Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20](O)=[O:21])[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]2)=[O:21])[N:10]=1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.066 g, 0.329 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.26-1.28 (m, 4H), 3.91 (s, 3H), 7.24 (d, J=9.3 Hz, 1H), 7.11-7.48 (m, 6H), 7.98 (t, J=7.5 Hz, 2H), 8.27 (s, 1H), 8.74 (s, 1H), 12.56 (br s, 1H); MS (m/z): 545.31 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:6][C:7]=1[F:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:5]1[N:6]=[C:7]([F:8])[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1nc(NCc2ccccc2Cl)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccccc2Cl)nc1F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 93.5 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (17, 1.85 g, 5.86 mmol) in 25.0 mL of tetrahydrofuran under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (3.00 mL, 2.00 M in tetrahydrofuran, 6.00 mmol) was added over 10 minutes. After 50 minutes, tert-butyllithium (7.80 mL, 1.70 M in hexane, 13.3 mmol) was added over 5 minutes. After 20 minutes, N,N-dimethylformamide (1.09 mL, 14.0 mmol) was added and the reaction mixture stirred at −78° C. for 20 minutes, then brought to room temperature over 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 35% ethyl acetate in hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (18, 1.45 g). MS (ESI) [M+H+]+=265.4.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:23][NH:22][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][C:12]=2[CH:18]=1)=[NH:20]
Reactant: NO
Reactant: CC(C)N1CCN(c2nc3ccc(C#N)cc3s2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Yield: 71.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (5.0 g, 17.5 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3.6 g, 52.4 mmol), water (8 mL) and potassium carbonate (7.2 g, 52.4 mmol). The reaction mixture was heated overnight at reflux. The mixture was allowed to cool and then concentrated in vacuo. The residue was dissolved into THF (30 mL) and then filtered. The filtrate was concentrated in vacuo to give 4 g of crude N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[N:17][CH:16]=[N:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:9]
Reactant: NCCCn1cncn1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1cncn1

Procedure:
When 5-chloroisatoic anhydride was reacted with 3-(1H-1,2,4-triazol-1-yl)propanamine by the procedure of Example 11, this compound, mp 116°-118° C., was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([C:24]([F:23])([F:38])[F:39])[CH:26]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 172, intermediate a) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated and the residue purified by preparative HPLC (Gemini NX column) using a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2). Colorless solid (10%). MS (ESI): m/z=549.105 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].[Cl:16][C:17]1[CH:22]=[C:21](I)[CH:20]=[C:19]([Cl:24])[N:18]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=2)[CH:20]=[C:19]([Cl:24])[N:18]=1
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Reactant: Clc1cc(I)cc(Cl)n1
Product: COC(=O)C1CC1c1ccc(C#Cc2cc(Cl)nc(Cl)c2)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 2,6-dichloro-4-iodopyridine (121 mg, 0.44 mmol) according to the general procedure IF to give 19 mg (23%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:10): Rf=0.36 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.45 (d, J=8.2 Hz, 2H), 7.34 (s, 2H), 7.11 (d, J=8.2 Hz, 2H), 3.73 (s, 3H), 2.61-2.48 (m, 1H), 2.02-1.90 (m, 1H), 1.67 (dt, J=10.0, 5.1 Hz, 1H), 1.35 (ddd, J=8.4, 6.4, 4.8 Hz, 1H); 13C NMR (CDCl3) δ 173.4, 150.7, 142.5, 136.5, 132.2, 126.4, 124.4, 119.2, 96.7, 84.7, 52.1, 26.1, 24.4, 17.3; ESI-MS m/z 368.1 (M+Na+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18].O>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(OCCOC(C)=O)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a suspension of sodium hydride (60% active, 124 mg) in dimethylformamide (2 ml) at ambient temperature was added ethyl 4-hydroxycinnamate (500 mg) under nitrogen, and the mixture was stirred for 1 hour. 2-Bromoethyl acetate (522 mg) was added to the mixture at same temperature, and the mixture was allowed to stand for 19 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform to give ethyl 4-(2-acetoxyethoxy)cinnamate (716 mg) as an oil.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Br:2])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A solution of PBr3 (2.0 mL, 20 mmol) in anhydrous CH2Cl2 (25 mL) was added slowly to a stirred solution of 4-(dodecyloxy)benzyl alcohol (3.0 g, 10 mmol) in CH2Cl2 (50 mL) at 0° C. The reaction mixture was stirred for 3 h at room temperature and slowly poured into a large amount of water (ca. 600 mL). The product was extracted with CHCl3 (3×50 mL). The combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2 SO4, and concentrated in vacuo to give a yellow solid (3.01 g, 90%). 1H NMR (300 MHz, CDCl3, δ): 7.32 (d, J=6.6 Hz, 2H), 6.86 (d, J=6.6 Hz, 2H), 4.50 (s, 2H), 3.97 (t, J=6.6 Hz, 2H), 4.05-4.00 (m, 6H), 1.79-1.72 (m, 2H), 1.45-1.21 (m, 12H), 0.90 (t, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[N:16]=[C:15]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:13][C:12]=1[CH:43]=[CH:44][CH2:45][CH2:46][OH:47])[NH:6]2>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[CH2:43][CH:44]([CH2:45][CH2:46][OH:47])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=CCCO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CCO)C4)cc12
Reaction time: 3 h
Yield: 33.3 %

