Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Product: CC(C)(O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5 step 4) (198 mg, 0.5 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (80 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (143 mg, 67%). MS (ISP) 428.3 [(M+H)+]; mp 148-150° C.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.C([Li])CCC.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([C:14]1[S:15][C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[C:13]=1[CH3:17])=[O:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)N1CCc2sc(Br)c(C)c2CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(C)(C)C)sc2c1CCNCC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
The product of step (h) (60 mg, 0.19 mmol) was dissolve in 2 mL THF and cooled to −78° C. Butyl lithium (0.15 mL of 1.6M) was added and the reaction was stirred for 5 minutes. Trimethylacetyl chloride (36 uL, 0.3 mmol) was added and the reaction was warmed to room temperature. The reaction was quenched with water (5 mL) and the product was extracted into DCM (2×). The extracts were concentrated to dryness and treated with 4 mL of 1:1 EtOH:40% KOH (aq) and heated to 100° C. for 14 hours. The reaction was cooled and diluted with water. The product was extracted into DCM (2×5 mL). The extracts were concentrated and the title compound was purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 3.38-3.31 (m, 4H), 3.23 (t, J=5.1 Hz, 2H), 3.04 (t, J=5.2 Hz, 2H), 2.30 (s, 3H), 1.32 (s, 9H); MS: ESI (positive): 252 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:34]([CH3:35])[CH:33]=[N:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:34]([CH3:35])[CH:33]=[N:32][N:31]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cn1cnnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2nncn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0.334 mmol), 3-(chloromethyl)-4-methyl-4H-1,2,4-triazole (65 mg, 0.5 mmol) and Cs2CO3 (325 mg, 1 mmol) were suspended in DMF. The mixture was stirred overnight at room temperature, then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford N-(3-(5-cyano-2-methoxyphenyl)-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23.2 mg, yield: 15%). 1H NMR (CDCl3, 400 MHz) δ: 9.59 (s, 1H), 8.77 (dd, J=2.0, 7.2 Hz, 1H), 8.70 (s, 1H), 8.51 (dd, J=2.0, 4.4 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.99 (q, J=4.4, 6.8 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C:7]2[N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]=[CH:13][C:6]1=2)=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:32][C:33]1[NH:37][N:36]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:34]=1>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:7]3[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:37]4[C:33]([CH3:32])=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36]4)[C:6]=3[CH:13]=[N:12]2)=[CH:15][CH:16]=1
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 75 °C
Yield: 66.9 %

Procedure:
2-Chloro-1-(1-(4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (118 mg, 0.4 mmol) was diluted in 1.2 mL of 2:1 THF:DMF and treated with K2CO3 (111 mg, 0.8 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole (60 mg, 0.4 mmol). The slurry was heated to 75° C. for 2 hours. The reaction slurry was purified by normal phase flash chromatography (24 g column, eluting with 10-80% EtOAc in hexanes) to provide 109 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 0.8H), 7.59 (s, 0.2H), 7.42-7.47 (m, 2H), 7.12-7.25 (m, 2H), 5.25 (s, 0.4H), 5.14 (s, 1.6H), 3.92 (m, 0.4H), 3.86 (m, 1.6H), 2.86 (t, J=6.2 Hz, 2H), 2.37 (s, 2.4H), 2.36 (m, 0.6H), 2.11 (m, 1.6H), 2.04 (m, 0.4H); MS: (ES) m/z calculated for C19H18F4N5O [M+H]+ 408.1, found 408.1.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1
Reactant: O=C(NCCCl)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCN1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of methyl 4-trifluoromethylaniline (3.47 g, 21.6 mmol) in dry toluene (50 mL) was added 2-chloroethylisocyante (2.50 g, 2.02 mL, 23.7 mmol). The mixture was stirred at 40° C. for 12 h. After cooling to room temperature, the solid was collected by filtration and washed with toluene, water and dried in air to provide 1-(2-chloro-ethyl)-3-(4-trifluoromethylphenyl)urea [5.28 g, 92.0%, >95% pure by LC/MS MS (ES+) m/z: 267, 269]. The urea (5.27 g, 23.7 mmol) was then stirred in DMF (50.0 mL) with K2CO3 (3.27 g, 11.98 mmol) at room temperature for 12 h. The solid was filtered off and the solvent was removed in vacuum. The crude product was dissolved in dichloromethane and passed through a silica column (50 g) and eluted with dichloromethane:ethyl acetate, 8:2 to give pure cyclic urea intermediate, 1-(4-trifluoromethylphenyl)imidazolidin-2-one, as white crystalline material (3.85 g, 84.7%). MS (ES+) m/z: 231.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:12].[C:13]([O-])([O-:15])=[O:14].[Na+].[Na+]>O1CCOCC1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].O.C(=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O)=O>[CH3:12][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:13]([OH:15])=[O:14])[CH:3]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2c(C)cc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: O=C=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Temperature: 165 °C
Yield: 17 %

