Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(O)C3)o2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reaction time: 7 h
Yield: 71.9 %

Procedure:
A suspension of 73A (5.45 g, 19.8 mmol) in dichloromethane (100 ml) was cooled in an ice-bath. Triethylamine (4.4 mL, 31.7 mmol) was added followed by methanesulfonyl chloride (2.3 mL, 29.7 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The mixture was transferred to a reparatory funnel and was washed with water followed by aqueous NaHCO3 (sat.). The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was filtered. The product was washed twice with diethyl ether and then dried in vacuo. There was obtained 5.03 g (72%) of 73B as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 3.90 (s, 3H), 4.42 (dd, 1H), 4.64 (dd, 1H), 4.86 (dd, 1H), 5.11 (dd, 1H), 5.40 (m, 1H), 7.02 (d, 2H), 8.09 (d, 2H), MS (APCI+) m/z 354 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>CO.Cl.B#[Ni]>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)=[CH:11][C:10]=1[CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cc2ccc([N+](=O)[O-])cc2)n(C)c1C(=O)c1ccccc1
Agent: B#[Ni]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(Cc2ccc(N)cc2)n(C)c1C(=O)c1ccccc1
Temperature: 75 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a slurry of 4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]nitrobenzene (3.55 g, 10.6 mmol) [prepared as in Example 2, Step (a)] in methanol (170 ml) and hydrochloric acid (50 ml, 1M) was added nickel boride (3.41 g, 26.6 mmol), and the mixture was stirred at 75° C. for 15 h. The reaction mixture was cooled, basified with ammonium hydroxide and the product was extracted into ethyl acetate. The organic phase was washed with water and dried over sodium sulfate. Evaporation of the solvent gave 4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (3.11 g, 96%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:16][C:17]1[CH:40]=[CH:39][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:31][C:30]([C:32](OCC)=O)=[C:29]([CH3:37])[CH:28]=3)[C:23]2=[O:38])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:7]([CH:8]1[CH2:9][NH:10][C:32]([C:30]2[S:31][C:27]([N:24]3[CH2:25][CH2:26][N:22]([CH2:21][C:20]4[CH:39]=[CH:40][C:17]([F:16])=[CH:18][CH:19]=4)[C:23]3=[O:38])=[CH:28][C:29]=2[CH3:37])=[N:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C1=NC(Cc2ccccc2)CN1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a stirred solution of (S)-3-phenylpropane-1,2-diamine (0.37 g, 2.48 mmol) in toluene (20 mL) at 0° C. under nitrogen atmosphere was added dropwise trimethylaluminum (1.24 mL of 2.0 M solution in toluene, 2.48 mmol). When the fuming ceased, ethyl 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate (0.60 g, 1.66 mmol) in toluene (5 mL) was added slowly. The resulting mixture was stirred at reflux for 18 h, cooled to ambient temperature and partitioned between ethyl acetate (75 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3×75 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with dichloromethane/methanol/triethyl amine (9/1/0.1) to afford the title compound as brown viscous oil in 29% yield (0.06 g): MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N+:6]([O-:8])=[O:7])[CH3:2].[CH3:10][Si:11](C)([CH3:15])[CH2:12]CO.O>C1C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N+:6]([CH2:5][C:4]([O:3][CH2:1][CH2:2][Si:11]([CH3:15])([CH3:12])[CH3:10])=[O:9])([O-:8])=[O:7]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C[Si](C)(C)CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: c1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOC(=O)C[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a stirred solution of nitroacetic acid ethyl ester (5.0 g, 37.6 mmol) and 2-(trimethylsily)ethanol (7.27 g, 61 mmol) in dry benzene (100 mL) is added titanium tetraisopropoxide (1.05 q, 3.69 mmol) and the mixture is heated at reflux for 1 hour. The solution is cooled to 40° C. and water (2 mL) is added and stirring is continued for 10 minutes at room temperature. The solvents are evaporated and the residue is taken up in dichloromethane and dried over anhydrous magnesium sulfate. The mixture is filtered through a small pad of Celite and the solvent is evaporated. The residue is purified by distillation to give nitroacetic acid, 2-(trimethylsily)ethyl ester (6.10 g, 79%) as a colorless liquid. B.pt. 90°-95° C./0.3 mmHg.
Reaction SMILES: [CH3:1][CH:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]([C:15]1([CH2:19]O)[CH2:18][O:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]12[CH2:16][O:17][C:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[C:9]#[CH:10])([O:8][CH2:19]1)[O:7][CH2:18]2)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CC(C)CCCC(=O)O
Product: C#CC(C)CCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(4-methylhex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 5-methylhept-6-ynoic acid and 3-t-butyl-3-hydroxymethyl oxetane as described in Example I.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 6 (120 mg, 0.274 mmol) was reacted with isopropyl sulfonyl chloride (43 mg, 0.30 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.75 (d, J=8.54 Hz, 1 H) 8.20 (d, J=6.71 Hz, 1 H) 7.58 (d, J=8.54 Hz, 1 H) 7.26 (d, J=7.93 Hz, 1 H) 7.17-7.21 (m, 2 H) 7.08 (d, J=9.16 Hz, 2 H) 6.95 (d, J=8.54 Hz, 2 H) 6.15 (d, J=6.71 Hz, 1 H) 3.43-3.51 (m, J=13.43, 1H) 2.79 (t, J=7.63, 7.63 Hz, 2 H) 2.20 (s, 3 H) 1.61-1.67 (m, 2 H) 1.21 (d, J=6.71 Hz, 6 H) 0.78 (t, J=7.32 Hz, 3 H); MS (ESI+) m/z 508 (M+H)+.
Reaction SMILES: [Br-].[Li+].[C:3]([Br:6])(=O)[CH3:4].[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[CH:13]=CC(Cl)=[N:16][CH:17]=1)[CH3:8].[OH-].[Na+]>C(#N)C.O>[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[CH:13]=[CH:4][C:3]([Br:6])=[N:16][CH:17]=1)[CH3:8]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CC(=O)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1ccc(Br)nc1
Temperature: 90 °C
Yield: 49.5 %

