Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.C(O[CH:7]([CH:19]1[C:28]2[N:27]=[CH:26][C:25]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)C>C(N(CC)CC)C>[N:30]1([CH2:29][C:25]2[CH:24]=[C:23]3[C:28]4[N:27]([CH:26]=2)[C:9](=[O:11])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:19]=4[CH2:20][CH2:21][CH2:22]3)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)C(C(=O)OCC)C(OCC)C1CCCc2cc(CN3CCOCC3)cnc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Reaction time: 12 h
Yield: 101.2 %

Procedure:
A 250 mL round bottom flask equipped with a condenser is charged with ethanol (150 mL), triethylamine (0.93 mL) and diethyl 2-(ethoxy(3-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-yl)methyl)malonate (Preparation 17, 750 mg). The solution is heated to reflux. After 12 h, the mixture is concentrated to give a yellow solid, which is purified by flash chromatography (silica gel, 6% MeOH: methylene chloride) to give 603 mg of the title compound. Physical characteristics: 1H NMR (DMSO-d6): δ9.02, 8.04, 7.58, 4.24, 3.59, 3.57, 3.01, 2.88, 2.42, 1.89, 1.30; 13C NMR (DMSO-d6): δ165.3, 154.1, 141.6, 138.3, 134.4, 132.8, 126.9, 125.3, 110.0, 104.3, 66.1, 59.7, 59.1, 52.9, 29.2, 27.8, 20.7, 14.3; IR (KBr) 3079, 3037, 2958, 2931, 2913, 2850, 2828, 1731, 1679, 1647, 1628, 1600, 1509, 1462, 1450, 1297, 1270, 1251, 1227, 1206, 1114, 1097, 1079; HRMS m/z 357.1818.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[C:7]=2[CH3:29])=O.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O.C(O)(=O)C>[OH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]1[NH:30][CH2:1][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:19][CH:20]=1)[C:7]=2[CH3:29]
Reactant: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(C=O)cnc12
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(CN[C@H]3CCCC[C@@H]3O)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (1.0 g) obtained in Reference Example 2% and trans-2-aminocyclohexanol (546 mg) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (395 mg, yield 32%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH3:16])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C

Procedure:
The title compound, MS: m/e=232.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and methyl iodide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55](=[O:62])[C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccncc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and isonicotinoyl chloride hydrochloride as the starting materials in 30% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z=556.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][CH:20]2[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]2)[N:3]=1
Reactant: Oc1cccc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2cccc(Cl)n2)O1
Temperature: 85 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxypyridine (0.58 g, 4.50 mmol) and 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (1.29 g, 4.50 mmol) in DMF (10 mL) was added cesium carbonate (2.97 g, 9.00 mmol). The reaction mixture was stirred at 85° C. for 18 h, and then partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was separated, washed with water (2×50 mL), then brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (1.03 g, 94%) as an off-white solid that was used without further purification. δH (DMSO-d6) 7.78 (1H, dd, J 8.1 and 7.5 Hz), 7.11 (1H, dd, J 7.5 and 0.6 Hz), 6.86 (1H, dd, J 8.1 and 0.6 Hz), 4.45-4.35 (1H, m), 4.33-4.18 (2H, m), 4.11-4.01 (1H, m), 3.77 (1H, dd, J 8.5 and 6.2 Hz), 1.34 (3H, s), 1.29 (3H, s). LCMS (ES+) 244.1 (M+H)+, RT 3.63 minutes (Method 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=O)[C:20](O)=[O:21]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:20](=[O:21])[C:19]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)=[N:12]2)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)c1cccs1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-Diamino-benzoic acid ethyl ester and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 72 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (117 mg, 72% yield) as a white powder. 1H-NMR (CDCl3) δ 7.91 (s, 1H), 7.24 (m, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.84 (br s, 1H), 5.37 (m, 1H), 3.87 (m, 1H), 3.23 (q, J=18.6, 9.2 Hz, 3H), 2.83 (m, 6H), 2.69 (m, 2H), 2.20 (br s, 2H), 2.07 (br s, 2H), 1.82 (br s, 2H), 1.35 (br s, 6H). LC/MS (ESI+)=561 (M+H). MP=122° C. dec.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DIEA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A solution of N-acetylethanolamine (10.0 g, 6.79 ml, 97 mmol) in a mixture of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (10 ml) was added to a stirred suspension of 80% sodium hydride in oil dispersion (2.90 g, 97 mmol) in dry tetrahydrofuran (140 ml), under nitrogen, at room temperature. After 1 hour, the reaction mixture was heated to 40°-50° C. and then, after a further 0.5 hour, cooled to ice-bath temperature. Next, benzyl bromide (13.8 ml, 116 mmol) was added and the resulting suspension stirred at room temperature for 18 hours, before being cautiously quenched with water (400 ml). The resulting mixture was extracted with ethyl acetate (2×300 ml) and the combined extracts washed with water (200 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water, then the organic phase washed thrice with water, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of methanol:ethyl acetate (0:100 to 10:90), to give the required product (7.8 g) as an oil. Rf 0.21 (SS 17). LRMS: m/z 194.3 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1COCC1>[CH3:17][O:16][C:14]([C:10]1[CH:11]=[C:12]([O:13][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1)=[O:15]
Reactant: BrCC1CC1
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2CC2)n(-c2ccccc2F)n1
Temperature: 50 °C