Procedure:
To a reaction vessel containing a re-purified solution of 5-bromo-3,7-dimethyl-1H-indazole (prepared as described for Acid Preparation 26, 285 mg, 1.27 mmol) in dioxane (1.3 mL) was added hexacarbonylmolybdenum (264 mg, 1.0 mmol), Herrmann's catalyst (93 mg, 0.1 mmol) and a solution of Na2CO3 in water (636 mg in 2 mL water). The suspension was heated in a microwave at 165° C. for 15 minutes (high absorption). The vial was vented, acidified with 1 N HCl (to pH 2). The reaction mixture was filtered through diatomaceous earth, washed with EtOAc and the organic layer was washed with saturated aqueous NaCl (3×). The organic extract was concentrated to yield the title compound as a pink solid (65 mg, 17%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:17][C:16]([N:19](C)[C:20](=O)C(F)(F)F)([CH3:18])[CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]3[C:29](=[O:32])[NH:30][S:31][C:5]2=3)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:15][C:16]([NH:19][CH3:20])([CH3:18])[CH2:17]4)[CH:12]=3)[C:7](=[O:28])[C:6]3[C:29](=[O:32])[NH:30][S:31][C:5]2=3)[CH2:3][CH2:2]1
Reactant: CN(C(=O)C(F)(F)F)C1(C)CN(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)C1
Agent: [Na+]
Agent: [OH-]
Product: CNC1(C)CN(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)C1

Procedure:
By a procedure completely analogous to that described in Example 2, 9-cyclopropyl-6-fluoro-7-{3-[N-(methyl)trifluoroacetamido]-3-methyl-1-azetidinyl}-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 286°-290° C., is obtained, which product is hydrolyzed by heating it with 10% sodium hydroxide for 2 hours; 9-cyclopropyl-6-fluoro-7-(3-methylamino-3-methyl-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 300° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:48])[NH:21][C:22]([C:24]1[S:25][C:26]([S:46][CH3:47])=[C:27]([S:29]([C:32]2[CH:33]=[C:34]([C:38]3[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=3[NH2:45])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:28]=1)=[NH:23])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20](=[O:48])[NH:21][C:22](=[NH:23])[C:24]1[S:25][C:26]([S:46][CH3:47])=[C:27]([S:29]([C:32]2[CH:33]=[C:34]([C:38]3[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=3[NH:45][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][NH:6][S:3]([C:2]([F:14])([F:13])[F:1])(=[O:5])=[O:4])[CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH:28]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: O=C(Cl)CCCNS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of 4-trifluoromethanesulfonylamino-butyryl chloride (0.015 g, 0.058 mmol) [example 212, step b] in dichloromethane [1 mL] was added to a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.049 mmol) [example 25, step c] in dichloromethane [1 mL] at room temperature with vigorous stirring for 0.5 hours. The reaction mixture was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.020 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C29H33F3N4O7S4: 734.12; found: 734.7.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][C:16](=[O:18])[OH:17])[NH2:14]>O1CCCC1>[CH3:7][O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][C:16](=[O:17])[OH:18])[NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O
Reaction time: 20 h

Procedure:
4.5 parts of diketene were added dropwise to a stirred suspension of 14.7 parts α-L-aspartyl-L-phenylalanine methyl ester in 400 parts by volume of tetrahydrofuran and stirred for 20 hours at ambient temperatures. An additional 4.2 parts of diketene was added. After 18 hours, the solvent was removed under vacuum and the residue was purified by chromotography on silica gel to give N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester, mp 118.5°-121° C. which eluted in a 10:90:0.1 ethanol:methylene chloride:acetic acid mixture.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]([F:34])([F:33])[CH2:29][CH2:30][CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][CH2:30][CH2:29][C:28]([F:34])([F:33])[F:27])[CH:7]=1
Reactant: OCCCC(F)(F)F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCCC(F)(F)F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 4,4,4-trifluorobutan-1-ol (94.3 mg; 0.736 mmol), example 59 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17].O>O1CCCC1.C(OCC)(=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([Br:11])=[CH:9][CH:10]=2)(=[O:4])=[O:5])=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CNS(=O)(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CC(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid methyl-amide (608 mg) in tetrahydrofuran (5 mL) was added 60% sodium hydride (115 mg). After stirring for 20 minutes, 2-bromo-1-(4-fluorophenyl)ethanone (630 mg) was added. After adding water and ethyl acetate, and washing the organic layer with saturated sodium chloride water, this solution was dried with anhydrous sodium sulfate. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate) and the title compound (464 mg) was obtained as a yellow oily substance.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:10])[CH2:8][OH:9].Cl[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:9][CH2:8][CH2:7][O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][N:13]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.49 g (31.08 mmol) of potassium tert-butoxide are added to a solution of 3.51 g (56.51 mmol) of 1,2-ethanediol in 80 ml of dry DMF, and the mixture is stirred at RT for 15 min 4.0 g (28.26 mmol) of 6-chloronicotinaldehyde are then added. The reaction solution is stirred at RT for 20 h. The mixture is then poured into 200 ml of a 1:1 mixture of ethyl acetate and saturated sodium bicarbonate solution. The phases are separated, and the aqueous phase is then extracted with ethyl acetate (two times 100 ml each). The combined organic phases are washed with water (two times 100 ml each). The organic phase is dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 2:1).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:68])[F:69])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)cccc4C(F)(F)F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)cccc4C(F)(F)F)cc3)cc2C1=O
Yield: 62 %

