMSO-d6) δ9.78 (d, J=1.1 Hz, 1H), 8.21 (br s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.75 (ddd, J=8.2, 1.6, 1.1 Hz, 1H), 7.48 (s, 1H), 7.40 (dd, J=8.2, 1.1 Hz, 1H), 7.33 (dd, J=8.2, 7.7 Hz, 1H), 6.86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H). HPLC (method B) tR 5.70 min (100.0 area %). Anal. (C15H9NO2) C, H, N.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1
Reactant: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2cc(Br)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (213 mg, 1.25 mmol) was added to a suspension of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (187 mg, 0.570 mmol) and Cs2CO3 (1.11 g, 3.42 mmol) in anhydrous DMSO (3 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (10 mL) was added and the aqueous suspension was filtered. The solid was dried under reduced pressure. Flash chromatography on silica gel [4.75:4.75:0.5 MTBE/CH2Cl2/(9:1 EtOH/NH4OH)] afforded the title compound (113 mg, 47%) as a light yellow powder with data matching those reported in Example 9.