Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)=[N:10][CH2:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)=[CH:14][CH:13]=2)=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Cl[C:47]1[C:52]([Cl:53])=[N:51][CH:50]=[CH:49][N:48]=1.Cl>C1COCC1>[Cl:53][C:52]1[C:47]([CH:11]([NH2:10])[C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)=[CH:14][CH:13]=2)=[N:48][CH:49]=[CH:50][N:51]=1
Reactant: Clc1nccnc1Cl
Reactant: COc1ccc(C(=NCc2ccc3ccc(-c4ccccc4)nc3c2)c2ccc(OC)cc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
N-[bis(4-methoxyphenyl)methylidene]-1-(2-phenylquinolin-7-yl)methanamine (100 mg, 0.22 mmol) was added to a flask and protected by nitrogen. THF (2 mL) was added and a clear solution was obtained. The solution was cooled to −5° C. and then 1.0 M 1,1,1,3,3,3-hexamethyldisilazane, sodium salt in THF (0.26 mL, 0.26 mol) was added. After 20 min, 2,3-dichloropyrazine (36 mg, 0.24 mmol) in THF (1.0 mL) was added. After a further 20 min, 2M HCl (2 mL) was added and the mixture was stirred at room temperature for 10 min. The aqueous mixture was washed with DCM (3×) and then basified to pH 10 with solid potassium carbonate. A white solid precipitated from the aqueous solution and the resulting suspension was extracted with DCM. The organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light yellow oil (67 mg). The yellow oil was further purified by silica gel chromatography (eluted with ethyl acetate/methanol/triethylamine, 10:0.5:1) to yield a colorless oil (63 mg, 83% yield).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=1.[Li+].[OH-]>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:17]1[CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@H:4]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:30])[C:3]([OH:37])=[O:2])=[O:26])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1

Procedure:
Ester 4-5 (147 mg, 0.28 mmol), and 1N LiOH (0.70 mL, 0.70 mmol), were, combined in 3 mL THF. After 16 h the mixture was concentrated and purified by flash chromatography (silica, 33:20:1:1 EtOAc/EtOH/NH4OH/H2O) providing 4-6 as a white solid. Rf 0.33 (silica, 33:20:1:1 EtOAc/EtOH/NH4OH/H2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]#[N:9].[NH:15]([C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)[NH2:16].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]1[NH:9][C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Reactant: COc1ccc(OCC#N)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1OC
Temperature: 160 °C
Yield: 31.9 %

Procedure:
To a n-butanol (10 ml) solution of 2-(3,4-dimethoxyphenoxy)acetonitrile (1.26 g) and (S)-t-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (500 mg), K2CO3 (150 mg) was added. The resulting mixture was stirred at 160° C. for an hour under microwave irradiation. After distilling off the solvent under reduced pressure, water was added, followed by extraction with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography and NH-form silica gel chromatography to give the titled compound (281 mg).
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.N[C:42](N)=[S:43].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CI.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O>[C:20]([O:19][C@@H:8]1[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([S:43][CH3:42])[O:6][C@H:7]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]2[CH:40]=[CH:39][C:34]3[O:35][CH2:36][CH2:37][O:38][C:33]=3[CH:32]=2)[CH:24]=1)(=[O:22])[CH3:21]
Reactant: NC(N)=S
Reactant: CC(=O)OC1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1COCCO1
Product: CS[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To a solution of compound 137 (200 mg, 0.35 mmol) and thiourea (53 mg, 0.70 mmol) in 1,4-dioxane (5.0 mL) was added TMSOTf (96 μL, 0.53 mmol) and the reaction mixture was heated to 80° C. for 3 h. The mixture was cooled to room temperature, and MeI (55 μL, 0.87 mmol) and DIPEA (0.30 mL, 1.75 mmol) were added thereto and the mixture was stirred for 3 h. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by preparative HPLC (reverse phase) to provide the title compound (60 mg, 30%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]([C:21]([O:23]CC)=[O:22])=[CH:19][N:20]=3)[CH2:12][C@H:11]2[O:26][CH3:27])=[O:8])=[N:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[NH:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=3)[CH2:12][C@H:11]2[O:26][CH3:27])=[O:8])=[N:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(C(F)(F)F)c(C)[nH]3)[C@H](OC)C2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(C)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.3 %

