Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
N-tert-Butyl-2-(3-(1-hydroxyethyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (143 mg, 296 mol) was dissolved in dichloromethane (4.5 mL) and treated with trifluoroacetic acid (674 mg, 456 μL, 5.91 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (3 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, methanol in dichloromethane) gave N-tert-butyl-2-(3-(1-hydroxyethyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 156 μmol, 53%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.29 (s, 1H), 9.44 (s, 1H), 8.00 (s, 1H), 7.99 (s, 1H), 7.98 (d, J=2.8, 1 H), 7.78 (s, 1H), 7.19 (m, 2H), 6.91 (d, J=7.5, 1 H), 5.17 (d, J=4.0, 1 H), 4.70 (m, 1H), 3.38 (q, J=7.2, 1 H), 1.43 (s, 9H), 1.34 (d. J=6.3, 3 H), 1.09 (t, J=7.2, 1 H); MS (EI/CI) m/z: 354.2 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH3:14])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1.CO[CH:17]=[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=2)[C:21](=[O:29])[NH:20][C:19]1=[O:30]>CN(C)C=O>[I:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:29])[NH:20][C:19](=[O:30])[C:18]2=[CH:17][NH:1][CH2:2][C:3]1[N:4]([CH3:14])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1
Reactant: CCCOc1cn(C)c(CN)cc1=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CCCOc1cn(C)c(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1=O

Procedure:
A mixture of 2-aminomethyl-1-methyl-5-propoxy-1H-pyridin-4-one (196 mg, 1.0 mmole), 10 mL of N,N-dimethylformamide is stirred, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (329 mg, 1.0 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give an off-white solid, 124 mg, (24%); m.p. 176-96° C. dec; MS (ES+): m/z 494.0 (M+H).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][N:12]([CH3:23])[CH2:13][C:14]([CH3:22])([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5]/[CH:4]=[CH:3]/[CH2:2][N:18]1[CH2:19][CH2:20][CH:15]([C:14]([CH3:22])([CH3:21])[CH2:13][N:12]([CH3:11])[CH3:23])[CH2:16][CH2:17]1
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN(C)CC(C)(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(C)(C)C1CCN(C/C=C/C#CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
12 g (6.10-2 mole)of 1-bromo-6,6-dimethyl-2-hepten-4-yne (E/Z=3/1) in solution in 20 ml of N,N-dimethylformamide was added drop-wise to a mixture of 10 g (5.4×10-2 mole) of N,N,β,β-tetramethyl-4-piperidineethanamine and 14.9 g of potassium carbonate in 150 ml of N,N-dimethylformamide. The mixture was stirred for 48 hours at room temperature then poured into water. This was extracted several times with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. The residual oil obtained was purified by silica column chromatography, eluting with a 9/1 (v/v) methylene chloride/methanol mixture. After evaporation of the solvents under reduced pressure, 10.3 g (yield: 56%) of (E)-1-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N,N,β,β-tetramethyl-4-piperidineethanamine was obtained. The corresponding (Z)-2-butene-dioate was obtained from this in ethanol. M Pt=185°-188° C.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][C@H:39]1[O:44][C@@H:43]([CH3:45])[CH2:42][NH:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:45][CH:43]1[O:44][CH:39]([CH3:38])[CH2:40][N:41]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:42]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC(C)O1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 53 mg (0.47 mmol) of (2R,6S)-2,6-dimethylmorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 49 mg (64% of theory)
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[CH2:3]1.[C:21](=O)([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[O:22]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C@@H:33]([O:32][C:21](=[O:22])[NH:1][C@@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:9]=[C:10]([CH3:20])[CH:11]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:13]=2)[CH2:3]1)[CH3:38]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@H](N)C2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 60 °C

Procedure:
To a mixture of 2-[(3S,4R)-3-amino-4-methylpyrrolidin-1-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (10 ml) was added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (41 mg) prepared in Step 1 of Example 1 and DIEA (19 mg) at room temperature. After 4-hour stirring at 60° C., the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl{(3R,4R)-4-methyl-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow foam.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.CCOCC>[Br:7][C:8]1[CH:9]=[C:10]([C:16]2([C:17]#[N:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: BrCCOCCBr
Reactant: COc1ccc(CC#N)cc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1Br
Temperature: 0 °C
Yield: 62.5 %

