Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([NH:9][C:5]4[CH:4]=[C:3]([CH2:2][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH:8]=[CH:7][N:6]=4)[S:11][C:12]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: ClCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Reactant: C1CCNC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(-c2ccc3nc(Nc4cc(CN5CCCC5)ccn4)sc3c2)ccn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 0.23 mmol, 1 eq.) in 1 mL dioxane was treated with 15 mg of pyrrolidine and 20 mg DIEA. The reaction mixture was stirred at 140° C. under microwave condition for 1 h. After cooling to rt, the mixture was concentrated in vacuo. The residue was washed with EtOH to afford 6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 102 without further purification (67 mg). 1HNMR (CD3OD, 400 MHz) δ 8.83 (d, 2H), 8.60 (m, 1H), 8.54 (m, 1H), 8.46 (m, 2H), 8.10 (m, 1H), 7.92 (d, 1H), 7.52 (s, 1H), 3.37 (d, 1H), 4.53 (s, 2H), 3.62 (br s, 2H), 3.25 (m, 2H overlapping with signal from CD3OD), 2.22 (m, 2H), 2.09 (m, 2H). MS (ES-API): MH+=388.1. HPLC tR=2.16 min.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:21][C:14]1[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC(C)Oc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20 C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.24 (s, 1 H), 6.64 (s, 1 H), 4.48 (m, 1 H), 2.98 (m, 3 H), 2.87 (m, 3 H), 1.36 (m, 6 H), 1.30 (d, J=7 Hz, 3 H). MS calculated for C14H20BrNO+H: 298, observed: 298.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH2:18]([NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[C:33]([C:34]([NH2:36])=[O:35])[C:32]([OH:38])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C)C>[CH2:18]([N:25]([CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([C:34](=[O:35])[NH2:36])[CH:37]=1)[CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3ccccc3)cc2)ccc1O

Procedure:
A solution of 5.97 g of 4-(2,3-epoxypropoxy)-biphenyl and 6.87 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 140 ml of isopropanol is heated under reflux for 15 hours and the solvent is then removed in a rotary evaporator. The residue is recrystallised from diethyl ether, yielding 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(4-biphenyloxy)-2-propanol having a melting point of 135°-138°.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[N:18]1[CH:19]=[CH:20][C:15]([C:4]2[S:5][C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:7]([CH3:8])[C:3]=2[CH2:2][F:27])=[CH:16][CH:17]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethylaminosuifer trifluoride (DAST, 0.06 mL) in CH2Cl2 (5 mL) was added 3-hydroxymethyl-2,5-di(4-pyridyl)-4-methylthiophene (0.144 g) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. DAST (0.06 mL) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the whole was extracted with CH2Cl2 (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatographyeiuting with ethyl acetate-CH2Cl2 (1:1). The resulting solid was recrystallized from diisoplopanol-diisopropyl ether to give the title compound (0.056 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-methoxypyrrolidin-1-yl)quinolin-7-yl]ethanone (0.0445 g, 0.146 mmol) and ammonium acetate (0.112 g, 1.46 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.36 mL, 0.36 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H21ClN3O (M+H)+: m/z=306.1; Found: 306.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][C:9]=1[O:22][CH3:23])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[O:22][CH3:23])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(O)cc1OC
Yield: 99.8 %

Procedure:
2-(4-Benzyloxy-2-methoxy-phenyl)-trans-cyclopropanecarboxylic acid methyl ester (500 mg, 1.6 mmol) is dissolved in ethyl acetate (10 mL) and hydrogenated for 2 hours in a Parr apparatus at 1 bar using 10% Pd/C as the catalyst. The solution is filtered through celite and the solvent removed under vacuum to give the title compound (yield 355 mg).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[N+:11]([C:14]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])([O-:13])=[O:12]>ClCCl>[N+:11]([C:14]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]1[C:4](=[O:9])[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]1=[O:10])=[O:17])([O-:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: O=C1CC(=O)C2CCC1C2
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1