Procedure:
150 mg (0.635 mmol) of methyl 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylate were dissolved in 8 ml of THF. 207 mg (0.635 mmol) of cesium carbonate and 400 mg (2.96 mmol) of bromomethyl-cyclopropane were added and the mixture was heated to 50° C. for 6 h. Then the mixture was filtrated and the solvent removed in vacuo. The crude title compound was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:14]3[O:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[O:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH:7]=2)=[CH:2]1
Reactant: OC1(c2ccoc2)CCCc2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2ccoc2)c2occc2CC1
Yield: 96.2 %

Procedure:
To a mixture of 16.3 g of the above alcohol in 400 ml of toluene was added 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm/50° C.) until a brown-red residue was obtained yielding 14.3 g (96%) of 4,5-dihydro-7-(3-furyl)benzofuran as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[N:8]=[CH:7][C:6]([C:15]#[N:16])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([Cl:32])[CH:19]=1.C(N(C(C)C)CC)(C)C.[Cl:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][C:48](Cl)=[O:49]>O1CCCC1>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH3:14])=[C:2]([NH:1][C:48](=[O:49])[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43][Cl:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:15]#[N:16])=[CH:19][C:20]=1[Cl:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)C=CCCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)C=CCCCCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 6-amino-4-[4-(benzyloxy)-3-chloroanilino]-7-ethoxy-3-quinolinecarbonitrile (0.89 g, 2.0 mmol) and diisopropylethylamine (0.47 ml, 2.7 mmol) in 16 ml of tetrahydrofuran at 0° C. was added a freshly-prepared solution of 6-chloro-2-hexenoyl chloride in 4 ml of tetrahydrofuran during 30 s. The mixture was then stirred at 25° C. for 2.5 h and partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel with methylene chloride-ethyl acetate to give 0.83 g of amber solid; mass spectrum (electrospray, m/e) 574.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=1)=[C:16]([NH:22][C:23](=[O:25])[CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1COCC1>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:28][CH:27]=1)[CH:16]([NH:22][C:23](=[O:25])[CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:40][CH:39]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)=C(c1ccc(OC2CCCC2)cc1)c1c(C(=O)OCC)[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc2c1C(c1ccc(OC2CCCC2)cc1)C(NC(C)=O)C(=O)OCC

Procedure:
3-(2-Acetylamino-1-(4-cyclopentyloxyphenyl)-2-ethoxycarbonylvinyl)-5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester ('370 mg-, 0.58 mmol; see step (b) above) in MeOH (15 mL) and THF (115 mL) was hydrogenated (rt, 7 bar) over Pd—C (10%, 300 mg) for 6.5 h. The mixture was filtered through Celite® and concentrated to give sub-title compound. Yield 378 mg (1100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[N:22]=[N:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[CH:25]=1.[OH-].[K+]>CC(C)=O.CN(C=O)C.Cl>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:16]=[C:15]2[C:21]1[N:22]=[N:23][N:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])=[CH:30][CH:31]=2)[CH:25]=1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Yield: 130 %

Procedure:
4-methoxybenzylchloride (1.13 mL; 8.27 mmol; 1.5 eq.) was added dropwise to a solution of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (2.5 g; 5.5 mmol; 1.0 eq.) and KOH (0.34 g; 6.07 mmol; 1.1 eq.) in acetone (75 mL) and DMF (25 mL). The reaction mixture was stirred at RT O/N. It was then diluted with a 0.1N HCl solution and extracted three times with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) to give the title compound as an orange oil (4.1 g, 100%). UPLC/MS: (MS+) 573.0.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(OCCN2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reaction mixture of 1.22 g (4.24 mmol) 1-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-pyrrolidine, 1.47 g (4.67 mmol) TBAF and 25 mL THF is stirred for 3 h at RT. Then the reaction mixture is evaporated down and the residue is combined with 20 mL saturated NaCl solution and 50 mL EtOAc. The organic phase is dried over Na2SO4. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH2:4][N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=2[CH:29]=1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: CCNCC1COc2ccccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccccc2O1
Temperature: 76 °C
Yield: 51.6 %

Procedure:
N-Ethyl-2,3-dihydro-1,4-benzodioxin-2-methanamine (4.67 g, 24.2 mmole), 7-(3-bromopropoxy)coumarin (6.92 g, 24.4 mmole), and diisopropylethylamine (6.70 ml, 38.5 mmole) were combined in 300 ml of DMF and heated at 76° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue (10 g) was column chromatographed on 225 g of silica gel using 40% ethyl acetate/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the residue crystallized from isopropanol with the addition of 30 ml of 4N isopropanolic HCl to give 4.94 g of the title compound as a white solid, monohydrochloride, m.p. 147°-152° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:14])=[O:13])[C@H:8]([OH:26])[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[CH3:31][S:32]([O:26][C@@H:8]1[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])[CH2:10][C@H:9]1[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Benzyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (1.00 g) was added to methylene chloride (10 ml), and the obtained solution was then cooled to approximately 0° C. Triethylamine (0.52 ml) was added to the reaction solution, and methanesulfonyl chloride (0.28 ml) was then added dropwise to the mixed solution. The obtained mixture was stirred for approximately 1 hour. The precipitated crystals were collected by filtration, and were then washed with methylene chloride (1 ml). The obtained crystals were dried under reduced pressure to obtain 866 mg of the title compound (yield: 72%).
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.N#N.[H][H]>[Pd].C(OCC)(=O)C>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: [H][H]
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 50 °C
Yield: 89.7 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol) and 0.5 g of 10 wt % Pd—C were added to 20 mL ethyl acetate and the air was replaced with N2. Hydrogen was passed into the mixture and the mixture was heated to 50° C. and reacted for 20 hours. Filtered and the solvent was evaporated to provide 0.53 g of white solid in 90% yield.