Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OCC)(OCC)(OCC)[CH3:44].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[C:43]3[CH3:44])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2nc(C)n3Cc2cc(-c3ccc(F)cc3)no2)cc1
Yield: 23.6 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthoacetate (2.9 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional triethyl orthoacetate was added. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.48 g) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:22]CC2C=CC(OC)=CC=2)[C:5]([NH:8][C:9]([C:11]2[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=2[Cl:16])=O)=[N:6][CH:7]=1.[C:32](O)([C:34]([F:37])([F:36])[F:35])=O>>[C:17]([C:14]1[C:15]([Cl:16])=[C:11]([C:9]2[NH:22][C:4]3=[N:3][C:2]([C:18]4[CH:17]=[CH:14][CH:15]=[CH:11][C:32]=4[C:34]([F:37])([F:36])[F:35])=[CH:7][N:6]=[C:5]3[N:8]=2)[N:12]([CH3:21])[N:13]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1ccc(CNc2nc(Br)cnc2NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)cc1
Reactant: O=C(O)C(F)(F)F
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2ncc(-c3ccccc3C(F)(F)F)nc2[nH]1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide (28 mg, 0.04 mmol, prepared as described in the previous step) in TFA (3.5 mL) was stirred at 65° C. for 3 h. The resulting mixture was allowed to cool to room temperature, TFA was removed in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO3 (20 mL). EtOAc layer was separated, dried (Na2SO4), and concentrated in vacuo. The resulting residue was dissolved in HOAc (3.5 mL) and stirred at 100° C. overnight. The resulting mixture was allowed to cool to room temperature and the HOAc was removed in vacuo. The resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO3 (10 mL). EtOAc layer was separated, dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified on silica 0:100-50:50 EtOAc-hexane to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyrazine. 1H-NMR (CD3OD) δ: 8.53-8.57 (br s, 1H), 7.82-7.86 (m, 1H), 7.68-7.74 (m, 1H), 7.61-7.67 (m, 1H), 7.57-7.60 (m, 1H), 4.19 (s, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H18ClF3N6: 435.1 (M+H); Measured: 435.1.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[ClH:18].N([O-])=O.[Na+]>[Cl-].[Na+].O.O>[Cl:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: Cl
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A mixture of 7-ADCA (25 g, 0.117 mol), ethanol (700 ml), water (163 ml) and concentrated hydrochloric acid (163 ml) was cooled to 5° C. Sodium nitrite (11.5 g, 0.167 mol) was added in small portions over 25 minutes and the mixture was stirred for 3.5 hours at 0°-5° C.; 300 ml of brine was added and the reaction mixture was extracted with methylene chloride. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated (16.1 g, 58.9%). This crude acid was directly used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[N:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][S:17][CH2:18][CH2:19]3)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=2[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCSCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M26) (265 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[CH:2]=1.[OH-].[Na+]>CO>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:2]=1
Reactant: CCOC(=O)c1ccc(-c2cnn3cccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cnn3cccnc23)cc1
Temperature: 50 °C
Yield: 99.3 %

