Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.FC1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C(O)(=O)C>O1CCCC1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 2 h
Yield: 57.4 %

Procedure:
64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran, and, while the mixed solution was stirred and cooled on ice, a solution obtained by dissolving 258 g of diethyl malonate in 400 ml of tetrahydrofuran was dropped to the mixed solution through 1 hour and 40 minutes so that the reaction temperature was kept below 20° C. Then, while the reaction solution was stirred and cooled on ice, 200 ml of tetrahydrofuran solution dissolving 142 g of 2,3,4-trifluoronitrobenzene was dropped to the reaction solution through 2 hours so that the reaction temperature was kept below 10° C. After reacting at room temperature for 2 hours, 100 ml of acetic acid was added to the reaction solution and tetrahydrofuran was removed by distillation. To the residue, 1 1 of chloroform, 1.5 1 of water and 100 ml of concentrated hydrochloric acid were added, and the solution was separated. The organic layer was separated from the solution, and the solvent was removed by distillation. To the residue, 250 ml of 4 N hydrochloric acid and 200 ml of acetic acid were added, and the solution was heated under reflux for 11 hours. After removing 150 ml of content solution by distillation, 50 ml of acetic acid and 50 ml of water were added to the solution, and the solution was heated under reflux for 31 hours. After the solution was air-cooled, the precipitated crystal was filtered off, washed with diisopropyl ether and was dissolved in 400 ml of methanol. After treating with active carbon, the solvent was removed by distillation. The precipitated crystal was dispersed in diisopropyl ether and was filtered off to obtain 100 g of the subject compound (1) in a 56% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH2:8][C:7]=1[C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=1.[CH3:13][N:14]([CH2:18][CH2:19]Cl)[CH2:15][CH2:16]Cl.Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:7]12[CH2:8][C:4](=[CH:3][C:2]=1[N:1]1[CH2:19][CH2:18][N:14]([CH3:13])[CH2:15][CH2:16]1)[C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]2=1
Reactant: NC1=C2CC(=C1)c1ccccc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(C2=C3CC(=C2)c2ccccc23)CC1

Procedure:
2-Aminobenzobicyclo[2.2.1]heptene (1.1 g) was combined with mechlorethamine hydrochloride (1.4 g), potassium carbonate (1.5 g), and acetonitrile (25 ml) and heated to reflux for 24 hours. Water (50 ml) was added to the mixture and the resulting mixture was extracted with ether (3×50 ml). The combined ether solutions were dried over magnesium sulfate and the ether was removed on a rotary evaporator. The residue was combined with concentrated hydrochloric acid (5 ml) and 2-propanol (25 ml) and the solvent was removed on a rotary evaporator. The residue was suspended in 2-propanol and the solvent was removed on a rotary evaporator. This latter step was repeated. The residue was recrystallized from 2-propanol to provide the product as a tan solid. Analytical data are reported in Table I.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[O:4][N:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[O:4][N:3]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1cccc(-c2cc(O)no2)c1
Product: COc1cccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)c1
Yield: 80.6 %

Procedure:
3-Hydroxy-5-(3-methoxyphenyl)isoxazole (0.22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.31 g, 82%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:10]=1[CH:27]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>O>[CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:39]2[CH2:38][CH2:37][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:41][CH2:40]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 88 %

Procedure:
To 5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde, Intermediate 62 205 mg (0.52 mmol) in dichloroethane[DCE] (10 mL) were added BOC-piperazine, 137 mg (0.74 mmol), NaBH(OAc)3, 333 mg (1.6 mmol) and HOAc, 45 mg (0.8 mmol) and the mixture was stirred at room temperature in sealed test tube over night. Water was added, the phases were separated and the dried (MgSO4) organic phase was evaporated at reduced pressure and the black residue was chromatographed on a column of silica with CHCl3 100% as eluent to yield 260 mg (88%) of a blackish oil. MS (ESI+) for C31H35N3O5S m/z 562 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[I:23])[O:9][C:8]1=[O:24].[N+:34]([O-])([OH:36])=[O:35].O>CCOC(C)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([N+:34]([O-:36])=[O:35])[C:14]=2[I:23])[O:9][C:8]1=[O:24]
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)cc([N+](=O)[O-])c2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one was added in portions to 2 mL of fuming nitric acid at 0° C. The reaction mixture was stirred overnight at r.t., and then heated to 75° C. for 4 h. The reaction mixture was cooled and then added dropwise to a rapidly stirred mixture of 10 mL of water and 10 mL of EtOAc. The phases were separated and the organic phase was washed with 10 mL each of saturated NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc in hexanes over 10 CV, to provide the title compound. Mass spectrum (ESI) 643 (M+1).
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:11]=2)[NH:6][C:5]=1[C:24]([O:26]CC)=[O:25]>C1COCC1.CO>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][OH:16])[CH:11]=2)[NH:6][C:5]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1[nH]c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2ccc(OCCO)cc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
LiOH (1 N in water, 4 mL, 4 mmol) was added to a solution of ethyl 3-bromo-5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-2-carboxylate (0.121 g, 0.275 mmol) in THF (4 mL) and methanol (4 mL). The solution was stirred at room temp overnight. The reaction mixture was evaporated to a residue and partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, and evaporated to a crude solid to afford the title compound (0.081 g, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.14-13.33 (m, 1H), 11.97 (s, 1H), 7.34 (d, 1H), 6.97 (dd, 1H), 6.86 (s, 1H), 4.83 (t, 1H), 3.99 (t, 2H), 3.71 (q, 2 H). LC-MS (ES+) m/z 301 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (40 ml), and thereto are added ethyl 5-bromopentanoate (11.4 g) and potassium carbonate (6.38 g), and the mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=5:1 to 5:2). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (9.86 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[C:22](=[O:23])[C:21]2=[C:24]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[N:25]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[N:26]=[C:20]2[NH:19][C:18]1=[O:44]>>[CH3:16][N:17]1[C:22](=[O:23])[C:21]2=[C:24]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)[N:25]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[N:26]=[C:20]2[N:19]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])[C:18]1=[O:44]
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 80 °C

