Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:29]\[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)C)n1
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate (1.16 g) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 0.24 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.57 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:2, v/v) to give 2-isopropyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 1.2%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.O1CCC[CH2:22]1.[H-].[Na+].CI>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:22])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: C1CCOC1
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H- 1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([CH3:36])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: Cc1cc(P(C)(C)=O)ccc1N
Product: Cc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-methylaniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O.ClCCl>[CH2:28]([O:27][C:21]1[CH:22]=[C:23]([N:35]2[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])=[O:30])[CH3:29]
Reactant: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CN1CCCNCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 65.6 %

Procedure:
5-Fluoro-2-[4-fluoro-2-ethoxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (135 mg, 0.31 mmol) and 1-methylhexahydro-1,4-diazepine (177 mg, 1.55 mmol, 5 eq) were dissolved in 250 μL DMSO, in a 4 mL screw cap vial. The pale yellow solution was incubated at 100° C. for 36–40 hours. The solution was cooled, diluted with 12 mL of dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated in vacuo. The crude residue was purified first by chromatography on a silica gel cartridge (2 g/12 cc, Varian Sample Preparation Products, Harbor City, Calif.) using zero to ten percent methanol in dichloromethane, then by radial chromatography with zero to ten percent methanol in dichloromethane. Pure fractions were pooled, concentrated in vacuo and dried under high vacuum to yield 107 mg (65%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:20]=3)[NH:15][C:14]=2[CH3:29])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OC(C)c1ccc(F)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCC3)cc2c1C(=O)OC(C)c1ccc(F)cc1
Yield: 79.7 %

Procedure:
To a solution of the product of Step A (58 mg, 0.14 mmol) in dioxane (1 mL) was added pyrrolidine (0.14 mL, 1.4 mmol) and the resultant solution was heated at 70° C. overnight. The reaction solution was concentrated in vacuo and the crude product purified by flash chromatography (9:1 Ethyl Acetate:Methanol w/0.5% triethylamine) to provide the compound (44 mg, 80%) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>O1CCOCC1>[C:1]1([S:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)C1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 55 %

Procedure:
To a microwave vial were charged 4-(phenylsulfonyl)piperidine (300 mg, 1.33 mmol), 2-chloro-3-(trifluoromethyl)pyridine, (484 mg, 2.66 mmol), diisopropylethylamine (0.695 mL, 3.99 mmol) and 1,4-Dioxane (0.2 mL). The reaction mixture thus prepared was irradiated at 200° C. for 1 hour. The reaction was complete as determined by TLC. The residue was added with saturated NH4Cl (aq.) and extracted with ethylacetate, washed with 10% HCl (aq.), water then brine. Organic layer was dried over MgSO4. Solvent evaporation afforded 2-[4-(phenylsulfonyl)piperidin-1-yl]-3-(trifluoromethyl)pyridine in 55% yield (270 mg) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:27]#[N:28])[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8]C1N=C(NC2C=CC(C#N)=CC=2)N=C(N)C=1Br.[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[CH:33]=[C:32](Cl)[N:31]=1.CC1C=C(C=C(C)C=1O)C#N>>[Cl:29][C:30]1[N:31]=[C:32]([O:8][C:7]2[C:2]([CH3:1])=[CH:3][C:4]([C:27]#[N:28])=[CH:5][C:6]=2[CH3:26])[CH:33]=[C:34]([Cl:36])[N:35]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C#N)cc(C)c1Oc1cc(Cl)nc(Cl)n1

Procedure:
WO 2010150279 describes a process for the formation of Etravirine, comprising condensation of 2,4,6-trichloropyrimidine with 3,5-dimethyl-4-hydroxybenzonitrile to give 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethyl benzonitrile, which is condensed with 4-aminobenzonitrile. Aminolysis of the resulting compound followed by halogenation gives Etravirine.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:22]3[C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:15]=3)=[CH:7][CH:6]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN(C=O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[C:22]3[N:10]([CH2:9][C:8]4[CH:37]=[CH:38][C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:6][CH:7]=4)[C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:20]=2[CH:26]=1)=[CH:15][C:14]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:13][CH:12]=4
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 65 °C

Procedure:
Intermediate #18, 11-[4-(2-Chloroethoxy)-benzyl]-8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo[a]carbazole, (6 g, 11.5 mmol) in DMF was treated with KI (2.5 g, 15.0 mmol) and piperidine (12 mL) and heated to 65° C. for 18 hours. The reaction was worked up by pouring the crude reaction mixture into water and extracting with ethyl acetate. The ethyl acetate layer was washed with NaHCO3 aq., brine and dried over MgSO4. The resultant was chromatographed on silica gel using CH2Cl2 (100%), CH2Cl2 :MeOH (98:2), CH2Cl2 :MeOH (96:4) as the eluting solvents. The product (3.2 g) was isolated as an oil: 1H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J=8.4 Hz, 2.6 Hz), 6.73 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 3.98 (t, 2 H, J=6.0 Hz), 3.70 (s, 3 H), 2.85-2.78 (m, 2 H), 2.75 (s, 2 H), 2.60 (t, 2 H, J=6.5 Hz), 2.42-2.38 (m, 4 H), 1.70-1.58 (m, 4 H), 1.58-1.35 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH3:2].[CH:9]1([N:12]=[C:13]=[O:14])[CH2:11][CH2:10]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:7][CH2:6][C:5]([O:8][C:13](=[O:14])[NH:12][CH:9]1[CH2:11][CH2:10]1)=[N:4][O:3][CH2:1][CH3:2]
Reactant: CCONC(=O)CCl
Reactant: O=C=NC1CC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCON=C(CCl)OC(=O)NC1CC1
Temperature: 25 °C

