Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[CH3:19])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:42])[F:41])[N:32]=[CH:31][C:30]=1[CH:44]([CH3:46])[CH3:45]>CC#N>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:42])([F:41])[F:43])[N:32]=[CH:31][C:30]=3[CH:44]([CH3:46])[CH3:45])=[CH:14][C:13]=2[CH3:19])[CH:5]=1
Reactant: CC(C)c1cnn(-c2ccccc2C(F)(F)F)c1CBr
Reactant: COC(=O)c1cccc(C=Cc2ccc(O)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)cnn3-c3ccccc3C(F)(F)F)cc2C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-[2-(4-hydroxy-2-methyl-phenyl)-vinyl]-benzoic acid methyl ester (107 mg, 0.4 mmol) and potassium carbonate (138 mg, 1 mmol) in CH3CN (4 mL) is added 5-bromomethyl-4-isopropyl-1-(2-trifluoromethyl-phenyl)-1H-pyrazole in CH3CN (4 mL, approximately 0.1 mmol/mL). The reaction mixture is stirred at 80° C. for 5 hours and filtered through a Celite® pad eluting with EtOAc. The combined filtrate is concentrated and purified by column chromatography (0 to 20% EtOAc in hexanes) to give the desired product, 136 mg (64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH:16]([C:18]2[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[OH:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCC1(C(=O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
Yield: 64.3 %

Procedure:
A mixture of 3-[(4,5-dichloro-thiophen-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.423 g, 1.07 mmoles) and manganese(IV) oxide (1.3 g, 12.7 mmoles) in toluene (20 ml) was refluxed for 2 hours and filtered through a celite pad. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to yield 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester as pale yellow solid (0.27 g, 64%). M+Na: 414.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[CH3:8][C:9]([CH3:18])([CH3:17])[C:10](=O)[CH2:11][C:12](OC)=[O:13].C[O-].[Na+].O>CO.C(O)(=O)C>[CH3:8][C:9]([C:10]1[N:7]=[CH:5][N:6]=[C:12]([OH:13])[CH:11]=1)([CH3:18])[CH3:17]
Reactant: N=CN
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Formamidine acetate (2.172 g, 20.86 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (3.0 g, 18.96 mmol) were added to a mixture of sodium methoxide (2.203 g, 40.8 mmol) in methanol (20 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. Water (5 mL) and acetic acid (2.2 mL) were added and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated with ethyl acetate, filtered and washed with a small volume of ethyl acetate. The solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (1.66 g);
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:10][O:11][CH2:12][C:13]#[CH:14])[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([NH:4][C@H:5]([CH2:10][O:11][CH2:12][C:13]#[CH:14])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C#CCOC[C@@H](NC(C)=O)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCOC[C@@H](NC(C)=O)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
(R)-Methyl 2-acetamido-3-(prop-2-ynyloxy)propanoate (1.00 g, 5.03 mmol) was dissolved in THF (24 mL) and cooled to 0° C., and LiOH (aqueous 0.6 M sol., 8.4 mL, 5.03 mmol) was added. The reaction solution was stirred at 0° C. (2 h) and then concentrated in vacuo. The resulting aqueous phase was diluted with H2O (12 mL) and washed with Et2O (2×20 mL). The aqueous layer was acidified to pH 1-2 with aqueous 1 M HCl, and extracted with EtOAc (6×20 mL). The combined organic phases were washed with saturated aqueous brine (80 mL), dried (Na2SO4) and evaporated in vacuo to yield 0.87 g of desired product (94%) as a yellow oil: Rf=0.35 (15/5/1 EtOAc/hexanes/AcOH); IR (nujol mull) 2924, 2120, 1726, 1642, 1548, 1459 cm−1; 1H NMR (CD3OD) δ 2.01 (s, CH3C(O)), 2.88 (t, J=2.6 Hz, CH2CCH), 3.77 (dd, J=3.6, 9.7 Hz, CHH′OCH2), 3.92 (dd, J=5.0, 9.7 Hz, CHH′OCH2), 4.18 (d, J=2.6 Hz, OCH2C), 4.61-4.64 (m, CH); 13C NMR (CD3OD) δ 22.5 (CH3C(O)), 54.1 (CH), 59.3 (CH2CCH), 70.4 (CH2OCH2), 76.5 (CH2CCH), 80.2 (CH2CCH), 173.1, 173.5 (2 C(O)); HRMS (ESI) 186.0761 [M+H+] (calcd. for C8H12NO4 186.0766); Anal. (C8H11NO4, 0.14H2O) Calcd.: C, 51.18%; H, 6.06%; N, 7.46%. Found: C, 51.15%; H, 6.13%; N, 7.27%.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[O:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:4][C:23]1[C:19]([O:18][C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:10][C:9]=2[Cl:17])=[N:20][NH:21][C:22]=1[CH3:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Sulfuryl chloride (0.48 g, 3.6 mmol) was added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.93 g, 3.0 mmol) in acetic acid (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of 4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.57 g, yield: 55.0%). mp: 156-158° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (s, 3H), 7.65 (s, 2H), 8.75-9.15 (br s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with naphthalene-1-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(naphthalen-1-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([Li])(C)(C)C.C[Si]([N:28]=[C:29]=[O:30])(C)C>O1CCCC1>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C@H:5]1[CH2:6][C:7]2[CH:8]=[C:9]([C:29]([NH2:28])=[O:30])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)[CH2:2][CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(Br)cc2C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1CCc2ccc(C(N)=O)cc2C1
Reaction time: 0.13 h
Yield: 132.4 %

