Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]#[N:44]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:42][C:43]#[N:44])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:9]1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenol (0.295 g, 0.662 mmol) was reacted with K2CO3 (0.110 g, 0.794 mmol) and bromoacetonitrile (0.095 g, 0.794 mmol) in acetone (10 ml) to give the product (0.265 g, 0.547 mmol, 83%) as a waxy solid, mp 97-99° C. 1H NMR (DMSO-d6) δ 0.72 (t, J=7.0 Hz, 3H), 1.11-1.19 (m, 4H), 1.47-1.57 (m, 2H), 2.65 (t, J=7.6 Hz, 2H), 5.16 (s, 2H), 5.24 (s, 2H), 6.80 (d, J=6.7 Hz, 2H), 7.10-7.18 (m, 5H), 7.32-7.48 (m, 7H), 7.64 (d, J=8.9 Hz, 2H), 7.75 (s, 1H); [ESI(+)], m/z 486 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:46][Si:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][CH3:49])([CH3:45])[CH3:44].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:46][Si:47]([CH2:52][CH3:53])([CH2:48][CH3:49])[CH2:50][CH3:51])([CH3:45])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 95.1 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (200 mg, 0.367 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (227 mg, 0.734 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol), 15-crown-5 (81 mg, 0.368 mmol) and tetrahydrofuran (0.5 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 1 hour), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (270 mg, 95%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH2:13][CH:14]=C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[O:7]2.O=O>CCOC(C)=O>[CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]=2[C:9]2[CH:13]=[CH:14][O:12][C:10]=2[CH:11]=1)=[O:16]
Reactant: C=CCc1c(O)cc(C)c2ccc(=O)oc12
Agent: O=O
Solvent: CCOC(C)=O
Product: Cc1cc2occc2c2oc(=O)ccc12
Temperature: 100 °C
Yield: 22.7 %

Procedure:
The following is a specific description of the method: 5-methyl-7-hydroxy-8-allylcoumarin (VIII; 3.0 g) was dissolved in EtOAc (200 ml) and into the solution cooled in an ice bath a stream of ozonized oxygen was bubbled until 1.1 times the stoichiometric amount was added. The solution was then submitted immediately to hydrogenation in the presence of Pd 10% on CaCO3 (0.3 g) and the mixture stirred until rapid absorption of hydrogen ceased. The catalyst was removed by filtration, the solvent evaporated, 85% H3PO4 (60 ml) added and the mixture heated at 100° C. for 20 min. The mixture was chilled, diluted with two volumes of water and extracted with CHCl3. From the dried (Na2SO4) organic phase the solvent was evaporated and the residue chromatographed on a silica gel column election with CHCl3 which furnished 5-methylangelicin (XXVIII; 0.63 g; m.p. 191°-2° C. (from MeOH)). ##STR31##
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CO>[N:12]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1cc2ccccc2cn1
Solvent: OCCO
Product: c1ccc2cc(N3CCNCC3)ncc2c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
A mixture of 3-chloroisoquinoline (200 mg, 1.22 mmol) and piperazine (2.10 g, 24.4 mmol) in ethylene glycol (2 ml) was heated to 150° C. and stirred at that temperature for 24 hours. The reaction was allowed to cool down to room temperature. The crude mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuo. The residue was and purified on silica gel by flash column chromatography to give the title compound as a pale brown solid (131 mg, 50% yield).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].CO.C1COCC1>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(CN2CCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 0.3 g (1.15 mmol) of ethyl (E)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylate and 0.4 g (9.53 mmol) of lithium hydroxide monohydrate in 20 mL of a 1:1 mixture of methanol, THF, and water is stirred for 48 hours at ambient temperature. Then the reaction mixture is evaporated down, the residue is diluted with water and acidified with hydrochloric acid. The mixture is evaporated down, combined with methanol and dichloromethane, filtered, and the filtrate is evaporated to dryness. Yield: 0.27 g, C14H17NO2 (M=231.29); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: starting spot (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH2:25][CH2:26][O:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1.C(O)(C(F)(F)F)=[O:30]>C(Cl)Cl.N>[O-:24][N+:13]1[C:14]2[CH:23]=[C:22]3[C:18](=[CH:17][C:15]=2[N+:16]([O-:30])=[C:11]([CH2:10][CH2:9][CH2:8][N:7]([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][CH2:5][O:4][CH3:3])[N:12]=1)[CH2:19][CH2:20][CH2:21]3
