Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH:19]([CH3:30])[CH2:18]2)=[N:14][CH:15]=1)#[N:9]>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:30][CH:19]1[NH:20][CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:15][N:14]=2)[CH2:18]1
Reactant: CC1CN(Cc2ccc(C#N)cn2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C#N)cn2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.8 mL) was added dropwise to the cold solution of tert-butyl 4-((5-cyanopyridin-2-yl)methyl)-2-methylpiperazine-1-carboxylate (200 mg, 0.63 mmol) in CH2Cl2 (3 mL) at 0° C. and the reaction mixture was further stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 6-((3-methylpiperazin-1-yl)methyl)nicotinonitrile TFA salt (180 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C12H16N4: 216.14. found: 217.0 (M+H)+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:25][Mg]Br.Cl>O1CCCC1.C(=O)=O.CC(C)=O.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]([OH:20])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (8.49 g, 25.5 mmol) in anhydrous tetrahydrofuran (102 mL) in dry ice/acetone bath was added methylmagnesium bromide (1 M in butyl ether, 25.5 mL, 25.5 mmol). The solution was then warmed to room temperature and stirred overnight. The reaction was acidified with hydrogen chloride (2 N, 10 mL) until pH 2, diluted with water, and extracted with ethyl acetate (2×). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as an orange liquid (8.80 g, 94%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.27-8.11 (m, 2H), 7.90-7.68 (m, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 4.98 (q, J=6.5 Hz, 1H), 1.54 (d, J=6.5 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 350 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:14]([NH:16][NH2:17])=O>C(O)CCC>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:14]=[N:16][N:17]=3)[N:4]=2)[CH:9]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: c1cncc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.5 g. of 3-chloro-6-(3-pyridyl)pyridazine and 0.96 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is refluxed for 48 hours. The reaction mixture is concentrated, partitioned and crystallized as described in Example 1 to afford 1.0 g. of the product of the Example as a cream colored solid, m.p. 199°-200°.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[N+:18]([C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)[CH:12]=[CH:13][C:14]=1[OH:17])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Oc2ccnc3[nH]ccc23)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Oc2ccnc3[nH]ccc23)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)phenol (Step b, 5.6 g, 24.8 mmol, 1.0 eq.) was dissolved into AcOH (100 ml) and HNO3 (70%, 2.4 mL, 26.7, 1.1 eq.) was added dropwise. The reaction was stirred for 1 h at RT. The acids were removed by evaporation and the residue was taken up in NaHCO3 (aq., saturated, 100 mL) and CH2Cl2 (200 mL). Separated the layers and washed the organic layers with NaHCO3 (aq., saturated, 50 mL) and brine (50 mL). Back extracted aqueous layers with CH2Cl2 (100 ml) and dried the combined organic layers over MgSO4, filtered and concentrated. Further purification by column chromatography (0-100% EtOAc/Hexane) yielded 2-nitro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[S:32][C:33]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[CH2:7][C:8](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[N:2]1.OO.[Li+].[OH-].Cl.[C:51]([O-])([O-])=[O:52].[K+].[K+].IC>C1COCC1.CCOC(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[S:32][C:33]([C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=4)=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[CH2:7][C:8]([O:52][CH3:51])=[O:9])=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 61.5 (76 mg, 0.12 mmol) in THF (1 mL) were added 30% H2O2 (0.14 mL, 1.2 mmol) and 1N LiOH (0.60 mL, 0.60 mmol) at 0° C. The mixture was stirred for 1 hour at 0° C., adjusted to pH 3 with aqueous HCl, and extracted with EtOAc. The combined organic layers were washed with 1N Na2SO3 (pH 3) and brine, dried (Na2SO4), and concentrated. The residue was dissolved in 9:1 MeCN/DMF (1 mL), and to the solution were added K2CO3 (25 mg, 0.18 mmol) and iodomethane (11 μL, 0.18 mmol). The mixture was stirred overnight at room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-40% EtOAc/hexane) to afford 61.6 as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([F:17])([F:16])[F:15])=[C:8]2[CH2:18][C:19]([NH2:21])=[O:20])[CH3:3].C[O:23][C:24](=O)[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=O.CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O.CN(C=O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([F:16])([F:15])[F:17])=[C:8]2[C:18]1[C:19](=[O:20])[NH:21][C:24](=[O:23])[C:25]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH3:3]
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN(C)Cc1ccc2[nH]c(C(F)(F)F)c(CC(N)=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2[nH]c(C(F)(F)F)c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetamide (59.2 mg, 0.198 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (60.3 mg, 0.297 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (0.989 mL) under an argon atmosphere at 0° C., followed by the addition of DMF(1.0 mL). The resulting deep red reaction mixture is stirred for 1 h at room temperature, diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. The crude product is dissolved in DMF (1.0 mL), DBU (300 1μL) is added, and the thus obtained solution is heated for 5 min. at 100° C. After cooling, the reaction mixture is diluted with EtOAc and washed with brine. The aqueous layer is extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford a red solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 8:1:1) affords the title compound as an orange solid (11 mg, 0.024 mmol, 12%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=12.54 (bs, 1H), 11.78 (bs, 1H), 11.06 (bs, 1H), 7.95 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (t, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.51 (t, J=8.1 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 3.10 (AB-system: δA=3.24 (d, JAB=−12.4 Hz, 1H), δB=2.97 (d, JAB=−12.4 Hz, 1H), 1.70 (s, 6H). MS (ES+): 453 (M(C24H19F3N4O2)+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.ClC1SC2NC(C(NC3CC4C(=CC=CC=4)N(CC(O)CO)C3=O)=O)=CC=2C=1.[Cl:40][C:41]1[S:70][C:44]2[NH:45][C:46]([C:48]([NH:50][CH:51]3[CH2:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]([CH2:61][C@@H:62]4CO[C:64](C)(C)[O:63]4)[C:52]3=[O:69])=[O:49])=[CH:47][C:43]=2[CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[S:70][C:44]2[NH:45][C:46]([C:48]([NH:50][CH:51]3[CH2:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]([CH2:61][CH2:62][O:63][CH3:64])[C:52]3=[O:69])=[O:49])=[CH:47][C:43]=2[CH:42]=1
Reactant: CC1(C)OC[C@@H](CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Solvent: ClCCl
Product: COCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 42 %