Procedure:
To a mixture of the compound form Step 1 ethyl 4-(pyrazolo[1,5-a]pyrimidin-3-yl)benzoate (64 g, 0.24 mol) in MeOH (1 L) was added an aqueous solution of sodium hydroxide (600 mL, 1.2 mol, 2 M). The mixture was heated at 50° C. for 3 h. The mixture was then concentrated to remove the volatiles. The resulting suspension was diluted with water, and aqueous HCl (1 N) was added dropwise until pH 4. The acidified suspension was filtered, and the solids were collected and dried to give the title compound (57 g, 99%) as a yellow solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([F:16])[CH:9]=1>C1COCC1.[Cl-].[Na+].O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:1])=[C:10]([F:16])[CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)cc1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A solution of KOt-Bu (19.5 g, 174 mmol) in dry THF (300 mL) was cooled with an ice/water bath. Portionwise addition of MePPh3Br (62.2 g, 174 mmol) resulted in a suspension, which was stirred for 5 min at 0° C. and for 1 h at 15° C. Subsequently, the temperature was lowered to 0° C. and a solution of 4-chloro-2-fluorobenzaldehyde (25.1 g, 158 mmol) in dry THF (100 mL) was added dropwise. The temperature was raised to room temperature slowly. The reaction mixture was stirred at room temperature for 20 h. Addition of brine (100 mL) resulted in a clear two phase system and a white solid. The combination of layers was decanted from the solid. The layers were separated, the aqueous layer was combined with the solid residue and Et2O (200 mL). The combination of layers was decanted from the solid. The layers were separated, the combination of organic layers was dried (Na2SO4) and concentrated at a controlled vacuum of 100 mbar. The residual oil was combined with pentane (300 mL) and Na2SO4. The suspension was triturated. Filtration and pentane washing provided a filtrate, which was concentrated at a controlled vacuum of 100 mbar to arrive at 26.76 g (97%, 90% purity) of impure title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])C.[OH-].[Na+].Cl>CO>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]([CH:6]=[C:5]([CH3:20])[C:4]([OH:21])=[O:3])=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=1
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=C(C)C(=O)O)c([N+](=O)[O-])cc1OC
Yield: 99 %

Procedure:
Into 250 ml of methanol, 11.3 g of thus obtained 3-(4,5-dimethoxy-2-nitrophenyl)-2-methyl-2-propenoic acid ethyl ester (1) were dissolved. With 45 ml of a 2-N aqueous sodium hydroxide solution being added thereto, the resulting mixture was reacted for 4 hours at 40° C. After the completion of the reaction, 1-N hydrochloric acid was used so as to adjust the pH of the solution at 4, the solution was cooled, and the precipitated crystal was filtered out, whereby 10.1 g of the aimed compound were obtained (yield: 99%).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1>O1CCCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[N:5]=[N:4][C:3]([NH2:1])=[N:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Reactant: N
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(F)cc2)nn1
Temperature: 50 °C

Procedure:
Ammonia gas was bubbled through a solution of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (600 mg, 0.0029 mol) in tetrahydrofuran (8 mL) for 5 min at −40° C. The reaction mixture was sealed and heated at 50° C. for 2 hours. The mixture was concentrated under reduced pressure to yield the desired product (550 mg) which was directly used in the next step without further purification. LCMS: (M+H)=209.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24].[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][N:31]=1)(=[O:29])=[O:28])[CH3:26]>>[CH2:25]([S:27]([C:30]1[N:31]=[CH:32][C:33]([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[O:6][C:2]([CH3:1])=[C:3]([CH2:22][CH2:23][OH:24])[N:4]=3)=[CH:12][CH:11]=2)=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc(I)cn1
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Product: CCS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)cn1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Intermediate 9 using 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (See Intermediate 3) and 2-Ethanesulfonyl-5-iodo-pyridine (See Intermediate 22). MS (m/e) 373.3 (M+1)
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CNCCC1(OC)OC
Reaction time: 3 h

Procedure:
The title compound was prepared by taking tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate (424 mg, 0.00154 mol) in Methylene chloride (10 mL, 0.2 mol) and adding Trifluoroacetic Acid (1 mL, 0.02 mol). The reaction was stirred for 3 h. The solvent was removed in vacuo and the crude taken to the next step (270 mg, 99%). MS calculated for C8H17NO3: (M+H) 176; found 176.1.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:27]([NH:30][CH3:31])(=[O:29])=[O:28].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[O:9])=[C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:5]=[CH:4][C:3]=1[S:27]([NH:30][CH3:31])(=[O:29])=[O:28]
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1F
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1F

