Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[Na+].Cl.[CH2:30]([OH:32])C>C(OCC)(=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:14]([C:8]2[CH:9]=[CH:10][C:11]([O:32][CH3:30])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:3])=[O:26])=[O:25])=[C:18]([F:24])[CH:19]=1
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NCc2ccc(Br)cc2F)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester (1.23 g, 2.8 mmol) in ethanol (16 mL, 0.18 M) was cooled to 0° C. and treated with aq NaOH (1.25 M, 7.0 mL, 8.7 mmol). After stirring for 2.5 h, the solution was warmed to room temperature and stirred an additional 24 h. Next, the solution was acidified to pH 1–2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give (2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-methoxy-phenoxy]-acetic acid as a white solid (1.03 g, 89%): mp 203–204° C.; Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.02 (br t, J=5.9 Hz, 1 H), 7.84, (d, J=8.2 Hz. 1 H), 7.50, (br d, J=8.7 Hz, 1 H), 7.48–7.29 (m, 2 H), 6.69–6.80 (m, 2 H), 4.87 (s, 2 H), 4.49 (d, J=5.8 Hz, 2 H), 3.79 (s, 3 H). ESI-LC/MS m/z calcd for C17H15BrFNO5: 411.0; found 412.0 (M+1)−. Anal. calcd for C17H15BrFNO5: C, 49.53; H, 3.67; N, 3.40. Found C, 49.48; H, 3.68; N, 3.39.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][C:51]([NH:53][CH2:54][C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]>>[C:46]([O:50][C:51]([NH:53][CH2:54][C:55]([O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:41]=[CH:42][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:43][CH3:44])[CH:33]=1)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: COc1cc(C(=O)OCCOC(=O)CNC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 3, 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate was reacted with 2-(tert-butoxycarbonylamino)acetic acid to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-tert-butoxycarbonylamino-acetoxy)-ethyl ester. MS (ES+) m/z calcd. for C40H45Cl2F2N4O8: [(M+H)+]: 817. found: 817.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:11]#[N:12].C[OH:21]>C(OCC)(=O)C>[ClH:19].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:11]([NH2:12])=[O:21]
Reactant: N#CC(NCCc1cccs1)c1ccccc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
Into 700 ml of ethyl acetate at 0–10° C. 109.8 g (3 mol) of hydrogen chloride gas is introduced and to the solution 83 g (0.3 mol) of the [2-(2-thienyl)ethylamino](2-chorophenyl)acetonitrile of formula (I), prepared according to Example 1. or 2., and 15 ml (0.37 mol) of methanol are added and the mixture is slowly, in a period of 20 minutes, heated to 45–50° C. The reaction mixture is then stirred at 45–50° C. for 4 hours, the crystalline product is filtered off at room temperature, washed with ethyl acetate and dried. Weight: 90.4 g (91%) op.: 231–232° C. The quality of the product is identical to that of the product of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.[CH2:21](O)[CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3([CH3:14])[O:23][CH2:22][CH2:21][O:15]3)[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1
Reactant: OCCO
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC2(C)OCCO2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of methyl 7-bromo-1-(2-oxopropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.29 g), ethylene glycol (2.3 g) and p-toluenesulfonic acid monohydrate (36 mg) in toluene (10 ml) was heated to reflux for 3 days while removing water. After cooled to room temperature, an aqueous solution of sodium hydrogen carbonate was added to alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4) to give methyl 7-bromo-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (992 mg).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1)=[O:5])C.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:11][C:8]1[N:7]=[C:6]([C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[O:5])[O:10][N:9]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)c1nc(C)no1
Product: Cc1noc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)n1

Procedure:
Following the procedure of Example 1A but employing as reactants 3-methyl-1,2,4-oxadiazole-5-carboxylic acid ethyl ester and p-(β-aminoethyl)-benzenesulfonamide, there is obtained p-(β-(3-methyl-1,2,4-oxadiazole-5-carbonylamino)ethyl]-benzenesulfonamide, M.P. 218°-220°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:23](OCC)(=[O:29])[C:24](OCC)=[O:25]>CCOCC>[F:12][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:23](=[O:29])[C:24](=[O:25])[N:13]2[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(NCc2ccc(OC)cc2)cc1F
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Yield: 99 %

