Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[NH2:13][NH2:14]>CCO>[F:6][C:5]([F:8])([F:7])[C:4]1[NH:14][N:13]=[C:2]([NH2:1])[CH:3]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Product: Nc1cc(C(F)(F)F)[nH]n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (5.00 g, 27 mmol) and hydrazine (1.05 g) in anhydrous EtOH (20 mL) was stirred at 80° C. in a sealed vial overnight. The reaction was quenched with water (50 mL), and extracted with EtOAc (100 ml, then 2×50 mL). The EtOAc layers were combined and sequentially washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated to give a light brown oily residue. The crude product was purified by silica chromatography (30-100% EtOAc in hexanes gradient) to give 5-(trifluoromethyl)-1H-pyrazol-3-amine as an off white solid; ESMS m/z 152.0 (M+H+).
Reaction SMILES: C(N(CC)S(C1C=C(C(=O)C[Br:16])C=CC=1Cl)(=O)=O)C.ClC1C=CC(NC(NC)=S)=CC=1.Br.[CH2:33]([N:35]([CH2:61][CH3:62])[S:36]([C:39]1[CH:40]=[C:41]([C:46]2(O)[CH2:50][S:49][C:48](=[N:51][C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=3)[N:47]2[CH3:59])[CH:42]=[CH:43][C:44]=1[Cl:45])(=[O:38])=[O:37])[CH3:34]>C(O)(=O)C>[BrH:16].[CH2:61]([N:35]([CH2:33][CH3:34])[S:36]([C:39]1[CH:40]=[C:41]([C:46]2[N:47]([CH3:59])[C:48](=[N:51][C:52]3[CH:53]=[CH:54][C:55]([Cl:58])=[CH:56][CH:57]=3)[S:49][CH:50]=2)[CH:42]=[CH:43][C:44]=1[Cl:45])(=[O:38])=[O:37])[CH3:62]
Reactant: CCN(CC)S(=O)(=O)c1cc(C2(O)CSC(=Nc3ccc(Cl)cc3)N2C)ccc1Cl
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Br
Agent: CNC(=S)Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(Cl)cc3)n2C)ccc1Cl

Procedure:
Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 3'-diethylsulfamoyl-2-bromo-4'-chloroacetophenone and 1-(4-chlorophenyl)-3-methylthiourea, or (b) by a procedure analogous to that of Example 1(b), by boiling 4-(3-diethylsulfamoyl-4-chlorophenyl)-2-(4-chlorophenyl-imino)-3-methylthiazolidin-4-ol hydrobromide for 2 hours in glacial acetic acid and filtering off the crystals after cooling. Melting point 207° C. (with decomposition).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]12([NH:23][OH:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([N+:23]([O-:24])=[CH:1][C:3]3[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: ONC12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: O=S(=O)(O)c1ccc(C=[N+]([O-])C23CC4CC(CC(C4)C2)C3)o1
Yield: 59 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-adamantylhydroxylamine, the title compound was prepared in 59% yield as the sodium salt, m.p. 236.9° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Br)cn2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C

Procedure:
To a solution of 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3) (7.10 g, 33.3 mmol) in dry acetonitrile (150 mL) at 5° C. was added triethylamine (11.6 mL, 83.3 mmol) followed by acetyl chloride (2.35 mL 83.3 mmol). The reaction mixture was then allowed to warm to room temperature (20° C.) and stirred until all starting material was consumed (if required, further triethylamine (4.64 mL, 33.3 mmol) and acetyl chloride (33.3 mmol) were added to ensure complete reaction). After this time the solvent was removed in vacuo and to the resultant residue was added 7 N (Methanolic ammonia solution (50 mL)). The reaction mixture was stirred at room temperature (20° C.) to hydrolyze any bis-acylated material. After 16 h evaporation in vacuo and trituration from diethyl ether (50 mL) afforded the title compound which was collected by filtration, washed with water (2×50 mL), acetone (50 mL) and diethyl ether (50 mL) and then dried in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=O)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[Cl:38])[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)N2CCC(n3c(Cl)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 0.45 g (0.97 mmol) of 1-[1-(1-benzyl-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which is described hereinafter) and phosphorus oxychloride (6 ml) was stirred at 100° C. for 2 hours and then allowed to cool. The reaction mixture was poured into ice-cold water, 10N NaOH was added until the ph=14, and the mixture was extracted with AcOEt. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 0.32 g (68%) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone as white crystals. ES-MS m/e (%): 483.6 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.33 h