Procedure:
1-(chloromethyl)-2-methylbenzene (0.045 ml) and potassium carbonate (0.6 g) were added to a solution of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2 ml). The mixture was heated at 80° C. for 18 hours then cooled to room temperature. Solids removed by filtration and the crude product was purified on preparative HPLC to give the title compound (0.057 g). Mass: 487.87 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid (100 mg, 0.30 mmol), benzotriazol-I -yloxytris(dimethylamino)phosphonium hexafluorophosphate (200 mg, 0.45 mmol), triethylamine (0.13 mL, 0.93 mmol) and 2-aminothiazole (52 mg, 0.45 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (61 mg, 47.9%) as a white solid: mp 162-163° C.; EI-HRMS m/e calcd for C22H26N2O2S (M+) 382.1715, found 382.1718.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.O>CO>[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH2:17][S:11][C:7]2[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])[N:6]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1nc(S)nc(S)c1N
Reactant: Fc1c(Cl)cccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(SCc2cccc(Cl)c2F)nc(SCc2cccc(Cl)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of potassium hydroxide powder (2.5 g) in methanol (80 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (3.6 g) followed by 3-chloro-2-fluorobenzyl bromide (6.3 g). The reaction mixture was stirred for one hour at room temperature then poured into water (180 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropyl alcohol and diethyl ether, to give the subtitled compound as a pale brown solid (5.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Br:16])=[CH:14][C:5]2[C:6]([C:10]([NH:12][CH3:13])=[O:11])=[C:7]([I:9])[O:8][C:4]=2[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O.O[Li].O>N1C=CC=CC=1>[Br:16][C:15]1[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][C:4]2[O:8][C:7]([I:9])=[C:6]([C:10]([NH:12][CH3:13])=[O:11])[C:5]=2[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(I)oc2cc(N)c(Br)cc12
Agent: [Li]O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)c1c(I)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
To a solution of 6-amino-5-bromo-2-iodo-N-methylbenzofuran-3-carboxamide (1 g, 2.53 mmol) in pyridine, MsCl (580 mg, 5.06 mmol) was added dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 h. After the solvent was removed, the reaction mixture was adjusted to pH=5-6 with 1 N HCl. After filtration, the solid was dissolved in THF:H2O=5:1 (15 mL) and then LiOH.H2O (800 mg, 20 mmol) was added. The mixture was stirred for 30 minutes at room temperature. After the solvent was removed, the reaction mixture was adjusted to pH=5-6 with 1 N HCl. Finally the precipitate was collected to give 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (800 mg, 90% purity by HPLC, yield: 60%), which was used for the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 7.84 (s, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 3.07 (d, J=4.8 Hz, 3H), 2.99 (s, 3H). MS (M+H)+: 473/475.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]2[CH2:15][O:14]2)[CH2:8][CH2:7]1.[CH3:20][NH2:21]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([OH:14])[CH2:15][NH:21][CH3:20])[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCN(C[C@@H]3CO3)CC2)cc1Cl
Reactant: CN
Solvent: CCO
Product: CNC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 79.3 %

Procedure:
A solution of 4-(3,4-dichlorophenoxy)-1-[(2R)-oxiran-2-ylmethyl]piperidine (1 g, 3.31 mmol) and methylamine (2.56 ml 40% in H2O, 33.1 mmol) in ethanol (15 ml) was heated at 60° C. in a sealed vessel for 16 h. The solvent was evaporated at reduced pressure and the residue purified by flash column chromatography eluting with 8% 7M ammonia methanol in dichloromethane to give the title compound (875 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:7]([NH2:8])[C:6]=2[CH:9]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(N)=Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 7 h
Yield: 62.7 %