Procedure:
The title compound was prepared according to the procedure described for example 202 from 2,4-Difluoro-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide (example CD) and morpholine to yield the title compound as a colourless foam, MS (m/e): 529.3 (M+H, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH2:32][CH2:31]2)=[O:29])[CH2:24][CH2:23]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11](=[O:13])[NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH2:32][CH2:31]2)=[O:29])[CH2:24][CH2:23]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN)CC2)CC1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(NC(=O)OC(C)(C)C)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-tert-Butoxycarbonylamino-3-phenyl-propionic acid (0.43 g, 1.63 mmol) in DCM (20 mL), 1,1-carbonyldiimidazole (0.24 g, 1.48 mmol) was added and the reaction was stirred for 2 hours at room temperature. Then 1-[trans-4-(4-Aminomethyl-cyclohexanecarbonyl)-piperazin-1-yl]-2-methyl-propan-1-one (0.40 g, 1.36 mmol) was added and the mixture was left for 18 hours at room temperature. The mixture was diluted with 10 mL of 0.4 M Na2CO3, the organic phase was collected and the solvent removed under reduced pressure. The residue was washed with 20 mL solution of NH4Cl and the precipitate filtered. The titled compound was isolated as a white solid (0.65 g, 88% yield).
Reaction SMILES: C([Mg]Cl)C=C.BrCCl.[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C([Li:22])CCC.Cl>C1COCC1>[CH:9]1([Li:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Agent: C=CC[Mg]Cl
Agent: Cl
Agent: ClCBr
Solvent: C1CCOC1
Product: [Li]C1C=Cc2ccccc21
Temperature: 30 °C
Reaction time: 14 h

Procedure:
In Example 5, 3H-1-(but-3-enyl)indene was prepared. About 100 mL of a 2 M solution of allylmagnesium chloride in THF was added to a solution of 13 mL of bromochloromethane (200 mmol) in 50 mL of THF. This mixture was refluxed for 3 hr and then stirred for 14 hr. A solution of indenyl lithium was prepared from 30 mL of 90% indene (232 mmol) and 85 mL 2.5 M n-butyllithium in 100 mL of THF. This solution was then added by cannula to the mixture over 1 hr, and the resulting mixture was refluxed for 6 hr. Then, the mixture was poured into 200 mL of 1M HCl, followed by extraction with 100 mL of pentane. The extract was washed with 3×100 mL of water, dried over sodium sulfate and concentrated with a rotary evaporator while heating to 30° C. The residue was distilled through a 6-inch 14/20 Vigreux column at 0.01 mm Hg, and product collected at 79-80° C. Next, the product was evacuated to further remove light materials. The resulting indene material contained greater than 90% buttenylindene.
Reaction SMILES: [NH2-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][N:5]=1.N(C1C=C(C)C(F)=CN=1)[N+]([O-])=[O:14]>>[NH2:3][C:4]1[C:9]([OH:14])=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][N:5]=1
Reactant: Cc1cc(N[N+](=O)[O-])ncc1F
Reactant: Cc1cc(N)ncc1F
Agent: [NH2-]
Agent: [Na+]
Product: Cc1c(F)cnc(N)c1O

Procedure:
When 3-amino-4-picoline is subjected to diazotization in fluoboric acid as in Example I-1, there is obtained 3-fluoro-4-picoline. Treatment of the latter intermediate with sodium amide as in Example I-1, gives 2-amino-5-fluoro-4-picoline. Following the procedure of Example I-15, but substituting 2-nitramino-5-fluoro-4-picoline, there is obtained 2-amino-5-fluoro-4-methyl-3-pyridinol.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4]([CH:22]2[CH2:25][O:24][CH2:23]2)[CH2:3]1>CCO.[Pd]>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:20])([F:19])[F:21])[CH2:6][CH2:5][N:4]([CH:22]2[CH2:25][O:24][CH2:23]2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2CCN(C3COC3)C[C@H]2F)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O[C@@H]2CCN(C3COC3)C[C@H]2F)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)-1-(oxetan-3-yl)piperidine (0.9 g, 1.0 eq, 2.6 mmol) and Pd—C (10%, 0.3 g) in EtOH (50 mL) was hydrogenated at 30 psi for 1 hour. The mixture was filtered through celite and the filter cake washed with EtOH (2×10 mL). The filtrate was concentrated under vacuum to give the desired product in 90% yield. This product was taken to next step with out further purification.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4]1.[H][H]>CO.[Pd]>[ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N[C@H]1CCC[C@H]2CCCCN2C1=O
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To round bottom flask, 10% Pd/C (35 mg, 0.022 mmol) was added to a solution of (7S,10aR,Z)-7-amino-1,2,3,4,7,8-hexahydropyrido[1,2-a]azepin-6(10aH)-one hydrochloride (3.23 gm, 1.49 mmol) in MeOH (5 mL). A hydrogen atmosphere was introduced via balloon and the reaction mixture was stirred for 3 hr. The reaction mixture was diluted with MeOH and filtered. The filtrate was concentrated and the residue was dried under vacuum to give (7S,10aR)-7-aminooctahydropyrido[1,2-a]azepin-6(7H)-one hydrochloride (299 mg, 1.37 mmol, 92% yield) as a light yellow solid. Anal. Calcd. for C10H18N2O m/z 182.2. found: 183.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[F:19][C:20]([F:25])([F:24])[C:21](O)=O>Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:21]([C:20]([F:25])([F:24])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Agent: Cl
Product: FC(F)(F)c1nc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2[nH]1
Yield: 66 %