Procedure:
A solution of (R)-2-(dipropylamino)-7-bromo-1,2,3,4-tetrahydronaphthalene (7) (13.02 g) in dry tetrahydrofuran was cooled to -78° C. t-Butyllithium (1.7 M in pentane, 50.6 ml) was added via syringe over a period of 6 minutes, and the mixture was stirred for an additional 8 minutes. Trimethylsilylisocyanate (13.4 ml, 85% pure, 84.1 mmol) was added in one dose, and the mixture stirred at -78° C. for 10 minutes and at room temperature for 1.5 hours. The reaction mixture was quenched with 10% hydrochloric acid, and after stirring for 30 minutes, it was basified with 15% sodium hydroxide. The free base was extracted with diethylether and 1:1 tetrahydrofuran/diethylether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an oil (15.25 g). Crystallization from ethyl acetate/hexane gave off-white crystals (6.30 g), m.p. 132-132° C. [α]D =+67° (25° C., CH3OH, c=0.8139).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:7]=2[CH:14]=1)#[N:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][N:8]([C:15]3[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH:20]=3)[C:7]=2[CH:14]=1)#[N:2]
Reactant: O=C1CCCCC1=O
Reactant: CC1(C)CNc2cc(C#N)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CN(C2=CCCCC2=O)c2cc(C#N)ccc2O1
Yield: 66.7 %

Procedure:
In 15 ml of toluene were dissolved 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 0.33 g of cyclohexane-1,2-dione and a catalytic amount of p-toluenesulfonic acid and using a Dean-Stark trap, the solution was refluxed under heating for 4 hours. After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were washed with ethanol to give 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(6-oxo-1-cyclohexen-1-yl)-2H-1,4-benzoxazine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH:14]=[CH:13]3)=[O:5].[H][H].C(Cl)(Cl)Cl.CO>O.[Pd].CCOCC>[CH3:1][NH:2][CH2:3][C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH2:14][CH2:13]3)=[O:5]
Reactant: [H][H]
Reactant: CNCC(=O)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: CNCC(=O)NCC1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Yield: 65 %

Procedure:
The compound obtained in Example 233 (1.2 g, 3.5 mmol) was dissolved in water (40 ml). To the obtained solution, 10% palladium-on-carbon (1.3 g) was added, followed by stirring at 80° C. for 12 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was subjected to a recrystallizing procedure using chloroform--methanol--ether to obtain 690 mg of the title compound as colorless powdery crystals (58.0%).
Reaction SMILES: C[C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4](C)[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:2]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of cis-2,6-dimethylpiperazine and triethylamine in DCM at 0° C. was added dropwise methanesulphonyl chloride and the reaction mixture stirred at room temperature overnight. After quenching with water, extraction into DCM and being washed with brine, the organics were dried and the solvent removed under reduced pressure to yield 1-Methanesulfonyl-piperazine as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.C(N(C(C)C)CC)(C)C>[C:31]([O:34][CH2:35][C:36]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])=[O:37])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1