Procedure:
Lithium bromide (3.2 g, 37 mmol) and acetyl bromide (1.3 mL, 17 mmol) were added to a solution of (2-chloro-pyridin-5-yl)acetic acid ethyl ester (1.08 g, 5.42 mmol) in acetonitrile (7.2 mL), and the mixture was heated under reflux at an external temperature of 86 to 94° C. for 31 hours. The reaction mixture was dissolved in water. The solution was neutralized with a sodium hydroxide aqueous solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (655 mg, 53%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:27][C:22]1[CH:21]=[C:20]([S:19][C:13]2[N:12]([CH2:28][CH2:29][OH:30])[C:11]([CH2:10][CH2:9][OH:8])=[N:15][C:14]=2[CH:16]([CH3:18])[CH3:17])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CC(C)c1nc(CCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCO)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 94.9 %

Procedure:
In 15 ml of cocentrated hydrochloric acid was dissolved 1.5 g (3.2 mmol) of the alcohol compound (130d), and the mixture was heated at 110° C. for 7 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol/ethyl acetate), and 1.14 g of 2-(5-(3,5-dichlorophenylthio)-2-(2-hydroxyethyl)-4-isopropyl-1H-imidazol-1-yl)ethanol (131c) was obtained as oil (yield 94%).
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH2:8]2.[CH3:14][CH2:15][O-].[Na+].Cl>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH:8]2[CH2:10][CH:9]1[C:5]2[C:6](=[C:15]([CH3:14])[CH:11]=[CH:12][C:4]=2[CH3:3])[CH:7]=[CH:8]1
Reactant: CC[O-]
Reactant: Cc1ccc(C)c2c1C=CC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c2c1C=CC2CC1C=Cc2c(C)ccc(C)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Paraformaldehyde (2.08 g, 69.4 mmol) was added to a mixture of 4,7-dimethylindene (25.0 g, 174 mmol) and EtONa (5.9 g, 87 mmol) in DMSO (200 mL) at 25° C. After stirring at room temperature for 12 hours, the reaction mixture was heated at 65° C. for 8 hours. It was then cooled to room temperature and a solution of HCl (1 M, 400 mL) was added. The mixture was extracted with CH2Cl2 (400 mL); the organic phases were combined, washed with a saturated solution of NaCl and then with water, dried with MgSO4, filtered and finally concentrated to yield a brown viscous liquid. GC analysis showed only the final product and the starting material, no fulvene derivative being detectable. Precipitation occurred when the brown liquid was added into pentane (100 mL). Bis(4,7-dimethylindenyl)methane was obtained as a yellow solid after filtering and washing with pentane and EtOH, with a yield of 33% (6.8 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15](O)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)([Cl:23])=O>CN(C)C=O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[CH2:15][Cl:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: NS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
A suspension of 4.0 g. of 6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 120 ml. of thionyl chloride is treated with 1 ml. of dimethylformamide and stirred at room temperature for 4 hours. The mixture is diluted with 200 ml. of hexane and the precipitate of 6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride is collected, washed with hexane and dried. The acid chloride is used as such without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1