Procedure:
EDCI (225 mg, 1.17 mmol) was added to a suspension of 5-carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9, 234 mg, 1.06 mmol) and 3-amino-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one (Method 12; 215 mg, 1.06 mmol) in DCM (20 mL) and the reaction stirred for 18 hours. The reaction was evaporated and the residue was partitioned between DCM:MeOH (9:1) (100 mL) and water (25 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (9:1)) to afford the title compound (180 mg, 42%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Yield: 102.3 %

Procedure:
To a mixture of 2-chloro-4-methyl-5-nitropyridine (5.44 g, 26.3 mmol) and dibenzylamine (5.04 mL, 26.3 mmol) in toluene (13.1 mL) was added sodium carbonate (5.58 g, 52.6 mmol). After stirring under a nitrogen atmosphere under reflux for 36 h, the reaction mixture was filtered to remove the sodium carbonate. The filtrate was concentrated to provide the crude material as a light orange oil. The crude oil was dissolved in methylene chloride and treated with 2 N HCl. The resulting precipitate was filtered off and discarded. The filtrate was washed with 2 N HCl and the acidic layers were back-extracted with methylene chloride. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated to provide 2-(dibenzylamino)-5-nitro-4-methylpyridine (8.97 g, 102% theoretical) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ2.53 (3H, s), 4.85 (4H, s), 6.27 (1H, s), 7.19-7.37 (10H, m), 9.05 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH:25]([NH2:30])[CH2:24][C:23]1([CH3:32])[CH3:31]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:25]2[CH2:24][C:23]([CH3:31])([CH3:32])[N:22]([CH3:21])[C:27]([CH3:29])([CH3:28])[CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Product: CN1C(C)(C)CC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1(C)C

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1,2,2,6,6-pentamethylpiperidin-4-amine (20.4 mg, 0.12 mmol). The title compound was obtained as a solid (16.9 mg, 34% yield). MS m/z: 503.09, 505.08 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH3:9])[C@@H:3]([OH:7])[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][C@@H:2]([CH2:8][CH3:9])[C@@H:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC[C@H](N)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
0.759 g (5.70 mmol) of (2R, 3S)-3-amino-2-hydroxypentanoic acid were admixed with a solution of 1.199 g (14.28 mmol) of sodium hydrogen carbonate in 20 ml of water, and with 20 ml of dioxane. The resulting mixture was cooled with ice. To this solution was dropwise added a solution of 1.623 g (6.27 mmol) of 9-fluorenylmethyl chloroformate in 10 ml of dioxane under cooling with ice for 30 minutes. After the completion of the addition, the reaction mixture was stirred at room temperature for 2 hours, diluted with 100 ml of water, and successively washed with 150 ml of ether and 75 ml of ether. To the aqueous layer were added 2.8 ml of 6N hydrochloric acid to adjust to pH 1.5. Then the aqueous layer was extracted three times with 50 ml of ethyl acetate. The oil layer was washed with 50 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom, so that 1.622 g of crude (2R, 3S)-3-(9-fluorenylmethoxycarbonyl)amino-2-hydroxypentanoic acid were obtained.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl[CH:20](C)CC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH2:11][CH3:20])([CH3:7])[CH3:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Cl)CC(=O)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 74 %

