Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:36][CH2:35][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14])(C)(C)C.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:51]=[CH:50][S:49][C:48]=1C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:46][C:47]1[CH:51]=[CH:50][S:49][C:48]=1[C:13]([N:15]1[CH2:36][CH2:35][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14]
Reactant: O=C(O)c1sccc1Cl
Reactant: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1C(=O)Nc1ncc2c(n1)CCN(C(=O)c1sccc1Cl)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Trifluoroacetic acid 3.6 ml (49 mmol) was added to a solution of 2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 300 mg (0.753 mmol) in CH2Cl2 (10 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (2-ethoxy-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 225 μl and 3-chlorothiophene-2-carboxylic acid 129 mg (0.791 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 158 mg (0.828 mmol) and HOAt 15 mg (0.11 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-ethoxy-benzamide 170 mg (0.38 mmol, 51% of theoretical) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH3:29]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:37])[CH3:29]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CCOC(=O)CCCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol), ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) are heated together at reflux overnight. The reaction mixture is diluted with DCM (20 ml) and washed with 1M hydrochloric acid (15 ml), water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as an off white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:29]([O:33][C:34](=[O:58])[C@@H:35]([NH:40][C:41](=[O:57])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH:49]([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51])=[C:44]([NH2:56])[CH:43]=1)[CH2:36][CH:37]([CH3:39])[CH3:38])([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.O.C(Cl)CCl>[C:29]([O:33][C:34](=[O:58])[C@@H:35]([NH:40][C:41](=[O:57])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH:49]([CH:50]([CH3:52])[CH3:51])[CH:53]([CH3:54])[CH3:55])=[C:44]([NH:56][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:43]=1)[CH2:36][CH:37]([CH3:39])[CH3:38])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(NC(C(C)C)C(C)C)c(N)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1ccc(NC(C(C)C)C(C)C)c(NC(=O)Cc2cccs2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of 469 mg of thiophen-2-yl-acetic acid in 7.5 ml of dry DMF 449 mg of HOAT, 633 mg of EDC and 0.75 ml of DIPEA were added at 0° C. After 30 min 1259 mg of (S)-2-[3-Amino-4-(1-isopropyl-2-methyl-propylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester and 0.75 ml of DIPEA were added and the reaction was stirred at it for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by HPLC to yield 250 mg (15%)) (S)-2-[4-(1-Isopropyl-2-methyl-propylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=[O:30]>>[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: COC(=O)C1CCC(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)CC1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-(toluene-4-sulfonyloxymethyl)-cyclohexane carboxylic acid methyl ester (CAS Reg. No. 1003013-11-3). Brown solid (51%). MS (Turbo Spray): m/z=531.4 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:9]([N:13]1[C:18](=[O:19])[C:17]([CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)=[C:16](Cl)[CH:15]=[N:14]1)([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([N:13]1[C:18](=[O:19])[C:17]([CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)=[C:16]([NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[N:14]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccncc1
Reactant: CC1CCOC(c2c(Cl)cnn(C(C)(C)C)c2=O)O1
Solvent: CCO
Product: CC1CCOC(c2c(NCc3ccncc3)cnn(C(C)(C)C)c2=O)O1

Procedure:
Into 20 ml of an absolute ethanol solution of 2.7 g of 4-picolylamine, 20 ml of an absolute ethanol solution of 3.4 g of 2-tert-butyl-5-chloro-4-(4-methyl-1,3-dioxan-2-yl)pyridazin-3-(2H)-one was dropwise added at room temperature. The mixture was reacted overnight under heating and refluxing and then left to cool. Ethanol was distilled off under reduced pressure, and then 150 ml of ethyl acetate was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=30:1 to 12:1), 1.2 g of the desired product (Compound No. 44) having a melting point of from 150° to 153° C. and 0.18 g of amorphous 4-tert-butyl-5-(4-pyridylmethylamino)-4-(4-pyridylmethyliminomethylidenyl)pyridazin-3-(2H) -one (Compound No. 2) as a by-product, were obtained.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[CH2:29][C:30]([CH3:33])([NH2:32])[CH3:31].Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[CH2:29][C:30]([NH:32][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7])([CH3:31])[CH3:33]