Procedure:
To a solution of 10 g of bicyclo[3.2.1]octane-2,4-dione in 100 ml of dichloromethane was added dropwise 70 ml of a dichloromethane solution having dissolved therein 19.1 g of 2-nitro-4-methylsulfonylbenzoyl chloride while ice cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([S:34](=[O:40])(=[O:39])[NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:30][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([S:34](=[O:40])(=[O:39])[NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:30][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(S(=O)(=O)NC3CC3)ccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)cc1OC
Yield: 25.2 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (0.500 g, 0.83 mmol), TFA (2 mL) and DCM (10 mL) to afford 0.100 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.40 (m, 2H), 0.52 (d, J=5.4 Hz, 2H), 2.18 (m, 1H), 3.77 (s, 3H), 3.85 (s, 3H), 7.65 (d, J=9.0 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.93 (s, 2H), 8.18 (s, 2H), 12.8 (br s, 1H); MS (m/z): 478.97 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[OH:36]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])[CH:26]=[CH:25][C:24]=1[OH:36])=[O:17]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3-chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+:30].N1C=CC=CC=1.[S:37](=[O:40])(=[O:39])=[O:38]>C1COCC1>[S:37]([O-:40])([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([OH:15])[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:39])=[O:38].[Na+:30]
Reactant: O=S(=O)=O
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(=O)(=O)[O-])cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (257 mg, 0.67 mmol) in THF (2.0 mL) was added a solution of sodium methoxide (36 mg, 0.67 mmol) in THF (1.5 mL) at room temperature. After 20 minutes sulfur trioxide-pyridine (85 mg, 0.53 mmol) was added and the mixture was stirred for 40 minutes, then partitioned between H2O (25 mL) and Et2O (20 mL). The aqueous layer was concentrated under reduced pressure to provide a colourless solid (177 mg, 68%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 7.88 (dm, J=9.0 Hz, 2H), 7.56 (d, J=8.6 Hz, 1H), 7.36 (dm, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 1H), 5.86 (d, J=8.6 Hz, 1H), 5.49 (d, J=6.1 Hz, 1H), 5.08 (dd, J=4.3, 8.4 Hz, 1H), 4.40 (tq, J=3.9, 5.9 Hz, 1H), 2.33 (s, 3H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[C:26]1([C@H:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(N(CC)CC)C>[C:26]1([C@H:32]([NH:34][C:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]2)=[O:17])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (5 g, 20.5 mmol) was dissolved in THF, to which triethylamine (3 mL) was added. The reaction mixture was cooled to 0° C. and a solution of isobutyl chloroformate (2.8 g, 20.7 mmol) in THF was added dropwise. The resulting white suspension was stirred at room temperature for 30 min, after which a solution of (R)-1-phenylethanamine (2.9 g, 20.5 mmol) in THF was added dropwise. The reaction mixture was then stirred at room temperature for 4 h, after which LC-MS showed one major peak corresponding to desired product. The reaction mixture was concentrated, and the residue was diluted with water (250 mL). The resulting white precipitate was filtered, washing with ether, to afford a dry white solid tert-butyl trans-4-((R)-1-phenylethylcarbamoyl)cyclohexylcarbamate (5.2 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:26])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CC(C)=O>[OH:25][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[C:20](=[O:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:4](=[O:26])[CH2:3][CH2:2][N:31]2[C:27](=[O:37])[C:28]3=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]3[C:30]2=[O:32])[CH2:13]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCCl)[C@@]3(C)CC(=O)[C@@H]12
Agent: [K]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCN4C(=O)c5ccccc5C4=O)[C@@]3(C)CC(=O)[C@@H]12
Yield: 63.3 %