Procedure:
N-Ethoxychloroacetamide (13.7 grams; 0.1 mole), benzene (60 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. Cyclopropylisocyanate (10 grams; 0.12 mole) dissolved in benzene (20 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)=[N:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:21])#[N:25]
Reactant: COc1ccc(CN(CCN(C)CCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20° C. and is recrystallised from ethanol/ether; MS (+FAB method): m/z (rel. int. [%])=596 ([M+H]+, 1), 121 (100); IR (KBr): 2163 cm-1 (C≡N); m.p.: 56°-58° C. (ethanol/ether).
Reaction SMILES: C([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:17][C:14]1([F:16])[CH2:15][CH:9]2[NH:8][CH:13]1[CH2:12][C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:18])[CH2:10]2
Reactant: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)CC1(O)CC2CC(F)(F)C(C1)N2
Yield: 90 %

Procedure:
Step VIIII: A mixture of compound 116i (340 mg, 1 mmol, 1.0 eq) and Pd(OH)2/C (100 mg, 30%) in MeOH (20 mL) was stirred at room temperature for 16 h under 1 atmosphere of hydrogen. The mixture was filtered, and the filtrate was concentrated to give ethyl 2-(6,6-difluoro-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)acetate 116a as a colorless oil, 224 mg, yield: 90%. MS: calc'd (MH+) 250, measured (MH+) 250.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]C23C=CC=CC2C(NC3=O)=O)[C:4](=[O:21])[C:3]1=[O:22].O.[NH2:24]N.O.[ClH:27]>C(O)C>[ClH:27].[NH2:24][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:22])[C:4]1=[O:21]
Reactant: CN1CCN(CCC23C=CC=CC2C(=O)NC3=O)C(=O)C1=O
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCN(CCN)C(=O)C1=O
Temperature: 40 °C
Yield: 85 %

Procedure:
To a solution of 3.60 g (11.95 mmol) of 2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL of ethanol was added 695 μL (14.34 mmol) of hydrazine monohydrate and the mixture was stirred at 40° C. for over night. The reaction mixture was cooled to room temperature, then, 25 mL of water and 6 mL of 6N—HCl were added to this mixture and the mixture was stirred for 5 hours at room temperature. After removed off the insoluble substances by filtration, the filtrate was concentrated and the residue was re-crystallized by 2% water-ethanol solution to give 2.12 g (85%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH:44][CH3:45]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([N:44]([CH3:45])[CH3:43])=[O:22])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazole-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2.0 M tetrahydrofuran solution of dimethylamine (65.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(dimethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.2 mg).
Reaction SMILES: C(Cl)(C)(C)C.[Li].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.FC1C=CC=C(F)C=1[Li].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([C:9]1[C:8]([F:7])=[CH:13][CH:12]=[CH:11][C:10]=1[F:14])=[O:26]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Li]
Agent: [Li]c1c(F)cccc1F
Solvent: CC(C)(C)Cl
Solvent: C1CCOC1
Product: CC(=O)c1c(F)cccc1F
Temperature: -65 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of tert-butyllithium in THF is firstly produced by reacting 9.25 g of tert-butyl chloride with 1.4 g of lithium granules in 100 g of THF at −78° C. After a conversion of >97% (GC a/a) has been reached, 1,3-difluorobenzene (11.4 g) is added and the mixture is stirred for another 30 minutes at −78° C. and subsequently for 2 hours at −65° C. The resulting solution of 2,6-difluoro-1-lithiobenzene is added dropwise to a solution of 22 g of acetic anhydride in 35 g of THF which has been cooled to −5° C. After the usual aqueous work-up, 2,6-difluoroacetophenone is obtained in a yield of 92%.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29]C(=O)OC(C)(C)C.CO[Si](C)(C)C>CN1C(=O)CCC1>[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: CO[Si](C)(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1OC
Temperature: 150 °C
Yield: 35.5 %

Procedure:
To 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (500 mg, 1.6 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (692 mg, 3.2 mmol) in NMP (1.5 mL), methoxy trimethylsilane (0.5 mL, 3.6 mmol) was added and the mixture heated to 150° C. for 65 h. The mixture was concentrated under high vacuum to obtain a sticky crude mass that was purified by chromatography (silica, 100-200 mesh, 1-10% methanol in dichloromethane) to give 6-((1R,2S)-2-amino-cyclohexylamino)-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (220 mg 35%) as a yellow solid. LC-MS 388 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](I)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.[CH3:28][S:29]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([Sn](C)(C)C)[N:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:34]3[N:33]=[C:32]([S:29]([CH3:28])(=[O:30])=[O:31])[N:37]=[C:36]([N:38]4[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:40][CH2:39]4)[CH:35]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc(S(C)(=O)=O)n3)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.203 mmol) and tert-butyl 1-(2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (105 mg, 0.203 mmol) in DMF (1.5 mL) followed by Pd(PPh3)4 (11.74 mg, 10.16 μmol) and CuI (7.8 mg, 0.041 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water, and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-80% EtOAc in hexanes) to give tert-butyl 1-(6-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (86 mg, 0.119 mmol, 58.7% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 721.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:6]1[C:2]([CH3:1])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 26 mg of white crystals.
Reaction SMILES: [F:1][C:2]([F:42])([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([N+:24]([O-])=O)[CH:16]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:42])([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([NH2:24])[CH:16]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N)cc(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 70.1 %

Procedure:
4.99 g (8.38 mmol) of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.15 g of 3,5-diaminobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate as yellow crystals.