Procedure:
The compound of example 126 was prepared analogous to compound of example 98 by hydrolysis of compound of example 125.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:24][C:25]([CH3:32])([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:24][C:25]([CH3:32])([CH3:31])[CH2:26][S:27]([N:22]1[CH2:21][CH2:20][C:3]2([C:7](=[O:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH:2]([OH:1])[CH2:23]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)CS(=O)(=O)Cl
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)C(O)C1

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 7 step B) and 2,2-dimethyl-propane-1-sulfonyl chloride. Light yellow solid. MS (ESI): 463.2 (MH+)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
In a 200 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (25 mg, 0.088 mmol) and 3,4-dimethoxybenzoyl chloride (17.6 mg, 0.088 mmol) were combined with methylene chloride (3 mL) to give a yellow suspension. The reaction mixture was cooled to 0° C. After 15 min. stirring at reduced temperature, N,N-diisopropylethylamine (56.7 mg, 76.6 μL, 0.439 mmol) was added. The reaction mixture quickly became a yellow solution, then was stirred at 0° C. for 1 hr. After this time, LC/MS indicated that the reaction was complete. The reaction mixture was warmed to room temperature, then stirred overnight. In the morning, the reaction mixture was concentrated over silica gel. Flash chromatography (25 gram Analogix column, 20% ethyl acetate-hexanes ramped to 100% ethyl acetate) was used to purify the product. N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,4-dimethoxy-benzamide (26 mg, 59%) was obtained as a white solid. MS calcd. for C25H21ClN2O4 [(M+H)+] 448.9, obsd. 449.1.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:8][S:9]([C:12]2[N:13]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:39].[Cl-].[NH4+]>CN(C)C=O.O>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([CH3:39])[S:9]([C:12]2[N:13]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CI
Reactant: O=S(=O)(NC(c1ccccc1)c1ccccc1)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 86.3 %

Procedure:
To a solution of N-diphenylmethyl-1-benzenesulfonylindole-2-sulfonamide (12.40 g, 24.67 mmol) in 120 ml of N,N-dimethylformamide was portionwise added sodium hydride (60% in oil, 1.18 g, 29.61 mmol) with stirring at 0° C., and iodomethane (1.85 ml, 29.61 mmol) was added thereto. The resulting solution was heated to 50° C. and stirred for 3 hours, followed by stirring at 70° C. for 3.5 hours. The reaction solution was neutralized with a saturated aqueous solution of ammonium chloride, and water was added thereto followed by extraction with chloroform. The resulting organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 18.1 g of a crude product. The obtained crude product was washed with ethanol under heating to give 11.0 g (yield: 86%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[Cl:43])[C:26]2=[O:44])=[CH:20][CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pt]=O.C(OCC)(=O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([Cl:43])=[C:34]([N:27]2[C:26](=[O:44])[N:25]([CH2:24][C:21]3[CH:20]=[CH:19][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:11])(=[O:10])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:23][CH:22]=3)[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A mixture of 128 mg (0.2 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H -1,2,4-triazol-3-one (from Example 24), 10 mg of 10% platinum oxide on carbon, and 2 mL of ethyl acetate was stirred under a hydrogen atmosphere (balloon) for 4 hours. The mixture was then filtered through Celite, and the product was chromatographed on a column of silica gel (gradient elution with 0.5-5% methanol in CH2Cl2) to yield 78 mg of the title compound as a white solid, mp 185°-188° C.; nearly homogeneous by TLC (9:1 CH2Cl2 --MeOH).