Procedure:
A mixture of sodium tert-butoxide (6.7 g, 70 mmol) in 100 mL NMP stirred at 0° C. was treated dropwise with a mixture of 2-(3-bromo-4-methoxyphenyl)acetonitrile (6.3 g, 28 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.5 g, 28 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and was stirred for 3 hours, M+Na=318/320. The mixture was quenched with 100 mL H2O carefully and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.18 g of crude product as a yellow solid. MS m/e=318/320 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(OCC)(O[CH2:35][CH3:36])(=O)=O.CN(C)C=O>C(OCC)(=O)C>[CH2:35]([O:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:36]
Reactant: Cc1nc(O)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A mixture of 4′-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (3.01 g), diethyl sulfate (0.41 mL) and N,N-dimethylformamide (20 mL) was stirred at 0° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 16%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Fc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Fc1cncc(NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 85 °C
Yield: 81.6 %

Procedure:
To a stirred and degassed solution of 3-bromo-5-fluoropyridine (1 g, 5.68 mmol), benzophenone hydrazone (1.23 g, 6.25 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (329 mg, 0.57 mmol) in anhydrous toluene (15 mL) at rt under an argon atmosphere, was added palladium acetate (128 mg, 0.57 mmol). The vessel was sealed and heated at 85° C. for 15 h. The reaction mixture was cooled to rt and partitioned between ethyl acetate and water. The organic layer was separated and washed with water, then brine, then dried over magnesium sulfate and filtered. Concentration under reduced pressure gave a brown solid which was purified via silica gel column chromatography (eluting with a gradient of 12% ethyl acetate in hexanes to 100% ethyl acetate) to afford 3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (1.35 g, 82%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.30-7.65 (m, 11H); LC-MS (ESI) m/z 292 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a stirred solution of 0.50 g (3.10 mmol) 1H-indole-3-carboxylic acid in 5 ml DMF was added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromide was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 0.61 g (78%) of 1-benzyl-1H-indole-3-carboxylic acid as a white solid. ES-MS m/e (%): 250 (M−H+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1([C:7]([O:9]CC)=[O:8])[CH2:6][CH2:5]1.C[S-].[Na+].CS(OCC1(C(OCC)=O)CC1)(=O)=O>CN(C)C=O.O>[CH3:1][S:2][CH2:3][C:4]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(CSC)CC1
Agent: CCOC(=O)C1(COS(C)(=O)=O)CC1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC1(C(=O)O)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
Preparation of ethyl 1-(methylthiomethyl)cyclopropanecarboxylate—Sodium methanethiolate (700 mg, 9.9 mmol, 2.0 equiv) was added to a stirred solution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (1.1 g, 4.9 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at 23° C. The resulting brown suspension was stirred at 23° C. for 18 h. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×100 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (860 mg, 99%): 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.34 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.39 g, 56% yield), mp=89–91° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=+24.0° (c=1, EtOH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([NH:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([NH:15][C:2]4[C:11]5[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:17][C:18]=3[CH:24]=2)=[O:27])=[CH:30][C:31]=1[C:36]([F:38])([F:37])[F:39]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Product: COc1cc2c(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)ncnc2cc1O

