Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 20 °C

Procedure:
To a solution of 2-bromo-propionic acid ethyl ester (1 eq.) in MeCN was added benzylamine (0.9 eq.) and potassium carbonate (1.5 eq.). The reaction was refluxed for 4 h then cooled to 20° C. and diluted with EtOAc. The crude was filtered, the filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 7/3) to afford 2-benzylamino-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[N:25]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][N:22]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:21]12>>[C:1]1([N:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][N:22]3[CH2:32][CH2:33][CH2:34][CH2:35][CH:21]3[CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(Nc2ccccc2)cc(OC)c1OC
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Product: COc1cc(N(C(=O)CCCN2CCN3CCCCC3C2)c2ccccc2)cc(OC)c1OC

Procedure:
The procedure is as for Example 2 using as substrate phenyl-(3,4,5-trimethoxyphenyl)amine and the compound obtained in Step B of Example 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][O:15][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O2)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a stirred solution of ((4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid t-butyl ester (2.24 g, 7.73 mmol), N,N-diisopropylethylamine (2.00 g, 15.46 mmol), 4-dimethylaminopyridine (0.95 g, 7.3 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (2.23 g, 11.59 mmol) at 23° C. under nitrogen and stirred for 3 h. The reaction mixture was diluted with dichloromethane and washed with 2N hydrochloric acid, saturated sodium chloride solution and the organic layer separated, dried over magnesium sulfate and concentrated in vacuo which afforded [(4R,6S)-2,2-dimethyl-6-(toluene-4-sulfonyloxymethyl)-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (2.54 g, 80%) as a yellow waxy solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[Cl:28][C:20]1[CH:19]=[C:18]([C@@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][N:31]([CH3:32])[CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 30, 138.5 mg, 0.28 mmol) in tetrahydrofuran (2.6 mL) was cooled to 0° C. and then was treated with a 2.0M solution of dimethylamine in tetrahydrofuran (275 μL, 0.55 mmol). The reaction was stirred at 0° C. for 30 min and then at 25° C. for 1 h. A second aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (275 μL, 0.55 mmol) was added, and the reaction was stirred at 25° C. for 1 h. A third aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (138 μL, 0.28 mmol) was added, and the reaction was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was concentrated in vacuo and then was diluted with ethyl acetate (50 mL), washed with water (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 100% methanol) afforded impure 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazin-2-yl)-propionamide as an orange oil. This impure product was re-purified by reverse phase high-performance liquid chromatography (Waters symmetry packing, acetonitrile/water with 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient). The fractions containing product were concentrated in vacuo to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazin-2-yl)-propionamide (50.4 mg, 39%) as a light yellow foam: mp 88.0–91.5° C. (foam to gel); (ES)+-HRMS m/e calcd for C22H29ClN4O3S (M+H)+ 465.1722, found 465.1726.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[F:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[CH:31]([F:32])[CH:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:26][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (60 mg, 0.096 mmol) and Pd(OH)2 on carbon, (20 wt %, 6 mg, 8.54 μmol) in THF (960 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (47.6 mg, 93%) as a yellow foam. 1H NMR (400 MHz, methanol-d4) δ ppm 1.23 (dd, J=6.4, 2.4 Hz, 6H), 1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.98-2.14 (m, 2H), 2.68 (qd, J=12.6, 2.5 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 3.40-3.51 (m, 2H), 3.52 (t, J=6.3 Hz, 2H), 4.10-4.16 (m, 1H), 4.16 (s, 2H), 5.53 (dd, J=46.5, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 420.3.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH3:30]O>S(=O)(=O)(O)O>[C@H:1]1([O:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CO
Reactant: O=C(O)Cc1cccc(-c2cccc(CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(-c2cccc(CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c2)c1
Yield: 77 %