Procedure:
Analogously to the process described in Example 9, 125 mg (0.247 mmol) of the compound from Example 3A and 50 mg (0.495 mmol) of 4-hydroxypiperidine were used to obtain 16 mg (12% of theory) of the title compound.
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][CH2:8][CH:9]([C:11](=[O:20])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:10])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:36]1([C:42]([NH:44][CH:45]([CH2:49][S:50]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)(=[O:52])=[O:51])C(O)=O)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.FC(F)(F)C(O)=O>[CH2:13]([NH:12][C:11]([C:9](=[O:10])[CH2:8][NH:7][C:6]([CH:45]([NH:44][C:42]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:43])[CH2:49][S:50]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)(=[O:52])=[O:51])=[O:21])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCC(O)C(=O)NCc1ccccc1
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=C(CNC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
(2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.2 g, 0.68 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). After stirring for 2 h at ambient temperature, the solution was evaporated under vacuum and the residue was dried under high vacuum. To this residue were added EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.28 mmol), 2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (200 mg, 0.56 mmol), dichloromethane (5 mL) and 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO3 (30 mL) and brine (30 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (500 mg, 1.18 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with 0.26M Na2S2O3 in sat. aqu. NaHCO3 (30 mL), sat. aqu. NaHCO3 and brine, dried with MgSO4, and evaporated under vacuum. The product (morpholine-4-carboxylic acid [1-(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide) was crystallized from ethyl acetate/diethylether and was obtained as a white solid (153 mg, 0.29 mmol). 1H NMR: (DMSO) 9.24 (t, J=6.4 Hz, 1H), 8.19 (t, J=5.6 Hz, 1H), 7.39–7.19 (m, 10H), 7.08 (d, J=8 Hz, 1H), 4.83–4.76 (m, 1H), 4.49 (s, 2H), 4.48–4.33 (m, 2H), 4.31 (d, J=6.8 Hz, 2H), 3.68–3.25 (m, 10H). MS: (M+H)+ 531.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]3[N:22]4[CH:23]=[C:24]([C@@H:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=3)=[N:15]2)=[CH:10][C:9]=1[F:45])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]3[N:22]4[CH:23]=[C:24]([C@@H:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=3)=[N:15]2)=[CH:10][C:9]=1[F:45])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 80.5 %

Procedure:
2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-7-yloxy)ethyl acetate (40 mg, 0.063 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield 2-(2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl acetate (27 mg, 80% yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 505 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.5 %

Procedure:
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0° C. was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49% yield) as pale yellow oil. LC/MS, (ESI) m/z 206.1 [(M+H)+, calcd for C7H6Cl2NO2 205.97]; LC/MS retention time (method D): tR=0.85 min. 1H NMR (300 MHz, CD3OD) δ ppm 8.42 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][C:21]1([CH3:31])[N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:24]2[C:23](=[O:30])[NH:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]3[C:21]([CH3:31])([CH3:20])[NH:22][C:23](=[O:30])[CH:24]3[CH2:29]2)=[CH:7][CH:8]=1
Reactant: CC1(C)NC(=O)C2CNCCN21
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC1(C)NC(=O)C2CN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CCN21

Procedure:
A mixture of 169.8 parts of 1,1'-(4-chlorobutylidene)bis[4-fluorobenzene], 93.5 parts of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 128.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 1200 parts of 4-methyl-2-pentanone was stirred and refluxed for 8 hours using a water-separator. After cooling overnight to room temperature, the reaction mixture was filtered. The filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was filtered off and dried, yielding 108 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one; mp. 148.4° C. (intermediate 90).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B(Br)(Br)Br>C1CCCCC1>[OH:19][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccc3c(Sc4ccccc4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Solvent: C1CCCCC1
Product: Oc1cccc(-c2ccc3c(Sc4ccccc4)c(O)ccc3c2)c1

Procedure:
The compound was prepared by reacting 2-methoxy-6-(3-methoxyphenyl)-1-(phenylsulfanyl)naphthalene (376 mg, 1.01 mmol, 1 eq.) with boron tribromide (8 ml of a 1 M solution in cyclohexane, 8 mmol, 8 eq) according to method G. Yield: 325 mg (94%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:29]([F:32])([F:31])[F:30])=[N:20][N:21]([CH:24]([CH3:28])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:29]([F:31])([F:30])[F:32])=[N:20][N:21]([CH:24]([CH3:28])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]propanoic acid (0.035 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.044 mmol, 32%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.02 (s, 1H), 7.34-7.24 (m, 2H), 7.21-7.11 (m, 2H), 5.05 (q, J=7.2 Hz, 1H), 3.03-2.91 (m, 1H), 2.38 (s, 3H), 1.90 (d, J=7.2 Hz, 3H), 1.25 (dd, J=13.9, 7.1 Hz, 3H), 1.08 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H20ClF4N5O [M+H]+ 458.1, found 457.9.