Procedure:
The title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one in methanol and adding excess concentrated HC1 and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaOH solution until pink. Excess acetic acid is added and the mixture is extracted three times with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.[Br:16]N1C(=O)CCC1=O>CO>[Br:16][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:5]=1[CH2:4][CH2:3][S:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSCCc1cc(-c2ccccc2)n[nH]1
Solvent: CO
Product: CSCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole (4.0 g, 18.32 mmol) in methanol (20 mL) was added N-bromosuccinimide (3.26 g, 18.32 mmol) slowly at 0° C. The reaction was stirred at 0° C. for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (3.4 g). LCMS m/z=297.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.79 (t, J=7.83 Hz, 2H), 2.83-2.97 (m, 2H), 7.32-736 (m, 3H), 7.67-7.88 (m, 2H), 13.20 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:21])([CH3:20])[CH3:19].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)C(C)C)(C)C>CN(C=O)C>[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:10]([C:8]3[O:9][C:5]4[C:4]([Cl:17])=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:42][CH:43]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: COc1c(Cl)cc(Cl)c2oc(C(=O)O)c(C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(Cl)c2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
To 80 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 120 mg of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, 154 mg of BOP, 50 mg of N,N-diisopropylethylamine and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. The mixture was washed with brine and was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo and purification of the residue by column chromatography on silica gel gave 110 mg (60% yield) of (S)-2-{4′-[(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as an off-white solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].O.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>>[Br:20][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: Br
Reactant: N#Cc1ccc(N)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(Br)cc1C#N
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 4 (24 g, 0.17 mol) was suspended in a stirring solution of 100 ml HBr (48%) and 100 ml of H2O cooled to −10° C. Sodium nitrite (14 g, 0.20 mol) was dissolved in ice water and added dropwise to the solution of 4-aminophthalonitrile. The exothermic reaction was carefully monitored and kept under 0° C. After 2 hours of stirring, the solution was added dropwise to a solution of Cu(I)Br (27 g, 0.18 mol) in 100 ml of HBr (48%) at −3° C. and stirred at 0° C. for 2 hours. To minimize foaming as well as increase the yield, methylene chloride was added to the solution and the reaction was allowed to proceed overnight for at least 24 hours. The organic layer was removed, and the aqueous layer was also extracted with toluene. The combined organic layers were washed with water, Na2S2O3 (saturated aqueous solution), water, brine, water, dried over MgSO4 and evaporated under reduced pressure. 25 g of an orange product were collected (73%). 1H NMR (CDCl3) δ: 7.99 (d, 1H), 7.94-7.91 (dd, 1H), 7.72-7.70 (d, 1H).6 13C{1H}NMR (CDCl3) 136.68, 136.42, 134.44, 128.19, 117.39, 114.76, 114.65, 114.04 ppm.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (5-a) (240 mg, 0.489 mmol) and piperidine (1.2 mL) was added tetrakis(triphenylphosphine)palladium (53.5 mg, 0.049 mmol), copper(I) iodide (9.3 mg, 0.049 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (150 mg, 0.978 mmol). The reaction was purged with N2 and stirred at 60° C. for 1.5 hr. The reaction mixture was concentrated in vacuo. EtOAc (2 mL) was added to the residue and concentration in vacuo was repeated. The resultant residue was purified by flash chromatography (Isolute column, 100% DCM to 3% MeOH in DCM) to afford the title compound as a white solid: 1H NMR (250 MHz, DMSO) δ 1.87-1.97 (3H, m), 2.56 (3H, s), 6.91-7.00 (1H, m), 7.01-7.07 (1H, m), 7.10-7.23 (1H, m), 7.29-7.40 (1H, m), 7.65-7.73 (1H, m), 7.74-7.80 (1H, m), 7.81-7.90 (1H, m), 8.19-8.32 (1H, m), 8.76-8.92 (1H, m); LC-MS: m/z=+377.5 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH:31]1([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[Na+]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: O=C(Cl)CC1CCCC1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a stirred cold (ice bath) solution of 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (339 mg, 1 mmol, described in Example 7b) and pyridine (158 mg, 2 mmol) in methylene chloride (6.7 mL) was added cyclopentylacetyl chloride (161 mg, 1.1 mmol). After 15 min, the reaction was allowed to warm to ambient temperature and stirred for 18 h. The reaction was added methylene chloride (75 mL) and 1N sodium hydroxide (50 mL). The aqueous layer was extracted with methylene chloride (50 mL). The organic layers were combined and washed with 1N sodium hydroxide (2×50 mL), brine (35 mL) and dried (sodium sulfate). The solution was filtered and concentrated to give a foam. This material was chromatographed over silica gel (eluting in sequence with 1) methylene chloride; 2) 3:97 methanol:methylene chloride) and crystallized with ether to give the title compound as a white solid (323 mg, 72%), mp 149.5°-150.5° C.; MS(CI): 449 (M+H); NMR (300 MHz,DMSO-d6): 1.02-1.17(m, 2H), 1.26-1.74(m, 10H), 2.01(d, 2H, 2H, J=6.0 Hz), 2.09(m, 1H), 2.18-2.32(m, 2H), 2.47(m, 2H), 2.86-3.00(m, 2H), 3.28(d, 1H, J=14 Hz), 3.37(d, 1H, J=14 Hz), 3.54(m, 1H), 4.33(s, 1H), 6.89-7.00(m, 3H), 7.15-7.31(m, 4H), 7.61(d, 1H, J=7.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:17])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O