Procedure:
Compound 9s was synthesized by a procedure similar to that described for 9a using 3-chlorobutyrophenone (8j, 3.1 g, 0.0169 mol), TBDMSOTf (4.3 mL, 18.6 mmol), and Et3N (3.8 mL) in CH2Cl2 (30 mL). After purification, 3.7 g (74%) of the title product was isolated as colorless oil: 1H NMR (CDCl3) δ 7.48-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.31-7.29 (m, 2H), 5.16 (t, 1H, J=7.1 Hz), 2.30-2.19 (m, 2H), 1.09-1.03 (m, 3H), 1.01 (s, 9H), −0.04 (s, 6H); 13C NMR (CDCl3) δ 147.5, 141.7, 133.9, 129.2, 127.3, 125.9, 123.8, 114.9, 25.8, 19.5, 14.1, 0.0, −4.1. C16H25ClOSi.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[N:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[O:30][CH3:31].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][C:6]1[C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:3]([O:2][CH3:1])=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:29])[F:28])=[CH:21][C:20]=2[O:30][CH3:31])[N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CNc2cnc(-c3ccc(OC(F)(F)F)cc3OC)c(OC)n2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(OC)c(-c3ccc(OC(F)(F)F)cc3OC)nc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of {6-methoxy-5-[2-methoxy4-(trifluoromethoxy)phenyl]pyrazin-2-yl }[(4-methoxyphenyl)methyl]amine (870 mg, 2.0 mmol) in chloroform (10 mL) is cooled to 0° C. and N-bromosuccinimide (356 mg, 2.0 mmol) is added in portions. After the addition, the mixture is further stirred for 1 h while being allowed to warm to room temperature. The mixture is washed with saturated aqueous sodium bicarbonate, aqueous sodium chloride, dried (magnesium sulfate), filtered, and evaporated to give {3-bromo-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl }[(4-methoxyphenyl)methyl]amine (920 mg), a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 62B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:33])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(cc(NC3CCN(C)CC3)c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.42 h

Procedure:
To a mixture of 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (50. mg, 0.13 mmol, from Example 206) and formaldehyde (37 wt % solution in water, 12 mg, 0.15 mmol, Aldrich) in DCM (2.6 mL) was added Na(OAc)3BH (42 mg, 0.20 mmol, Aldrich). After 25 minutes, volatile solvent was removed in vacuo. The mixture was diluted with water and methanol, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (24.8 mg, 49%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:24]([CH3:25])=[CH:23][S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[C:24]([CH3:25])=[CH:23][S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cscc1-c1ccccc1C(Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 150 °C
Yield: 38.1 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep HPLC to give 15.1 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluro-1-(2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.94(d, J=8 Hz, 2H), 7.80(s, 1H), 7.50(m, 5H), 7.25(m, 2H), 7.03(s, 1H), 6.94(s, 1H), 4.31(t, J=5.6, 1H), 3.48(m, 1H), 3.26(m, 1H), 1.98(s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].[Cl:15]C1C=C2C(=CC=1)NC(=O)C2=O.BrCCC>>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available 5-chloroisatin (purchased from Fisher Scientific) and 1-bromo-propane (purchased from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.88 (d, 1H), 3.69 (t, 2H), 1.74 (m, 2H), 1.00 (t, 3H)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1>>[C:17]1([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(CCN2CCOCC2)cc1Br
Product: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1

Procedure:
This compound is prepared by Suzuki coupling of 2-bromo-4-(2-morpholin-4-yl-ethyl)-phenylamine (as prepared in the previous step) and 1-cyclohexen-1-yl-boronic acid according to the procedure in Example 1, step (e). Mass spectrum (ESI, m/z): Calcd. for C18H26N2O, 287.2 (M+H). found 287.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:42])[CH3:43])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous brown substance (266 mg, 65%).