Procedure:
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[2-(7-hydroxy-6-methoxy-quinazolin-4-ylamino)-benzothiazol-6-yl]-urea was prepared according to GP 1 starting from 4-Chloro-6-methoxy-quinazolin-7-ol and intermediate 3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][CH:5]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]cc(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
Sodium hydride (2.2 g, 54 mmol) was added portionwise to an ice-cold solution of 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4) (10.5 g, 45 mmol) in dimethylformamide (70 ml) under nitrogen. Thirty minutes later, tosyl chloride (8.7 g, 46 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was hydrolysed with water (˜150 ml) and a brown solid was obtained by filtration and dried in vacuo to afford the title compound (14.8 g, 85%). 1H NMR (CDCl3) 2.4 (3H, s), 7.3-7.4 (2H, d), 7.8-7.9 (2H. 2 s), 8.1-8.2 (2H, d), 8.4 (1H, s); MS (ES+) 387
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)C(C(O)=O)[C:9]2=[O:20]>CN(C)C=O.ClCCl>[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)[CH:1]([C:2]([Cl:4])=[O:3])[C:9]2=[O:20]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (4.1 mL, 46.9 mmol) was added dropwise to a solution of (1S,4S)-3-camphorcarboxylic acid (Intermediate 24; 4.0 g, 20.4 mmol) and N,N-dimethylformamide (3 drops) in dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at room temperature for 1.5 h. The solvent was evaporated, and the residue was co-evaporated three times with dichloromethane and then dried under high vacuum to give crude (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride as an orange-brown oil. The crude acid chloride was dissolved in dichloromethane (52 mL) at 0° C., and triethylamine (6.5 mL, 46.8 mmol) and N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 2.29 g, 15.7 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min and then at ˜50° C. for 2 h. The reaction mixture was cooled and partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were dried (sodium sulfate), filtered and evaporated to give crude N-methyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (6.15 g, 93%) which was used directly in the next step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C@@H:34]([CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[C:35]([OH:37])=O)[CH:29]=[CH:30][C:31]=1[F:32].NCC(CC1C=CC=CC=1)C([NH:55][C:56]1[S:57][C:58]([Cl:68])=[C:59]([C:61]2[N:65]([CH3:66])[N:64]=[CH:63][C:62]=2[Cl:67])[CH:60]=1)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:68][C:58]1[S:57][C:56]([NH:55][C:35](=[O:37])[C@@H:34]([CH2:33][C:28]2[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=2)[CH2:38][NH:39][C:40](=[O:41])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:60][C:59]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][C:62]=1[Cl:67]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)C(CN)Cc2ccccc2)sc1Cl
Reactant: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)O)OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CNC(=O)OCc2ccccc2)Cc2ccc(F)c(F)c2)sc1Cl
Reaction time: 12 h
Yield: 20.1 %

Procedure:
Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (401 mg, 0.859 mmol) was added in one portion to a solution of (2S)-3-(3,4-difluorophenyl)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]propanoic acid (200 mg, 0.573 mmol)[prepared in Preparation 4] and [5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine-HCl (163 mg, 0.573 mmol)[prepared in Example 3] in N,N-diisopropylethylamine (0.500 ml, 2.86 mmol) and dichloromethane (7.174 ml). After 12 h, the solution was dry loaded onto silica and purified by chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-2-[(3,4-difluorophenyl)methyl]-3-oxopropyl}carbamate (70 mg, 0.115 mmol, 20.05% yield) as an orange solid: LCMS (ES) m/e 579, 581 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) d ppm 11.61 (s, 1 H) 7.67 (s, 1 H) 7.53 (br. s., 1 H) 7.32 (s, 7 H) 7.03 (br. s., 1 H) 6.55 (s, 1 H) 5.01 (s, 2 H) 3.68 (s, 3 H) 3.19-3.28 (m, 2 H) 2.76-3.00 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:37][O:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:7]
Reactant: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 69 %

Procedure:
The title compound was prepared from reaction of the product of Example 25, Step C, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol, by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]-N-(2-hydroxyethoxy)benzamide as a cream solid (69%); m.p. (Et2O/hexanes) 136-137° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.77 (br s, 1 H), 7.43-7.36 (m, 1 H), 7.15-7.00 (m, 2 H), 6.95-6.77 (m, 2 H), 4.71 (br s, 1 H), 3.85 (t, J=4.8, 2 H), 3.56 (t, J=4.8, 2 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.56 (t, J=7.7 Hz, 2 H), 1.80-1.71 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1C.[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=1>O1CCCC1>[CH3:34][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:33]
Reactant: Cc1ccccc1N=C=O
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 56.1 %

Procedure:
A mixture of 0.93 g 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.37 g of o-tolyl isocyanate in 50 ml of tetrahydrofuran is heated at reflux under argon for 24 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.68 g of the desired product as crystals, m.p. 155°-158° C.