Reactant: CC(C)(N)CC1Cc2ccccc2C1
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (342 mg, 1.30 mmol) described in WO 2004/106280, 1-(2,3-dihydro-1H-inden-2-yl)-2-methylpropan-2-amine (234 mg, 1.24 mmol) described in WO 01/53254, and lithium perchlorate (79 mg, 0.74 mmol) in toluene (12 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and washed with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oily substance (206 mg, yield 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c(OC)c1C
Yield: 89 %

Procedure:
A solution of 1,3-dimethoxy-2-methylbenzene (1.86 g, 12.2 mmol) and N-bromo-succinimide (2.17 g, 12.2 mmol) in acetonitrile (30 mL) was stirred at 60° C. for 20 h. After most of the solvent was removed in vacuo, extraction in ethyl ether (2×75 mL) with water (2×50 mL) and flash chromatography with silica gel (gradient to 5% ether/hexanes) provided the title compound as a colorless liquid (2.51 g, 89% yield): 1H NMR (300 MHz, CDCl3) δ 2.19 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 6.54 (d, 1H, J=8.8 Hz), 7.32 (d, 1H, J=8.8 Hz).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:34][CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reactant: NCCc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NCCc4ccc(Cl)cc4)c(=O)c3=O)C2)cs1
Reaction time: 5 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.19 g.) in 35 ml. of methanol/chloroform (50:50 v/v) was added 2-(p-chlorophenyl)ethylamine (0.18 g.) and the resulting mixture allowed to stand at room temperature for 5 hours. After heating under reflux for 2.5 hours the reaction mixture was cooled and the precipitated buff-coloured solid collected to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-[2-(p-chlorophenyl)ethylamino]cyclobutene-3,4-dione. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.2 (m), 1.8 (m), 2.5 (t), 3.7 (m), 6.24 (s), 6.78 (br s).
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>C1COCC1>[C:32]1([S:38][CH:6]2[CH2:5][CH:4]3[CH:8]([C:2](=[O:1])[CH2:3]3)[CH:7]2[C:9]([O:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Sc1ccccc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2CC(=O)C12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C1CC2CC(Sc3ccccc3)C(C(=O)OC(c3ccccc3)c3ccccc3)C12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Twenty grams of 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, 13, were dissolved in 40 mL of THF by gentle warming. To this solution at room temperature was added 1.0 mL of triethylamine and 13.0 mL of thiophenol. The resulting solution was stirred under argon at room temperature for 1 hr, after which time 0.5 mL of acetic acid was added, and the solvent was removed by rotary evaporation at 40°. Crystallization from ether at room temperature afforded 21 g (78%) (total of 2 crops) of 3-phenylthio-7-oxobicyclo[3.2.0]heptan-2-carboxylic acid, diphenylmethyl ester, 14. NMR (220 MHz; CDCl3): δ 2.23 (1H, m), 2.43 (1H, m), 2.84 (1H, m), 3.07 (2H, m), 3.41 (1H, m), 3.80 (2H, m), 6.77 (1H, s), and 7.0-7.3 (15H, m).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1C
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccccc1C

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-2-sulphonyl)-pyrazolo[1,5-a]-pyrimidin-7-ylamine as colorless crystals, m.p.>250°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[CH2:13]([S:20][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1nccs1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CSc2nccs2)cc1
Yield: 85 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-bromothiazole (700 mg, 4.2 mmol), K2CO3 (884 mg, 6.4 mmol), benzylmercaptan (795 ml 6.4 mmol) in DMSO (6 ml) at 150° C. for 4 h in sealed tube gave the title compound (740 mg, 83%) after purification by column chromatography with n-hexane/EtOAc (98:2) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1c(F)cccc1I
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Under an argon atmosphere, 123 mg of 2-fluoro-6-iodobenzonitrile was dissolved in 2 mL of tetrahydrofuran, and 1.5 mL of a borane/tetrahydrofuran complex was added thereto, followed by stirring under reflux overnight. The reaction liquid was cooled to room temperature, and 2N hydrochloric acid was added thereto, followed by further stirring for 1 hour. After completion of the reaction, to the reaction liquid was added an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 87 mg (70%) of 2-fluoro-6-iodobenzylamine as a light yellow oily substance. This product, 68 mg of di-tert-butyl dicarbonate, and 31 mg of triethylamine were dissolved in 1 mL of chloroform, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (n-hexane:ethyl acetate=2:1) to obtain 80 mg (yield 81%) of a title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:25]([O-:27])=[O:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC(C)C)cc12