Procedure:
0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and 1.77 g (5 mmol) of N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and 7.5 ml of acetonitrile and stirred under reflux for 4 h. The reaction mixture is cooled, concentrated under reduced pressure and purified chromatographically on silica gel using the mobile phase dichloromethane. This gives 5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150° C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][O:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2occc12
Product: Clc1nccc2occc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5H-Furo[3,2-c]pyridin-4-one (5.9 g) was suspended with POCl3 (12 ml) and the reaction mixture was stirred for 3 hours at 120° C. After evaporating POCl3, crushed ice was added and poured into the mixture of ethyl acetate and saturated NaHCO3. The corresponding organic phase was separated and dried over Na2SO4 and then concentrated in vacuo. The resultant residue was purified by chromatography on a silica gel column to afford 4-chloro-furo[3,2-c]pyridine (5.6 g) 1H NMR (400 MHz, DMSO-d6) ppm 8.31 (d, J=5.8 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.79 (dd, J=1.0, 5.6 Hz, 1H), 7.13 (dd, J=1.0, 2.3 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=Cc1cccc(OCCCC(=O)O)c1
Yield: 92.8 %

Procedure:
A solution of 385 mg (1.63 mmol) of 4-(3-formylphenoxy)butanoic acid, ethyl ester and 850 mg (6.15 mmol) of potassium carbonate is stirred in 6 mL of methanol/water (3:2) at room temperature for 8 hours. The solution is then concentrated in vacuo. The residue is dissolved in 10 mL of 0.1N sodium hydroxide solution and washed with 20 mL of ether. The aqueous layer is separated and acidified with sodium bisulfate and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, then dried over magnesium sulfate. The mixture is then filtered and concentrated in vacuo to give 315 mg of 4-(3-formylphenoxy)butanoic acid as a white solid. The product is utilized in the next reaction without further purification. m.p. 62°-63°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 3000, 1700, 1690, 1590 cm-1 ; MS (CI low res) m/e 209 (M+H), 191, 123.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1.Cl>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15]
Reactant: O=C1CCCO1
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(Cl)c1
Temperature: 170 °C