Procedure:
A solution of (Z and E)-5-(6-(4-fluoro-1H-indol-2-yl)-5-(4-hydroxybut-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, 0.457 mmol) in DMAc (9 mL) was added K3PO4.3H2O (606 mg, 2.28 mmol) under N2. It was put into a pre-heated oil-bath at 110° C. for 3 hours. The mixture was diluted with H2O and it was extracted with EtOAc (500 mL×5). The combined organic phase was washed with brine, and dried over Na2SO4. The crude product was purified with Prep-HPLC to give the pure product of 5-(11-fluoro-6-(2-hydroxyethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 7.88˜7.92 (m, 2H), 7.63 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.09˜7.22 (m, 5H), 6.72 (t, J=8.4 Hz, 1H), 5.83 (s, 1H), 5.02 (d, J=6.4 Hz, 1H), 3.43˜3.55 (m, 4H), 3.35 (s, 3H), 3.10 (d, J=24.0 Hz, 1H), 2.94 (d, J=4.4 Hz, 3H), 2.61 (s, 3H), 1.78 (d, J=5.2 Hz, 2H). MS (M+H)+: 657.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12]([CH2:18][O:19][S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:14]1([OH:17])[CH2:13][CH:12]([CH2:18][O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH2:11][CH:10]2[CH:15]1[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2
Reactant: COc1ccccc1[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)C3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CC(COS(=O)(=O)c2ccc(C)cc2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 12.07 g .of (3aRS,6SR,7aSR)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-one in 50 cm3 of anhydrous tetrahydrofuran is run over a period of 15 minutes into a suspension, cooled to +5° C., of 2-methoxyphenylmagnesiumbromide (prepared from 6.4 cm3 of 2-bromoanisole and 1.24 g of magnesium) in 200 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred at 20° C. for one hour, cooled to +5° C., treated with 250 cm3 of saturated aqueous ammonium chloride solution and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 300 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether, and the crystals are filtered, washed with diisopropyl ether, subjected to suction and then dried under reduced pressure (2.7 kPa). 11.38 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-ol are obtained in the form of white crystals. M.p.K =153° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:10][CH2:9][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (S)-3-cyclohexyl-1-hydroxypropan-2-ylcarbamate (3.02 g, 11.7 mmole) in CH2Cl2 (50 mL) and triethylamine (4.0 mL, 28.6 mmol) was cooled to −20° C. (internal temperature). Neat methanesulfonyl chloride (2.0 mL, 25.7 mmol) was added dropwise, maintaining the internal temperature at −20° C. (+/−5° C.). The reaction mixture was stirred at −20° C. for an additional 30 min and at 0° C. for 1 h. Reaction progress was followed by TLC and LC-MS. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×20 mL), washed with water (3×10 mL), dried (Na2SO4), decanted, and stripped to give 4.13 g (quant) of product. 1H NMR (CDCl3) δ 0.80-1.40 (10H), 1.40 (s, 9H), 1.65 (t, 2H), 1.75 (d, 1H), 2.95 (s, 3H), 3.94 (m, 1H), 4.10 (m, 1H), 4.24 (m, 1H), 4.60 (m, 1H). MS ESI +ve m/z 236 (M(−BOC)+1).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:33]1([C:31]2[N:32]=[C:25]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:28])=[CH:5][CH:6]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]4)=[O:17])[CH2:13]3)[O:26][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Reactant: NC(=NO)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCS(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (0.48 mmol) of the compound from Example 39A and 96 mg (0.96 mmol) of N′-hydroxycyclopropanecarboximidamide were initially charged in 1.8 ml of DMF and reacted with 274 mg (0.72 mmol) of HATU and 0.25 ml (186 mg, 1.44 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 25 mg (10% of theory)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=1)[CH:5]=2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[C:3](=[O:16])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=1)[CH:5]=2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1C(O)=CC=C2C1=Cc1cc(O)ccc12
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC1=CC=C2C(=Cc3cc(OC(=O)C(C)(C)C)ccc32)C1=O
Reaction time: 2 h