Procedure:
By using 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.15 g 0.35 mmol), diisopropylethylamine (Aldrich) (150 μl ), 4-dimethylaminopyridine (0.04 g 0.32 mmol) and acetoxyacetyl chloride (Aldrich) (0.109 g 0.8 mmol), the title compound was obtained in the manner of Example 19 as a white solid (0.14 g 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-].O.C(Cl)Cl>C(O)C.[Fe].CO>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
A mixture of 5-chloro-4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 75, 350 mg, 0.71 mmol), iron (237 mg, 4.25 mmol) and NH4Cl (26.5 mg, 0.50 mmol) were heated at reflux in ethanol (24 mL) and water (8 mL) for 2 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and CH3OH, and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-5% methanolic ammonia in CH2Cl2 gave the title compound (288 mg, 88%) as a yellow dry film; 1H NMR: 2.26 (3H, s), 2.47-2.56 (4H, m), 2.88 (4H, t), 3.70 (3H, s), 4.29 (2H, d), 6.72 (1H, s), 7.04 (1H, t), 7.14 (1H, s), 7.15-7.22 (1H, m), 7.46 (1H, d), 8.18 (1H, s), 8.35 (2H, d), 8.48 (1H, d), 11.81 (1H, s); m/z: ES+ MH+ 464.49.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([F:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][N:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
3-(1,1-Difluoro-ethyl)-isoxazol-5-ylamine (100 mg, 0.68 mmoles) from the previous step was dissolved in 6 mL of dry THF. To this solution was added potassium carbonate (122 mg, 0.88 mmoles) and phenyl chloroformate (138 mg, 0.88 mmoles) and the reaction stirred overnight at room temperature. The reaction was filtered and concentrated to a yellow oil, and purified using silica gel chromatography with and ethyl acetate/hexane gradient 0-20% over 70 minutes to give phenyl 3-(1,1-difluoroethyl)isoxazol-5-ylcarbamate (141 mg) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.4-7.1 (m, 5H), 6.9 (m, 1H), 6.4 (s, 1H), 4.9 (s, 1H), 2.0 (m, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[C:35]([O:39][C:40]([NH:42][S:43]([C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49])(=[O:45])=[O:44])=[O:41])([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:48]([C:47]5[CH:51]=[CH:52][CH:53]=[CH:54][C:46]=5[S:43]([NH:42][C:40](=[O:41])[O:39][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:44])=[O:45])=[O:49])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (238 mg, 0.47 mmol, 1 eq.) in dimethylformamide (14 mL) was added 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoic acid 1b (140 mg, 0.47 mmol, 1 eq.) and N,N-diisopropylethyl amine (0.3 mL, 1.41 mmol, 3 eq.). After stirring at RT for several minutes, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (179 mg, 1.41 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried and concentrated to provide crude tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.Cl[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)C2=O.FC1C=C2C(=CC=1)NC(=O)C2=O>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]1[C:19](=[N:20][C:21]3[C:22]([C:10]1=[O:12])=[CH:23][CH:15]=[CH:16][CH:17]=3)[C:7]2=[O:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(Cl)ccc2-n2c1nc1ccccc1c2=O

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-chloroisatin for 5-fluoroisatin gave the title compound in 39% crude yield: mp 295°-296° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46-8.53 (m, 1H), 8.33 (d, 1H), 7.96 (d, 2H), 7.69-7.84 (m, 3H); MS (M+H)+ 283.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[CH:15])=[CH:10][N:9]=2)=[C:4]([CH3:16])[CH:3]=1.I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]#[C:15][C:18]3[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[N:12][CH:13]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1cnc(-c2ccc(Cl)cc2C)cn1
Product: Cc1cc(Cl)ccc1-c1cnc(C#Cc2ccc(OCCN3CCC(C)(O)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product was prepared analogously to Example 48.1c from 200 mg (0.88 mmol) of 2-(4-chloro-2-methylphenyl)-5-ethynylpyrazine and 316 mg (0.88 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (stirring the reaction mixture overnight at RT). Yield: 30 mg (7% of theoretical); C27H28ClN3O2 (M=461.983); calc.: molpeak (M+H)+:462/464 (Cl); found: molpeak (M+H)+:462/464 (Cl); HPLC-MS: 5.43 minutes (method G; Zorbax-Bonus).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33]C)=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 500 mg (20.9 mmol) LiOH in 10 mL water was added to a solution of 6.7 g (13.6 mmol) of (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 300 mg (12.5 mmol) LiOH were added and the reaction solution was stirred for 3 h at 40° C. It was evaporated down i.vac., the residue was taken up in 15% K2CO3 solution and extracted exhaustively with DCM. The aqueous phase was acidified with 4 M HCl, exhaustively extracted with DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH2:5]1)[CH:2]=[CH2:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCC1Cn2c(ncc(C(=O)OCC)c2=O)-c2cc(OC)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCc1cn2c(=O)c(C(=O)OCC)cnc2c2cc(OC)ccc12

Procedure:
A mixture of ethyl 7-allyl-6,7-dihydro-10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.5 g., 4.41 mmoles) and DDQ (1.1 g., 4.85 mmoles) in toluene (30 ml.) containing acetic acid (0.05 ml.) was refluxed for 18 hours. The mixture was filtered and the filtrate concentrated to dryness. Trituration of the residue with methanol gave a solid which was recrystallized from ethanol to give 201 mgs. of brown crystals, m.p. 182°-186°. The methanol mother liquor was concentrated to dryness and the residue chromatographed on silicic acid with toluene-acetone (20:1) to give additional product (230 mgs.), m.p. 177°-183° after recrystallization from ethanol. The material with m.p. 182°-186° was chromatographed in a similar manner and the product so obtained combined with the material with m.p. 177°-183° and the lot recrystallized from ethanol to give yellow needles of the title compound, m.p. 187°-188°.