Procedure:
A dispersion was prepared by suspending 1 eq of NaOH (flakes) in 3-chlorophenol (1 eq). The obtained dispersion was heated to 170° C. up to complete solubilization of the base. 1.4 Eq. of γ-butyrolactone were then dropwise added maintaining the reaction mixture at 170° C. for 5 hours. The reaction mixture was then poured into ice and then acidified with HCl 6N. The reaction product was extracted with CHCl3, dehydrated over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (eluent oil ligroin/ethyl acetate 4:1 v/v) to obtain a yellow solid corresponding to 4-(3-chlorophenoxy)butyric acid. 27.96 mmoles of 4-(3-chlorophenoxy)butyric acid were added to 48 grams of polyphosphoric acid and the resulting mixture was maintained under stirring at 90° C. for 2 hours. At the end the reaction mixture was then poured on ice and extracted with CH2Cl2. The pooled organic phases were washed with a 10% Na2CO2 aqueous solution, dehydrated over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (oil ligroin/ethyl acetate 9/1 v/v). An orange oil corresponding to 8-chloro-1-oxo-2,3,4,5-tetrahydrobenzo-cycloheptan-5-one was obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC([N:16]=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH2:16])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To compound L (250 mg, 0.598 mmol) in CH2Cl2 (8 mL) was added benzoic acid (100 mg, 0.819 mmol), DCC (200 mg, 0.971 mmol), and DMAP (10 mg, 0.082 mmol) at room temperature. A heterogeneous mixture resulted after approximately 5 minutes and stirring was continued for an additional 3 hours. The contents were concentrated in vacuo and chromatographed on SiO2 (3% acetone-CH2Cl2) which afforded the benzamide contaminated with residual Ph3P. Repeated recrystallization of this material from Et2O afforded 198 mg (63%) of compound M as a pale off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:14])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1COC
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (0.700 g, 3.25 mmol) in DMF (30 mL) was added NaH (0.156 g, 60% dispersion in mineral oil, 3.90 mmol) followed by MeI (0.22 mL, 3.58 mmol). The mixture was stirred for 16 hours and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to a yellow oil. Purification by flash column chromatography (0% to 4% EtOAc in hexanes) gave the product as a clear oil (0.51 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 3.32 (s, 3 H), 4.35 (s, 2 H), 7.12 (m, 1 H), 7.24 (m, 1 H), 7.27 (d, J=2.1 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][CH:22]2[NH2:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][CH:22]2[NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=2)=[CH:18][CH:17]=1
Reactant: NC1CCc2ccc(F)cc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-6-fluoro-indan-1-ylamine (CAS no: 168902-77-0); MS: m/e=294.3 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[C:27]([O:29]CC2C=CC=CC=2)[C:26]([CH:37]([CH3:39])[CH3:38])=[CH:25][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=2)[CH2:14]1)=[O:12])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>CN(C=O)C>[C:57]([O:56][C:54]([N:61]1[CH2:62][CH2:63][N:64]([C:22]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:11](=[O:12])[C:10]2[CH:25]=[C:26]([CH:37]([CH3:39])[CH3:38])[C:27]([OH:29])=[CH:28][C:9]=2[OH:8])[CH2:21]3)=[O:23])[CH2:65][CH2:66]1)=[O:55])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3C2)c(O)cc1O
Yield: 102.2 %

Procedure:
A solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (Preparation D6) (0.5 g, 0.96 mmol), EDC (0.22 g, 1.15 mmol), HOBT (0.196 g, 1.15 mmol) and BOC piperazine (0.117 ml, 1.06 mmol) in DMF (10 ml) was stirred at room temperature for 48 hours, then evaporated under vacuum. The crude material was dissolved in ethyl acetate and extracted twice with saturated NaHCO3, organics washed with brine, dried (MgSO4), filtered then evaporated under vacuum and purified by flash column chromatography (80% EtOAc-P.E. as eluant) to give 0.5 g of 4-[2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester. MS: [M+H]+ 688.