Procedure:
3-(3-(α-D-mannopyranosyloxymethyl)phenyl)phenylacetic acid (0.05 g, 0.12 mmol), methanol (10 ml), and concentrated sulfuric acid (2 drops) were heated reflux for 1 hour in a 25 ml flask, then quenched with saturated sodium bicarbonate solution, diluted with water (5 ml), extracted with methylene chloride (3×5 ml), washed with brine (10 ml), dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5:1/methylene chloride:methanol) which gave methyl 3-(3-(α-D-mannopyranosyloxymethyl)phenyl)phenylacetate (0.04 g, 77%); 1H NMR: (300 MHz, DMSO-d6) 7.2-7.6 (comp, 8H), 4.70 (s, 1H), 4.49-4.80 (comp, 7H), 3.75 (s, 2H), 3.62 (s, 3H), 3.30-3.50 (comp, 5H) ppm; IR: 3383, 1738, 1135, 1066 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:38](O)=[O:39].O.[NH2:42][NH2:43]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:7][N:8]2[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:4][C:3]=1[C:38]([NH:42][NH2:43])=[O:39]
Reactant: NN
Reactant: O=C(O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Solvent: O
Product: NNC(=O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Yield: 25.7 %

Procedure:
In accordance with the method as described in Example 127, 110 mg of 6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic acid and 210 mg of hydrazine monohydrate were condensed, to afford 29 mg of the title compound as a yellow powder.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][C@H:19]([NH2:30])[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)Cl>CO>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][NH:30][CH:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH3:18])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(C)c1cccc3ccccc13)C2
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.48 g, 5.04 mmol) and S-(-)-1-(1-naphthyl)ethylamine (1.75 g, 10.2 mmol) was stirred in a hot bath at 150° C. for 3 hours. The reaction product was subjected to silica gel column chromatography (developer=chloroform: methanol=50:1) to obtain 1.78 g (91.9%) of a crude target material as a mixture of 2 types of diastereomers which are different at the position C-2. This product was further subjected to silica gel column chromatography (developer=chloroform: methanol=100:1), and the first eluted fraction was condensed under reduced pressure. As a result, 535 mg of a first diastereomer of the title compound was obtained as pale yellow powder (27.6%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:15])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([Cl:15])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(C(=O)Cl)ccc1F
Temperature: 80 °C
Yield: 99.7 %

Procedure:
In a 250 mL round bottom flask a mixture of 3-cyano-4-fluorobenzoic acid (7.75 g, 0.047 mol) and thionyl chloride (28 mL, 0.38 mol, 8 eq) was heated to 80° C. for 1 h. The reaction mixture was concentrated in vacuo to give 8.6 g of 3-cyano-4-fluorobenzoyl chloride which can be used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.49-8.43 (m, 1H), 8.42-8.36 (m, 1H), 7.44 (t, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:20]2[N:25]=[CH:24][N:23]=[C:22]3[N:26]([C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)[N:27]=[CH:28][C:21]=23)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Reactant: Cc1ncccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1cccnc1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
Sodium hydride (21.49 mg, 0.54 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (110 mg, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (110 mg, 0.45 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×20 mL). The combined organics were washed with saturated brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (24.0 mg, 11.8%). 1H NMR (400 MHz, CDCl3) δ1.23 (t, 3H), 2.45 (s, 3H), 3.59-3.72 (m, 2H), 4.05-4.16 (m, 2H), 6.06 (t, 1H), 7.31-7.38 (m, 1H), 7.66-7.71 (m, 1H), 7.73-7.78 (m, 1H), 8.21-8.27 (m, 2H), 8.42 (s, 1H), 8.57 (s, 1H), 8.64-8.69 (m, 1H), 8.89 (s, 1H). m/z (ESI+) (M+H)+=454.31; HPLC tR=1.83 min
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=3)=[N:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:26](I)[CH3:27]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=3)=[N:8][C:9]([N:12]([CH2:26][CH3:27])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCI
Reactant: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)cn(C)c1=O
Product: CCN(c1ncc(OCC2CC2)c(-c2cc(C)c(=O)n(C)c2)n1)S(C)(=O)=O