Procedure:
The solution of methyl 5-amino-2-fluoro-4-(4-methoxybenzylamino)benzoate (30 g, 98.58 mmol) in diethyl oxalate (100 ml) was stirred for 3 h at reflux and then cooled with a water/ice bath, diluted with ether (500 ml). The product was collected by filtration to afford methyl 7-fluoro-1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid (35.0 g, 99%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32](OC)=[O:33])[CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Li+]>C(O)C.C1COCC1>[OH:33][CH2:32][CH2:31][N:29]1[CH:30]=[C:26]([CH2:25][N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:27]=[N:28]1
Reactant: COC(=O)Cn1cc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(CCO)c1)c1ccc(C(C)C)cc1)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
Methyl 2-(4-{[N-(4-isopropylphenyl)-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)amino]methyl}pyrazol-1-yl)acetate (0.34 g) was dissolved in a mixed solvent (10 mL) of ethanol: THF (2: 1), and sodium borohydride (0.11 g) and lithium chloride (0.12 g) were added thereto. The mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:9][C:10]1[NH:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.[I-].[Li+]>CN(C=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:9][C:10]1[N:15]([CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[CH:18]([CH3:20])[CH3:19]
Reactant: ClCc1ccncc1
Reactant: Cc1cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)cc(C2OCCO2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccncc2)cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
6-(3-[1,3]Dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (2.66 g, 8 mmol) and anhydrous powdered potassium carbonate (1.31 g, 16 mmol) were dissolved in DMF (40 ml). With vigorous stirring, 4-chloromethylpyridine hydrochloride (2.21 g, 16 mmol) and lithium iodide (1 g, 8 mmol) were added in this order. The mixture was stirred for overnight at room temperature and evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through a celite pad, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (9:1)) to afford 1.36 g (40%) of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1-pyridin-4-ylmethyl-1H-pyrimidine-2,4-dione as a white foam. 1H NMR (200 MHz, CDCl3) δ 1.13 (6H, d, J=7.0 Hz), 2.32 (3H, s), 2.74 (1H, m), 3.98-4.17 (4H, m), 4.87 (2H, s), 5.71 (1H, s), 6.63 (1H, s), 6.79 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.11 (1H, s), 7.53 (2H, dd, J=1.6 Hz, J=4.4 Hz), 9.37 (1H, s).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]1([CH2:50][NH:51][C:52]([C:54]2[NH:55][C:56]3[C:61]([CH:62]=2)=[CH:60][C:59]([O:63][CH2:64][CH2:65][O:66][CH3:67])=[CH:58][C:57]=3[N:68]([CH3:78])[S:69]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=2)(=[O:71])=[O:70])=O)[CH2:49][CH2:48][S:47][CH2:46][CH2:45]1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[S:43]1[C:44]2([CH2:49][CH2:48][S:47][CH2:46][CH2:45]2)[CH2:50][N:51]=[C:52]1[C:54]1[NH:55][C:56]2[C:61]([CH:62]=1)=[CH:60][C:59]([O:63][CH2:64][CH2:65][O:66][CH3:67])=[CH:58][C:57]=2[N:68]([CH3:78])[S:69]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=1)(=[O:70])=[O:71]
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC3(SCc4ccccc4)CCSCC3)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CC#N
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC4(CCSCC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
To a solution of triphenylphosphine oxide (2.0 g) in acetonitrile (14 mL) was added dropwise trifluoromethanesulfonic anhydride (1.0 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The obtained suspension was diluted with acetonitrile (36 mL), and a solution of N-{[4-(benzylthio)tetrahydro-2H-thiopyran-4-yl]methyl}-5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.9 g) and thioanisole (0.70 mL) in acetonitrile (50 mL) was added. The reaction mixture was stirred at 0° C. for 2 hr, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (9:1-3:7, volume ratio) to give the title compound (0.26 g, yield 17%) as colorless crystals.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:45]2[NH:53][C:52]3[CH2:51][CH2:50][NH:49][C:48](=[O:54])[C:47]=3[CH:46]=2)O1>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:1]([NH:5][C:6]1[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:45]1[NH:53][C:52]3[CH2:51][CH2:50][NH:49][C:48](=[O:54])[C:47]=3[CH:46]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2nc3cccc(B4OC(C)(C)C(C)(C)O4)c3nc2NC(C)(C)C)c(OC)c1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CNc2nc3cccc(-c4cc5c([nH]4)CCNC5=O)c3nc2NC(C)(C)C)c(OC)c1
Temperature: 105 °C
Reaction time: 3 h
Yield: 125 %