Reactant: COCCN(CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3)CCOC
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: COCCN(CCCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3)CCOC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFM (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 80 (1.50 g, 4.2 mmol) and TFA (1.5 mL, 1.95 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (36 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 81 (533 mg, 35%) as a red gum: 1H NMR δ 8.28 (s, 1H, H-9), 8.24 (s, 1H, H-5), 3.78 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.40-3.45 (m, 6H, 3×CH2), 3.33 [s, 6H, 2×OCH3), 3.19-3.23 (m, 2H, CH2), 3.12-3.17 (m, 4H, H-6, H-8), 2.34-2.38 (m, 2H, CH2), 2.22-2.28 (m, 2H, H-7); 13C NMR δ 155.5, 152.5, 151.1, 139.0, 134.0, 115.8, 113.8, 67.2 (2), 58.9 (2), 52.9 (3), 33.4, 32.9, 27.2, 25.5, 18.8; HRMS (FAB+) calcd for C19H29N4O4 (MH+) m/z 377.2189, found 377.2185.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[F:25])[N:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([NH:36][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:5]=[C:4]([NH:14][C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=4[F:25])[N:3]=3)[CH2:34][CH2:35]2)=[CH:31][CH:32]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate (0.93 g, 2.45 mmol) in THF (10 mL) was added 1-(4-chlorophenyl)cyclopropanamine (0.5 g, 2.45 mmol) and Hunig's Base (1.71 mL, 9.8 mmol). The resulting mixture was refluxed at 80° C. for 16 hs. The precipitate was filtrated through a plug washing with THF to give a crude product that was purified by Biotage eluting with 4/1 to 3/2 hexane/ethyl acetate to give 1.2 g of methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoro ethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as product.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([NH2:24])=[O:23].I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].C(=O)C=O>C(OCC)(=O)C.[Cl-].[Na+].O.CCCCCC.O.CO.CN(C)C(=O)C>[CH:26]([N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:22]([NH2:24])=[O:23])=[CH:6]2)([CH3:28])[CH3:27]
Reactant: COCn1c(C(N)=O)cc2cccc(NS(=O)(=O)c3cccs3)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: O=CC=O
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.0 g), 2-iodopropane (574 mg), potassium carbonate (1.13 g) and N,N-dimethylacetamide (5 mL) was stirred at room temperature for 1 week. The reaction mixture was diluted with ethyl acetate and saturated brine. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate and filtrated. The filtrate was concentrated, subjected to NH silica gel column chromatography, and eluted with an ethyl acetate.hexane (2:1) mixture to give a solid. A mixture of this solid, oxalic acid dihydride (605 mg), methanol (15 mL) and water (15 mL) was stirred at 100° C. for 3.5 days. The reaction mixture was cooled to room temperature, and the obtained solid was collected by filtration, washed with water, a hexane. diisopropyl ether mixture and hexane in this order. The obtained solid was subjected to NH silica gel column chromatography, and eluted with an ethyl acetate.hexane mixture (2:1) to give the title compound (340 mg, yield 34%) as an amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=3)[O:15][C:16]3[CH:28]=[CH:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]=4[CH:17]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[Na+].Br[C:60]1[CH:65]=[C:64]([C:66]([CH3:69])([CH3:68])[CH3:67])[CH:63]=[CH:62][N:61]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1>[C:66]([C:64]1[CH:63]=[CH:62][N:61]=[C:60]([N:19]2[C:18]3[CH:17]=[C:16]([O:15][C:14]4[CH:29]=[CH:30][CH:31]=[C:12]([N:10]5[CH:11]=[C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[CH:8]=[N:9]5)[CH:13]=4)[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:65]=1)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)c1ccnc(Br)c1