Procedure:
21-Chloromethyl-3α-hydroxy-5α-pregnane-11,20-dione (600 mg) in acetone was treated at reflux with potassium phthalimide (600 mg) for 10 hours, poured into water and the oily precipitate extracted into ether. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to a white foam (700 mg). Purification by preparative t.l.c. in ethyl acetate/petrol (1:1) gave a foam which on trituration with ether gave title compound (490 mg) as a white solid m.p. 187°-189° [α]D + 58.8° (c = 0.97).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)=[O:20])[C:14]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[N:65]1([C:28]([CH:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:19]([C:15]3[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]4\[C:6](=[O:11])[NH:7][C:8]5[C:4]\4=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)[NH:17][C:16]=3[CH3:18])=[O:20])[CH2:27][CH2:26]2)=[O:30])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1
Reactant: C1COCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To the solution of 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid in 20 mL of DMF were added HATU (0.161 g, 0.424 mmol), DIEA (0.072 mL, 0.424 mmol) and morpholine (0.0737 g, 0.847 mmol). The reaction mixture was stirred at r.t. overnight. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (5 mL). The precipitate was collected by filtration, washed with methanol and dried in vacuum to give title compound (69 mg, 32.9% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.53-7.55 (d, 1H), 6.81-6.92 (m, 2H), 3.95-3.96 (m, 1H), 3.29-3.54 (m, 8H), 2.64-2.67 (m, 1H), 2.39-2.41 (ds, 6H), 1.47-1.88 (m, 8H). LC/MS: 495.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH:36][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([C:29]([F:39])([F:40])[F:28])=[CH:31][CH:32]=3)=[N:7][CH:6]=2)=[CH:10]1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)nc2)c2cccnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cc2c[nH]c3ncccc23)cn1)c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To 3-(6-Bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (6a, 50.0 mg, 0.000174 mol, prepared as described in Example 2) in 1,4-dioxane (4.0 mL) were added 4-trifluoromethyl-benzamide (51, 70.0 mg, 0.37 mmol), Xanthphos (15.0 mg, 0.026 mmol), cesium carbonate (130.0 mg, 0.40 mmol) and Tris(dibenzylideneacetone)-dipalladium(0) (25.0 mg, 0.024 mmol) under an atmosphere of nitrogen. The reaction was heated to 120° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a white solid (P-0072, 4.7 mg, 6.8%). MS (ESI) [M+H+]+=397.2.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[N:5][NH:4][C:3]=1[NH2:14].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:13][C:9]1[CH:8]=[C:7]([C:6]2[C:2]3[S:25][C:24]([NH:23][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:14][C:3]=3[NH:4][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1[nH]nc(-c2cccc(Cl)c2)c1Br
Solvent: C1COCCO1
Product: O=C(Nc1nc2[nH]nc(-c3cccc(Cl)c3)c2s1)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a stirring solution of 4-bromo-5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine (50 mg, 0.183 mmol) in dioxane (1 mL) was added benzoyl isothiocyanate (27 μL, 0.202 mmol). The reaction mixture was stirred overnight at 90° C., cooled at room temperature, and partitioned between ethyl acetate and sodium bicarbonate. The organic layer was isolated and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 10.8 mg (17%) of N-[3-(3-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-benzamide as a white solid. 1H NMR (d6-DMSO) δ: 13.70 and 13.72 (2 broad s, 1H, NH+tautomer), 12.9 (broad s, 1H, NH), 8.12 (d, 2H), 7.81 and 7.85 (2 broad s, 1H, tautomers), 7.65-7.74 (m, 2H), 7.54-7.62 (m, 3H), 7.45 (m, 1H); HPLC/MS m/z: 355 [MH]+.
Reaction SMILES: C([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)C=C.Cl>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:6]23[CH2:5][NH:4][CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCN1CC2CONC2(c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: c1ccc(C23CNCC2CON3)cc1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
5-Allyl-6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (3.89 g, 16.89 mmol) is dissolved in chloroform (168 mL) and the solution is degassed with dry nitrogen for 10 minutes. N,N-Dimethylbarbituric acid (13.19 g, 84.45 mmol) is added to the solution and the solution is degassed with nitrogen for another 5 min Tetrakis(triphenylphosphine) palladium (1.95 g, 1.69 mmol) is added and the reaction is stirred for 18 hours. 1 N Hydrochloric acid (50 mL) is added and the mixture is stirred for 20 minutes. The solution is extracted with aqueous hydrochloric acid (3×75 mL) and the combined HCl solution is washed with dichloromethane. The pH is adjusted to approximately 13 with 5 N sodium hydroxide solution. The mixture is extracted with dichloromethane (3×75 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (3.21 g, 92%). El/MS (m/e): 191.3 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].O>[C:16]1([C:15]([NH:1][CH:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=3)[CH2:3]2)=[O:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCc2ccc([N+](=O)[O-])cc2C1)c1ccccc1

Procedure:
To 2-amino-7-nitrotetralin (1.8 g, 9.39 mmol, derived from dibenzoyl-D-tartaric acid) in THF (50 ml) and 10% K2CO3 (100 ml) was added benzoyl chloride (1.2 ml, 10.1 mmol). After the addition was complete, the mixture was diluted with water to a volume of 250 ml. The precipatated solids were collected by filtration, washed with water and dried in vacuo: (2.8 g, 100%), m.p. 208°-209° C., [α]D +21.9° (c 0.33 DMSO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[O:19][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22]
Reactant: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)OC

Procedure:
A mixture of 66.1 g (0.234 mol) of 2-Hydroxy-4-octyloxy benzoic acid methyl ester obtained in Step 1, 44.7 g (0.30 mol) of 5-Bromopent-1-ene, 207 g (1.5 mol) of K2CO3 and 700 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered and the butanone is distilled off under reduced pressure. After drying the residue under vacuum a slightly yellow oil (77.5 g, 95%) is obtained, which can be used in the next step without further purification.