Procedure:
Ethyl cis(±)-2-(4-{[(5-methyl-4-trifluoromethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (36f) (30 mg, 0.065 mmol) was dissolved in methanol (1 mL). A 1 N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with 1 N hydrochloric acid, and the residue was purified by reverse phase silica gel column chromatography (elution solvent: distilled water, methanol/distilled water=20/80, 60/40) to obtain 9.1 mg of the title compound as a white solid (32%).
Reaction SMILES: [CH:1]1([C:7]2[CH:33]=[CH:32][C:10]([O:11][CH2:12][C:13]3[N:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:34]([F:37])([F:36])[F:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[C:45]([O:49]C(C)(C)C)(=[O:48])[CH:46]=[CH2:47].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH:1]1([C:7]2[CH:33]=[CH:32][C:10]([O:11][CH2:12][C:13]3[N:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH2:47][CH2:46][C:45]([OH:49])=[O:48])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:34]([F:36])([F:35])[F:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(COc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCN(c2ccc(COc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[6-(4-cyclohexyl-3-trifluoromethyl-phenoxymethyl)-pyridin-3-yl]-piperazine-1-carboxylate (0.021 mmol) in DCM (1 mL) is added trifluoroacetic acid (2 mL). The reaction mixture is stirred at room temperature for 1 hour and evaporated to dryness. The residue is mixed with tert-butyl acrylate (0.3 mmol) and DIEA (0.6 mmol) in MeOH (1.5 mL). The mixture is heated in a microwave oven at 90° C. for 30 minutes and evaporated to dryness. To a solution of the residue in DCM (1.5 mL) is added trifluoroacetic acid (1.5 mL). The reaction mixture is stirred at room temperature for 1 hour. After concentration, the crude residue is purified by preparative RP LC-MS to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-phenoxymethyl)-pyridin-3-yl]-piperazin-1-yl}-propionic acid. 1H NMR (400 MHz, CD3OD) δ 1.18-1.79 (10H), 2.75 (t, J=11.2 Hz, 1H), 2.80 (t, J=6.8 Hz, 2H), 3.37-3.78 (8H), 3.43 (t, J=6.8 Hz, 2H), 5.16 (s, 2H), 7.13 (dd, J=8.4, 2.8 Hz, 1H), 7.15 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.8, 2.8 Hz, 1H), 8.30 (s, 1H); ESI-MS m/z 492.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]C)=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:5]=1[CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:5]=1[CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(C(C)=O)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 64.8 %