Reactant: c1ccc(-c2cnn(-c3cccc(Oc4ccc5c(c4)[nH]c4ccccc45)c3)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(Oc4cccc(-n5cc(-c6ccccc6)cn5)c4)cc32)c1
Temperature: 105 °C
Reaction time: 39 h

Procedure:
2-(3-(4-Phenyl-1H-pyrazol-1-yl)phenoxy)-9H-carbazole 6 (401 mg, 1.0 mmol, 1.0 eq), Pd2(dba)3 (46 mg, 0.05 mmol, 0.05 eq), JohnPhos (30 mg, 0.10 mmol, 0.1 eq) and tBuONa (154 mg, 1.6 mmol, 1.6 eq) were added to a dry pressure Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and back-filled with nitrogen, the evacuation and back-fill procedure was repeated twice. Then dry solvent toluene (4 mL), dioxane (4 mL) and 2-bromo-4-tert-butylpyridine (418 mg, 2.0 mmol, 2.0 eq) were added under a nitrogen atmosphere. The tube was sealed and the mixture was stirred at a temperature of 100-110° C. for 39 hours, and cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (20:1-15:1-10:1-5:1) as an eluent to obtain the desired product, 9-(4-tert-butylpyridin-2-yl)-2-(3-(4-phenyl-1H-pyrazol-1-yl)phenoxy)-9H-carbazole Ligand ON6-tBu, as a brown solid (460 mg in 86% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.24 (s, 9H), 7.04 (dd, J=8.0, 2.6 Hz, 1H), 7.16 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.32-7.47 (m, 6H), 7.53 (t, J=8.4 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.66 (t, J=2.0 Hz, 1H), 7.69-7.72 (m, 3H), 7.78 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 9.05 (s, 1H).
Reaction SMILES: [C:1]([NH:18][CH2:19][C:20]([OH:22])=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>ClCCl>[C:1]([NH:18][CH2:19][C:20]([F:31])=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-Glycine (5.02 g, 16.82 mmol) (Bachem) was dissolved in dichloromethane (85 mL). Pyridine (1.36 mL, 16.82 mmol) (Aldrich) and cyanuric fluoride (2.27 g, 16.82 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-glycyl fluoride as a white powder. (Yield 3.67 g, 73%).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=2)=[O:12])=[C:34]([F:40])[CH:35]=1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2ccc(Cl)cc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of rac-4-{[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (142.6 mg, 0.24 mmol) in THF/MeOH (3.4 mL/0.8 mL) was added 4 N LiOH (1.4 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (111.6 mg, 80.6%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1472.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](NS(C)(=O)=O)[CH:8]=2)[CH:3]=[CH:2]1.C1(CBr)CC1.NC1SC=CN=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: Nc1nccs1
Product: c1ccc2[nH]ccc2c1

Procedure:
N-(1H-indole-6-yl)-methanesulfonamide, R5X=cyclopropyl-methylbromide; NH2A=2-aminothiazole
Reaction SMILES: B.[CH:2]1([C:5]([N:7]2[CH2:11][CH2:10][C:9]([OH:25])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8]2)=O)[CH2:4][CH2:3]1.[ClH:26].Cl.CCOCC>C1COCC1>[ClH:26].[CH:2]1([CH2:5][N:7]2[CH2:11][CH2:10][C:9]([OH:25])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8]2)[CH2:4][CH2:3]1