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate (6.16 g, 18.76 mmol) in chloroform (22 mL) at −15° C. was added dropwise a cold solution of 70% nitric acid (11 mL, 172 mmol) in chloroform (22 mL). After stirring at 0° C. for 1 hour, the reaction mixture was washed with water (50 mL) and the organic phase was separated by hydrophobic filter tube then evaporated under vacuum to afford a brown solid. The solid was triturated in methyl tert-butyl ether (25 mL) and the resulting pale yellow powder was filtered off, washed with heptane and dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=764 (2M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:16][C:14]=2[NH2:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Yield: 56.5 %

Procedure:
A mixture of 2-nitro-3-chloroaniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31 mmol) and K2CO3 (5.41 g, 39 mmol) in acetonitrile was stirred at 70° C. for 48 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/Heptane/NH3 4:1:5×0.2%) to give 1.6 g of product (unreacted starting material was isolated): 1H-NMR δ 7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m, 4H); MS (posES-FIA) m/z 333.0 (M++H). The product (1.06 g, 4.49 mmol) was dissolved in EtOH:THF (4:1). Raney-Ni and hydrazine (1.12 mL, 22 mmol) were added. The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite pad, followed by removal of the solvent afforded 0.802 g of 2-amino-5-(4-methyl-1-piperazinyl)aniline which was used without further purification in the next step. 3-Fluorobenzenesulfonyl chloride (0.133 g, 0.68 mmol) was added to a solution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.141 g, 0.68 mmol) and pyridine (514 mL, 6.39 mmol) in CH2Cl2. After 1 h the mixture was washed with aq NaHCO3 (10%), dried (MgSO4) and the solvent was removed. Purification by chromatography (SiO2, CH2Cl2/methanol/heptane, 4:1:5) gave 3-fluoro-N-[2-amino-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.140 g, 57%). MS (posES-FIA) m/z=found: 365.2. calcd: 364.14. Anal. (C17H22ClFN4O2S.3H2O) C, H, N, S. The reaction produced a small amount of bis-sulfonylated compound 3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.010 g, 3%). The products were transformed into their HCl-salt before analysis; MS (posES-FIA) m/z=found. 523.5. calcd: 522.12. Anal. (C23H25ClF2N4O4S2) C, H, N, S.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][CH:11]=[CH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromobenzaldehyde (15.8 g, 85.6 mmol) in dry diethyl ether (200 mL) at 0° C. under nitrogen atmosphere with stirring is added allylmagnesium bromide solution in ether (85.6 mL, 85.6 mmol) dropwise. The resulting mixture is warmed to room temperature over 1 hr and is quenched by the addition of 1 N HCl aqueous solution. The reaction is extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 0% to 100% dichloromethane in hexanes over 50 minutes to give the title compound as a racemic mixture (17.01 g, 88%). ES/MS m/e (79Br/81Br) 227, 229 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][CH:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(C)C(N)CO
Product: CC(C)(C)C(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 2-amino-3,3-dimethyl-1-butanol (CAN 3907-02-6, 74.8 mg, 0.64 mmol) as starting materials, and isolated (40 mg, 28.16%) as light yellow sticky solid; LC-MS (UV peak area, ESI) 89.43%, 334.2 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: COC(=O)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.70 g), methyl 2-(2-hydroxyphenyl)acetate (0.33 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.50 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][C:8]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: NC1CCc2cc(S(N)(=O)=O)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc2c(c1)CCC2NC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing 1-amino-2,3-dihydro-1H-indene-5-sulfonamide hydrochloride salt (93 mg, 0.38 mmol) suspended in dichloromethane (3 mL) was added triethylamine (61 μL) followed by 4-iodobenzoylchloride (100 mg, 0.38 mmol) and the reaction was stirred overnight at room temperature. The reaction was diluted with dischloromethane (25 mL) and washed with 10% aqueous hydrochloric acid (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated to afford the crude material as an off-white solid. Recrystallization from ethanol/water afforded MIP-1146 (19 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (m, 2H), 7.85-7.35 (m, 8H), 5.60 (m, 1H), 3.15-2.75 (m, 2H), 2.15-1.90 (m, 2H); (M+H)+ (443).