Procedure:
To a solution of methyl 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (125 mg) in ethanol (6 ml) was added 1N aqueous sodium hydroxide (0.7 ml), and the mixture was stirred under reflux for 1 hour. The resulting mixture was evaporated in vacuo, and the residue was acidified with 1N hydrochloric acid (0.75 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylic acid (78 mg) as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(CCC(=O)O)cc2)cn1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CCC=O)cc2)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the compound obtained from step d above (9.0 g) in dichloromethane (90 ml), 2,2,6,6,-tetramethylpiperidine N-oxyl (58.77 mg) and potassium bromide (447.57 mg) were added at 0° C. under nitrogen atmosphere. A 4% aqueous sodium hypochlorite (3.497 g) was added at pH 8-9 (maintained by adding saturated aqueous sodium bicarbonate solution). The reaction was stirred for 20 minutes at 0° C. Then, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, water, and brine. Finally, the organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (8.1 g) which was used as such in the next step.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[C@H:32]([NH2:37])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:37][C@H:32]4[C@@H:33]([CH3:36])[CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H]1CCN(Cc2ccccc2)C[C@H]1N
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CCN(Cc2ccccc2)C[C@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 88.5 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (692 mg, 2.10 mmol), racemic cis 1-benzyl-4-methyl-piperidin-3-ylamine (460 mg, 2.30 mmol) and diisopropylethylamine (1.25 mL, 7.20 mmol) in propan-2-ol (30 mL) was heated to reflux for 2 hours. The cooled reaction mixture was filtered and the yellow solid dried under vacuum to afford 940 mg (90%) of racemic cis (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-4-methyl-piperidin-3-yl)-amine. LCMS (Method H, ESI): RT=2.61 min, m+H=506.2; 1H NMR (400 MHz, DMSO) δ: 9.67 (d, 1H), 8.94 (s, 1H), 8.13 (dd, 2H), 7.75 (m, 2H), 7.66 (m, 2H), 7.30-7.10 (m, 6H), 4.54 (d, 1H), 3.49 (m, 2H) 2.83 (t, 2H), 2.27 (d, 1H), 2.07 (m, 1H), 1.91 (br s, 1H), 1.47 (m, 2H), 0.81 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1cncc(N)n1
Product: Cc1cncc(Nc2ccc(C)nc2C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 2-Amino-6-methylpyrazine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a brown solid, MS (ISP): m/e=324.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([I:15])[C:8]([NH:16][C:17](=[O:21])[CH2:18][O:19][CH3:20])=[C:7]([I:22])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:25])=O>CN(C)C(=O)C>[I:1][C:2]1[C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([I:15])[C:8]([NH:16][C:17](=[O:21])[CH2:18][O:19][CH3:20])=[C:7]([I:22])[C:3]=1[C:4]([Cl:25])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)Cl)c1I

Procedure:
A solution of 2,4,6-triiodo-5-methoxyacetamido-N-methylisophthalamic acid in N,N-dimethylacetamide is treated with an excess of thionyl chloride. After the reaction, the excess thionyl chloride is removed by evaporation and the product is suitable for use as intermediate in situ.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)=O>>[Cl:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]=1
Reactant: COc1cc([N+](=O)[O-])c[nH]c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc([N+](=O)[O-])cnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-5-nitro-2-pyridone (5.7 g, 0.034 mole) was added to a combination of phosphorus pentachloride (5.0 g) and phosphorus oxychloride (40 ml); the reaction mixture was refluxed for 2.5 hours, cooled, poured over ice/water (300 ml) and stirred for 30 minutes. The resulting solid was collected by filtration, washed with water and air dried; yield, 1.72 g (27 percent), m.p. 40° to 41° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[C:17]([F:20])[C:18]=1[F:19]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:15]3[CH:16]=[C:17]([F:20])[C:18]([F:19])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1cc(F)c(F)c(F)c1
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (7.394 mmol) and 3-(3,4,5-trifluoro-phenyl)-propionaldehyde (1.391 g; 7.394 mmol) afforded 3-ethyl-1-iodo-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.74 min.; [M+H]+=435.86 g/mol.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:19])([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[C:17]#[N:18])[CH3:6])(=[O:3])[CH3:2].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>>[C:1]([O:4][C:5]([CH3:19])([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:20](=[O:23])(=[O:22])[NH2:21])[C:11]=1[C:17]#[N:18])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CC(=O)OC(C)(C)CCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 4-(3-amino-2-cyanophenoxy)-2-methylbutan-2-yl acetate (Example 231b) and sulfamoyl chloride in 100% yield. MS 342 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:15][OH:16].C[O-].[Na+].CO>CO>[OH:16][N:15]=[C:10]([NH2:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1
Reactant: NO
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cccc(C(F)(F)F)c1)=NO
Yield: 20.6 %