Reactant: O=C(C1CC1)N1CCC(O)(c2ccccc2Cc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2Cc2ccccc2)CCN(CC2CC2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 ml of 1 M-borane in THF is added under dry nitrogen at 0° C., 6.36 g 1-cyclopropylcarbonyl-3-hydroxy-3-(α-phenyl-2-tolyl)pyrrolidine in 20 ml of dry THF. The solution is then brought to reflux and maintained there for 1 hour. The solution is permitted to cool to room temperature and 3.3 ml of 6 N-HCl is added slowly. The THF is removed by distillation at atmospheric pressure and the residue is crystallized with 50 ml of anhydrous ether and recrystallized from methanol/ether (30 ml/80 ml) to give colorless crystals. The mother liquid is made acid with a slight excess of HCl/ether and a second crop is obtained by suction filtration. The mother liquid is concentrated in vacuo to an oil and a third crop is obtained by crystallization with ether. Recrystallization from methanol/ether (20 ml/50 ml) yields 1-cyclopropylmethyl-3-hydroxy-3-(α-phenyl-2-tolyl)pyrrolidine hydrochloride, mp 168°-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH:20]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:27].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O-:46])=[O:45].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:45][C:44](=[O:46])[CH2:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:7])=[CH:4][C:3]=1[Br:27]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)OCCCCCl)cc(Br)c1N)C1CCCCCC1
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCCC1

Procedure:
This compound was prepared from 4-[4-amino-3-bromo-5-(N-ethyl-cycloheptylaminomethyl)-benzoyloxy]-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([C:46]([F:49])([F:48])[F:47])=[N:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].FC(F)(F)C(O)=O>>[CH3:1][N:2]([CH3:50])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([C:46]([F:49])([F:47])[F:48])=[N:24][NH:25][CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CCN(c2ccnc3ccc(-c4c[nH]nc4C(F)(F)F)cc23)CC1
Yield: 65.9 %

Procedure:
107 mg N1,N1-dimethyl-4-[6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]-1-piperazine sulfonamide obtained in Example 186 and 1 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 46 mg of the title compound as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+:27]>CO>[Na+:27].[C:19]1([NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][C:3]([O-:25])=[O:2])[CH2:11][CH2:10]3)=[CH:17][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
The compound from Example 1 (85 mg, 0.25 mmol) was dissolved in methanol (2 mL) followed by addition of 1N NaOH aqueous solution (0.27 ml, 0.27 mmol). The reaction solution was stirred at 60-70° C. for 4 h and then evaporated under vacuum to dryness. The residue was stirred with ethyl acetate (2 mL) and the solid was collected by filtration and washed with ethyl acetate to give the title product as an off-white solid (78 mg, 89.9%): MS (ESI) m/z 325 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 1.99 (m, 2H), 2.45-2.51 (m, 6H), 3.01 (t, J=4.8 Hz, 4H), 6.67 (m, 1H), 6.88 (m, 4H), 6.98 (d, J=9.2 Hz, 2H), 7.13 (m, 2H), 7.75 (s, 1H).
Reaction SMILES: II.O[PH2]=O.[F:6][C:7]1[C:16]([C:17]([C:20]2[N:24]3[N:25]=[C:26]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)(O)[CH3:18])=[C:15]([F:35])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2.[OH-].[Na+]>C(O)(=O)C>[F:6][C:7]1[C:16]([CH:17]([C:20]2[N:24]3[N:25]=[C:26]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)[CH3:18])=[C:15]([F:35])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: Cn1cc(-c2ccc3ncc(C(C)(O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Reaction time: 0.08 h

Procedure:
Iodine (723 mg, 2.85 mmol) and H3PO2 (0.777 mL, 14.25 mmol) were added to a solution of (rac)-1-(5,7-difluoro-quinolin-6-yl)-1-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethanol (Stage 191.1, 386 mg, 0.950 mmol) in acetic acid (8 mL). The RM was subjected to MW-irradiation at 150° C. for 5 min. The RM was neutralized with 2.5 M NaOH solution and extracted twice with EtOAc. The organics were joined and washed with brine, then dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O and the precipitate was filtered off to afford the title compound a yellow solid (tR 0.95 min (conditions 2), MH+=391, 1H-NMR in DMSO-d6: 8.90 (d, 1H); 8.49 (d, 1H); 8.18 (s, 1H); 8.04 (d, 1H); 7.81 (s, 1H); 7.67 (d, 1H); 7.56 (dd, 1H); 7.42 (d, 1H); 5.10 (q, 1H); 3.85 (s, 3H); 1.91 (d, 3H)).