Procedure:
The title compound of Example 153 was treated with ethyl iodide in a manner similar to Example 161 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36-0.42 (m, 2H) 0.60-0.66 (m, 2H) 1.25 (t, J=6.82 Hz, 3H) 1.29-1.40 (m, 1H) 2.09 (s, 3H) 3.48 (s, 3H) 3.56 (s, 3H) 3.88-4.20 (m, 4H) 8.13 (s, 1H) 8.49 (s, 1H) 8.69 (s, 1H).). LCMS: 393 (M+H)+
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[CH:6][C:3]=1[C:4]#[N:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 51.6 %

Procedure:
A mixture of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 43; 0.8 g, 2.8 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.8 g, 5.6 mmol), and DIEA (0.5 g, 3.7 mmol) in n-BuOH (4 ml) was heated in a sealed tube at 140° C. for 48 hrs. The reaction mixture was concentrated and purified by column chromatography (DCM:MeOH=50:1) to give the title compound (0.55 g, 50%). MS: Calcd.: 380. Found: [M+H]+ 381.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[NH:13][C:12]3[C:14]4[CH2:15][C:16]([CH3:26])([CH3:25])[O:17][C:18]=4[C:19]([C:21]([O:23]C)=O)=[CH:20][C:11]=3[N:10]=2)=[C:6]([CH3:27])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[NH:13][C:12]3[C:14]4[CH2:15][C:16]([CH3:25])([CH3:26])[O:17][C:18]=4[C:19]([C:21]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=4)=[O:23])=[CH:20][C:11]=3[N:10]=2)=[C:6]([CH3:27])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)ccnc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccnc(Cl)c1Nc1nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 56.3 %

Procedure:
Under inert atmosphere to a solution of methyl 2-((2-chloro-4-methylpyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-48, 0.200 g, 0.516 mmol) in dry toluene was added 3-trifluoromethyl aniline (0.124 g, 0.774 mmol) and trimethyl aluminium (2.0 M solution in toluene) (0.037 g, 0.516 mmol). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on neutral alumina eluting with 40.0% Acetone: petroleum ether to afford 0.150 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.24 (s, 3H), 3.08 (s, 2H), 7.45-7.37 (m, 3H), 7.59 (t, J=7.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 8.15 (d, J=4.2 Hz, 1H), 8.33 (s, 1H), 9.93 (s, 1H), 11 (bs, 1H); MS [M+H]+: 516.35.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[NH:5][CH2:4][C:3]3[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NCc1ccccc1N
Product: Clc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=257.9 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-chlorophenylisothiocyanate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:37])([F:36])[CH2:16][O:17][C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1>>[F:37][C:15]([F:14])([F:36])[CH2:16][O:17][C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 463 was prepared from 4-morpholinoaniline and 4-(5-(2,2,2-trifluoroethoxy)-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C26H23F3N4O3: 497.17; found: 496.97.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:33]([CH2:41][CH3:42])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH3:42])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Product: CC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (S)-(−)-hydroxybutyrate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 79-80° C.; MS m/e 617 (M−H)+;
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=O)[CH3:5].Cl.[NH2:10][OH:11].C(=O)(O)[O-].[Na+]>O>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=[N:10][OH:11])[CH3:5]
Reactant: NO
Reactant: CC(=O)CC(C)(C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(CC(C)(C)O)=NO
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxy-4-methyl-2-pentanone (10.0 g, 85.7 mmole) and hydroxylamine hydrochloride (22.17 g, 343 mmole) in 90 ml of water was stirred vigorously at room temperature. To this solution was added slowly over a period of an hour solid sodium bicarbonate (26.8 g, 343 mmole). After 3 hours the reaction mixture was extracted with ethyl acetate (3×, 100 ml), dried (MgSO4) and evaporated under reduced pressure, to give the product as an oil. Yield 11.2 g
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])[N:9]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)N1CCOCC1

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 8 ml of morpholine are boiled under reflux for 1 h. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethyl acetate/-hexane. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-1-morpholin-4-ylethanone remains as colorless crystals of m.p. 149-151° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Product: O=C1CC(c2cccc(-c3ccncn3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K4) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (96 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([N:17]([CH3:26])[CH3:16])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(N(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(N(C)C)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.