Procedure:
Combine 5-methyl-2-(2-nitro-phenylamino)-benzonitrile (4.03 g, 15.91 mmol), tin(II) chloride dihydrate (10.77 g, 47.74 mmol), 5N HCl (65 ml), and ethanol (40.0 ml) and stir the mixture at reflux. After 7 hours, cool to ambient temperature and chill in the refrigerator overnight. Remove the resulting precipitate by vacuum filtration and place the precipitate in ethanol (100.0 ml) and 5N HCl (20.0 ml) and heat at reflux for 19 hours. Cool the reaction mixture to ambient temperature and chill in the refrigerator. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 2.59 g (63%) of an orange solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[CH:12]2
Reactant: CC(=O)n1ncc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)n1ncc2cc(O)ccc21
Temperature: 50 °C
Yield: 91.9 %

Procedure:
A suspension of 939 mg of 1-(5-benzyloxyindazol-1-yl)ethanone, 1.33 g of ammonium formate and 939 mg of palladium-on-charcoal at 10% in 100 ml of absolute ethanol is heated at around 50° C. for about thirty minutes. When gas is no longer being given off, the catalyst is filtered through a paper filter and rinsed with absolute ethanol. The filtrate is concentrated under reduced pressure in a rotary evaporator to obtain 571.1 mg of 1-(5-hydroxyindazol-1-yl)ethanone.
Reaction SMILES: NN.C(O)COCCO.[C:10]([C:13]1[O:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[CH:17]=1)(=O)[CH3:11].[OH-].[K+]>O>[CH2:10]([C:13]1[O:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[CH:17]=1)[CH3:11]
Reactant: COc1ccc2cc(C(C)=O)oc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCc1cc2ccc(OC)cc2o1
Temperature: 190 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
Hydrazine (4.11 g, 69.4 mmol, up to 55%, Aldrich) was added to diethylene glycol solution of 2-acetyl-6-methoxybenzofuran (3.30 g, 17.3 mmol) . The mixture was heated to a temperature of 190° C. and stirred for 10 min. After cooled down to room temperature, potassium hydroxide (2.92 g, 52.1 mmol) was added, stirred in a range of 120° C. to 130° C. for 6 hours. Following this, the reaction solution was poured into water, extracted by dichloromethane, dried over MgSO4, and was concentrated under reduced pressure. Oil residue was purified by HPLC (silica gel, CHCl3) and target product (2.98 g, 16.9 mmol, 97%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:14]([O:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine is reacted with 2-benzyloxyacetyl chloride in dichloromethane in the presence of triethylamine to give 2-benzyloxy-1-(4-benzyl-piperazin-1-yl)-ethanone which is then hydrogenated over a palladium on carbon catalyst in a methanol/hydrochloric acid mixture to remove the benzyl group and give the title compound.
Reaction SMILES: [CH2:1]1[C@@H:4]([C:5]([OH:7])=[O:6])[NH:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1>O.CCOCC>[Cl:21][C:19]1[CH:18]=[C:17]([S:22]([N:3]2[CH2:2][CH2:1][CH:4]2[C:5]([OH:7])=[O:6])(=[O:23])=[O:24])[CH:16]=[C:15]([Cl:14])[CH:20]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C1CCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 2.0 g (19.8 mmol) of (L)-azetidine-2-carboxylic acid and 4.6 g (43.6 mmol) of Na2CO3 in 100 mL of H2O at 0° C. was added 5.8 g (23.8 mmol) of 3,5-dichlorophenylsulfonylchloride. The reaction was allowed to come to room temperature overnight and was then diluted with Et2O and H2O. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH˜4 with 1M HCl and extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give N-(3,5-dichlorophenylsulfonyl)-azetidine-2-carboxylic acid (6.0 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12](O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:12]=[N:8][CH2:7][CH2:6]2
Reactant: COc1cccc(CCN)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CCN=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
In tetrahydrofuran (100 ml), 3-methoxyphenethylamine (75.0 g) was dissolved, followed by the addition of formic acid (60 ml) and acetic anhydride (108 ml) under ice cooling. The resulting mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic lay-layer so separated was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in benzene (200 ml), followed by the dropwise addition of phosphorus oxychloride (140 ml) under ice cooling. After stirring at 70° C. for 15 minutes, ice and then 2N hydrochloric acid were added. The resulting mixture was stirred under ice cooling for one hour. The water layer was separated and neutralized with potassium carbonate. After extraction with dichloromethane, the extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:1), the title compound (13.5 g, 17%) was obtained.