Procedure:
A mixture of N3-(tert-butyl)-N2-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-2,3-diamine (304c; 109.6 mg, 0.09 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (80 mg, 0.37 mmol), K2PO4 (59 mg, 0.28 mmol), X-Phos (Strem Chemicals, Inc.) (4.46 mg, 9.35 μmol), and Pd2dba3 (Aldrich) (4.28 mg, 4.67 μmol) in a mixture of dioxane (1.0 mL) and water (0.20 mL) was stirred under argon at 105° C. for 3 h. Additional Pd2dba3 (4.28 mg, 4.67 μmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (4.46 mg, 9.35 μmol) were added, and the resulting mixture was stirred under argon at 105° C. for 15 h. The reaction mixture was subsequently diluted with DCM (10 mL) and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(tert-butylamino)-2-((2,4-dimethoxybenzyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (56.3 mg) as a yellow solid: m/z (ESI, +ve) 501.2 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNc1ncc(C=O)s1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCNc1ncc(C=O)s1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 299.1 %

Procedure:
Following the procedure as described in Example 11, except using material from Example 49 (3.8 g, 9.86 mmol), CH2Cl2 (41 mL), trifluoroacetic acid (8.21 mL, 107 mmol) and stirring at room temp for 16 h, 6.76 g (quantitative yield) of the title compound is isolated as a thick syrup as a TFA salt that is used directly “as is” in the next reaction. LC/MS (Condition A): ret. T=0.62 min, (M+H)+ 230.15.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](SC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)CCC>>[O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH3:28])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccsc2)c1Oc1ccccc1
Product: COC(=O)c1cc(SCc2ccsc2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 47 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid for 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid and following the procedure described, methyl 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoate is obtained with a melting point of 148°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33].S1C=CC=C1>C1COCC1.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) and (−)-(S)-α-methyl-benzenemethanamine (0.1 mol) in THF (500 ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (3 g) as a catalyst in the presence of titanium(VI) n-butoxide (28.4 g) and thiophene solution (3 ml). The catalyst was filtered off. Pd/C 10% (10 g) and thiophene solution (10 ml) were added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2, CH3OH and H2O. The mixture was alkalized with NaOH and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 19 g (74%) of [(R*,R*)(S)+(R*,S*)(S)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[(1-phenylethyl)amino)-1-methylpropyl]-3H-1,2,4-triazol-3-one (interm. 2).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)O)=[C:29]([F:42])[CH:28]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[C:29]([F:42])[CH:28]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Reaction time: 3 h

Procedure:
The title compound was prepared starting from 1.50 g (8.46 mmol) of the compound from Example 8 and 2.15 g (8.46 mmol) of the compound from Example 85A in analogy to the synthesis of the compound from Example 101. A difference was, however, that stirring was at 80° C. for 3 h. 0.66 g (19% of theory) of the target compound was obtained.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[CH:21][CH:20]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][O:17][CH3:16])[N:24]=2)[CH2:29][CH2:30]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: COCc1cccc(OCCN2CCNCC2)n1
Product: COCc1cccc(OCCN2CCN(CCCC(C#N)(c3cccs3)C(C)C)CC2)n1

Procedure:
The titile compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-(2-(6-methoxymethyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.N>ClCCl>[CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:20])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Product: NC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (preparation 36, 4.87 g, 20.8 mmol) was dissolved in dichloromethane (150 mL) and carbonyldiimidazole (3.37 g, 20.8 mmol) added in one portion. After stirring for 1 hour at room temperature, 0.880 ammonia (21 mL) was added and stirring continued at room temperature for 18 hours. The organic layer was separated, washed with brine (50 mL), dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a white foam in 92% yield, 4.56 g.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c([C@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC[C@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3S)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (95 mg, 0.22 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (47 mg, 0.25 mmol), HOBt (33 mg, 0.25 mmol), and N,N-diisopropylethylamine (117 μL, 0.67 mmol) in DMF (2 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MOON and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.61-6.67 (m, 1 H), 5.65 (s, 2 H); 3.95-4.94 (m, 2 H), 2.62-3.32 (m, 5 H), 2.05-2.23 (m, 7 H), 1.70-1.91 (m, 2 H), 1.40-1.64 (m, 1 H); ES-MS m/z 509.18 [M+H]+, HPLC RT (min) 2.23.