Procedure:
2.1 g (0.01 mole) of 2,7-dihydroxyfluorenone and 2.5 g (0.025 mole) of pivaloyl chloride were warmed to 50° C. in 6 mls of pyridine in a drying tube attached for 2 hrs. The solvent was removed via rotary evaporator and H2O was added. The crystals were filtered and air dried. Recrystallized from ethanol; 3 g (79%); M.P.~174°-175° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:35])([F:34])[F:33])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:33])([F:34])[F:35]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(OC(F)(F)F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4-[(trifluoromethyl)oxy]benzoic acid: MS (APCI) m/z 488 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[N:16]2[CH:23]=[N:22][CH:21]=[C:17]2[S:18][C:19]=1[CH3:20].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:24]1(=[O:34])[N:28]([CH2:14][C:15]2[N:16]3[CH:23]=[N:22][CH:21]=[C:17]3[S:18][C:19]=2[CH3:20])[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1sc2cncn2c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc2cncn2c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Under an argon atmosphere, 1.8 ml of diethyl azodicarboxylate was added dropwise to 30 ml of an anhydrous THF solution containing 962 mg of 3-hydroxymethyl-2-methylimidazo[5,1-b]thiazole, 1.68 g of phthalimide and 3.0 g of triphenylphosphine at room temperature, and the mixture was then stirred at room temperature for 2 hours as it was. The solvent was evaporated under reduced pressure, and the resulting residue was purified through a silica gel column chromatograph to obtain 1.7 g of 3-phthalimidomethyl-2-methylimidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)nc1
Yield: 83.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (5-bromopyridin-2-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2.4 g) described in Preparation Example 35 and (R)-4-methyloxazolidin-2-one (728 mg) described in Preparation Example 25, the title compound (2.1 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]=[C:6]([Br:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]1[C:15](O)=[O:16].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH:4]([CH:5]=[C:6]([Br:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]1[C:15]([Cl:21])=[O:16]
Reactant: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)Cl
Yield: 48.4 %

Procedure:
59 g (0.2 mol) of 2,2-dimethyl-3-(2-bromo-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid were dissolved in 500 ml of carbon tetrachloride, and 119 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. When the reaction period had ended, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. The oil which remained was distilled. 33.7 g (53.8% of theory) of 2,2-dimethyl-3-(2-bromo-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were obtained as a colorless liquid with a boiling point of 165°-166° C. under 8 mm Hg.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH2:34][NH2:35])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CC#N.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:27]3[C:28](=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:34][NH:35][C:1]2=[O:2])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CN)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3cc(Cl)ccc32)CC1
Temperature: 50 °C
Yield: 55.9 %

Procedure:
1,1′-Carbonyldiimidazole (0.51 g, 3.15 mmol) was added to a solution of 4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 2.25 mmol) in CH3CN (10 mL) over 3 h with stirring at 50° C. The reaction mixture was then cooled to room temperature and stirred for additional 2 h. The reaction mixture was dissolved in CH2Cl2 (100 mL), washed with water (2×10 mL), brine (1×10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 0.46 g (63%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C18H24ClN3O3, 365.15. m/z found, 388.1 [M++Na]. 1H NMR (CDCl3, 400 MHz): 7.18 (dd, J=6.26 Hz, 2.54 Hz, 1H), 7.05 (d, J=2.15 Hz, 1H), 6.94 (d, J=9.00 Hz, 1H), 6.29 (s, 1H), 4.32-4.18 (m, 4H), 4.13-4.02 (m, 1H), 2.88-2.71 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.73 (m, 2H), 1.49 (s, 9H).