Procedure:
A solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and hydrogen chloride (conc. 1 ml) was stirred overnight at 80° C. The reaction was then quenched water (100 ml), extracted with ethyl acetate (2×50 ml) and the organic layers combined. The resulting mixture was washed with saturated aqueous NaHCO3 (100 ml), dried over anhydrous sodium sulfate and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (82.4 mg, 66%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CC[C@H](O)C1

Procedure:
By using (S)-3-hydroxypyrrolidine (1.0 g) as a starting material, the title compound (195 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:13]=1[C:14](Cl)=[O:15].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:14](=[O:15])[C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[Cl:11])[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cc(F)ccc2Cl)c1
Yield: 57 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-chloro-5-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-chloro-5-fluorobenzamido)-isonicotinamide was obtained as a colorless solid in 57% yield: mp 180-181° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) (9.15 (d, J=13.8 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.07 (dd, J=6.6, 2.8 Hz, 1H), 7.58 (d, J=4.2 Hz, 1H), 7.52-7.46 (m, 1H), 7.36-7.12 (m, 6H), 6.67 (s, 1H), 4.65 (d, J=5.7 Hz, 2H); MS (ES+) m/z 384.5 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]([OH:16])[CH3:15])=[CH:13][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:6][CH2:5][C:4]1=[O:24])[CH3:2].CN(C)C1C=CC=CC=1.[CH3:34][O:35][CH2:36]Cl.Cl>>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]([O:16][CH2:34][O:35][CH3:36])[CH3:15])=[CH:13][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:6][CH2:5][C:4]1=[O:24])[CH3:2]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)O)ccc21
Reactant: COCCl
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)OCOC)ccc21
Reaction time: 96 h

Procedure:
A mixture of 3 g (9.2 mmol) of 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-2H-1,4-benzodiazepin-2-one, 4.7 ml of dimethylaniline and 1.4 ml of chlorodimethyl ether is left to stand under argon at 50° for 1 hour and at room temperature for 4 days. The mixture is made acid at 0° C. with 1 N hydrochloric acid, extracted with chloroform/ethanol (9:1) and the organic phase is washed with water. After drying and evaporating, the residue is chromatographed on 100 g of silica gel using chloroform as the elution agent. There is obtained 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(methoxymethoxy)ethyl]-2H-1,4-benzodiazepin-2-one as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1.[CH:17]([O-])=[O:18].[Na+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:14][C:13]=2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=2)[CH3:16]
Reactant: O=C[O-]
Reactant: CCn1c2c(c3cc(Br)ccc31)CCCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(C=O)ccc31)CCCC2
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 3-bromo-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole (2 g, 7.22 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), sodium formate (740 mg, 10.88 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (500 mg, 0.72 mmol, 0.10 equiv) and CO (500 mL). The resulting solution was heated to 110° C. in an oil bath for 3 hours. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the resulting solution was diluted with ethyl acetate (200 mL) and then quenched by the addition of brine (200 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehyde as pale yellow solid (1.5 g, 70%).