Procedure:
m-(Trifluoromethyl)phenylacetonitrile (30.0 g, 0.16 mol) was added to a suspension of hydroxylamine hydrochloride (18.8 g, 0.27 mol), methanol (145 mL) and 25% sodium methoxide/methanol (62 mL, 0.27 mol) at room temperature. The reaction mixture was then heated to reflux for 2 hours, cooled and concentrated in vacuo. The residue was partitioned between methylene chloride and water. The organic layer was separated and dried over magnesium sulfate. The organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by hexane/ethyl acetate (8/2). The desired product (7.2 g, 21%) was obtained as a white solid, m.p. 91°-92° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:29])([CH3:28])[C:5](=[O:27])[CH2:6][NH:7][C:8]([C:10]1[C:11]([S:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].CCCCCC.CC(=O)OCC>CCO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][S:16][C:11]2[C:10]([C:8]([NH:7][CH2:6][CH:5]([OH:27])[C:4]([CH3:28])([CH3:3])[CH3:29])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)C(=O)CNC(=O)c1cccnc1SCCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)C(O)CNC(=O)c1cccnc1SCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
70 mg (1.8 mmol) of NaBH4 were added in portions at 0° C. to a solution of 350 mg (0.9 mmol) of N-(3,3-dimethyl-2-oxo-butyl)-2-[3-(4-fluoro-phenyl)-propylsulfanyl]-pyridine-3-carboxylic acid amide (exemplary compound 125) in EtOH (7 ml). Stirring was then carried out for 2 h at RT. The mixture was then cooled to 0° C., quenched with a sat. aq. NH4Cl sol. (20 ml) and concentrated in vacuo. The residue was taken up in EA and the solution was washed with a 1M aq. NaHCO3 sol., water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 3:2) of the residue yielded 320 mg (0.82 mmol, 91%) of 2-[3-(4-fluorophenyl)-propylsulfanyl]-N-(2-hydroxy-3,3-dimethyl-butyl)-pyridine-3-carboxylic acid amide. MS: m/z 391.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([NH2:15])=[N:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:19])[C:17]#[CH:18]>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]2=[N:15][C:16](=[O:19])[CH:17]=[CH:18][N:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC[C@@H](COCc2ccccc2)O1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: O=c1ccn2c(n1)O[C@H](COCc1ccccc1)C2
Temperature: 25 °C
Yield: 27.5 %

Procedure:
To a solution of (S)-5-(benzyloxymethyl)-(4,5-dihydro-oxazol-2-yl)amine (6.02 g, 29.4 mmol) in ethanol (210 mL) was added ethyl propiolate (2.97 mL, 29.4 mmol). The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature, concentrated under vacuum and purified by column chromatography on silica gel (4:1 ethyl acetate:heptanes to 10% methanol in dichloromethane) to provide 2.09 g (28%) of the title compound. [α]D25 −30.09 (c 0.545, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH4+].[Cl-].C1C=CC2N(O)N=[N:20]C=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([NH2:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-2-thiophenecarboxylic acid (7.50 g, 43.3 mmol), NH4Cl (6.95 g, 130 mmol), HOBT (8.62 g, 56.3 mmol), and EDC (12.46 g, 65.0 mmol) were combined with DMF (100 mL) and DIEA (15.13 mL, 87.0 mmol). The reaction was stirred at room temperature overnight. The brown solution was concentrated, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. The solid residue was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([CH3:14])[CH:3]=1.BrC1C=CC([C@@H](O)C(F)(F)F)=C(N2C=CC(C)=N2)C=1>[Ir]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)C(F)(F)F
Agent: [Ir]
Agent: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Product: Cc1cc(Br)ccc1[C@@H](O)C(F)(F)F

Procedure:
Chiral reduction of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol provides (R)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [CH2:1]([C:5]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:26]([O:36]C)=[CH:25][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[CH2:1]([C:5]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:26]([OH:36])=[CH:25][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(-c2ccc(F)cc2)c(OC)cc1OCCCOc1ccccc1CCC(=O)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Yield: 56 %

Procedure:
Ethyl 3-(2-(3-(2-butyl-4-(4-fluorophenyl)-5-methoxyphenoxy)propoxy)phenyl)propionate in dichloromethane was treated with 2 equivalents of boron tribromide at -75° C. The mixture was stirred without cooling for 18 hours, washed with water, dried, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol to provide the desired title product in 56% yield. NMR.