Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]1[C:31]([Cl:37])=[N:32][CH:33]=[N:34][C:35]=1Cl>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:35]5[C:30]([NH2:29])=[C:31]([Cl:37])[N:32]=[CH:33][N:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ncnc(Cl)c4N)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 5-amino-4,6-dichloropyrimidine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]4[CH2:29][CH2:30][CH2:31][CH:25]4[CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:13]=1>>[CH2:24]1[N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27][N:26]2[CH2:29][CH2:30][CH2:31][C@@H:25]12
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN3CCCC3C2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN4CCC[C@H]4C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and racemic 4-(2-chloro-8-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine were reacted. The enantiomers were separated by SFC to give 415. LCMS m/z: 488.2 (MH+)
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].Cl[C:33](Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.[NH3:45]>O1CCOCC1.CO>[NH2:45][C:33]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11](=[O:21])[C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[CH:30][CH:31]=2)[N:4]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CN(Cc1ccc(-c2noc(N)n2)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
Prepared from INT-57. To a stirring suspension of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate INT-57 (820 mg, 1.91 mmol) in dioxane (10 mL) was added 2,2,2-trichloroacetic anhydride (420 μL, 2.30 mmol) and heated to 120° C. for 2 h. To this mixture was added 7 M ammonia in MeOH (10 mL) and stirred at room temperature for 18 h. The reaction mixture was pre-absorbed onto silica gel and purified by chromatography (EA/hexanes) to afford 342 mg (39%) of tert-butyl 2-(N-(4-(5-amino-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate) INT-67 as a white solid. LCMS-ESI (m/z) calculated for C22H23N5O6: 453; found 454 [M+H]+, tR=2.30 min (Method 10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37](I)([CH3:39])[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH:37]([CH3:39])[CH3:38])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CC(C)I
Product: CC(C)c1ccc(N(Cc2cnn(C(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 95717.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) and isopropyl iodide (0.16 mg) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.47 g) was obtained. By the reaction and treatment of this compound, in the same manner as in Example 17 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained. melting point: 185° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][C:20](=[C:25]([C:28]([OH:30])=O)[C:26]#[N:27])[CH2:21]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Br:31][C:32]1[C:33]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([Cl:38])[S:35][C:36]=1[Cl:37]>CN(C=O)C.CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][C:20](=[C:25]([C:26]#[N:27])[C:28]([NH:42][S:39]([C:33]1[C:32]([Br:31])=[C:36]([Cl:37])[S:35][C:34]=1[Cl:38])(=[O:40])=[O:41])=[O:30])[CH2:21]2)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=C(C#N)C(=O)O)C2
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=C(C#N)C(=O)NS(=O)(=O)c1c(Cl)sc(Cl)c1Br)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
120 μl of DIEA are added to a solution of 102 mg of 3-(carboxy-cyano-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 162 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide, 583 μl of PPA in DMF (50%) and 43 mg of DMAP in 4 ml of DMA, and the mixture obtained is stirred at RT for 48 hours. From the mixture obtained solvent is removed in vacuo and the residue obtained is subjected to preparative HPLC on an RP-18 column. 3-[2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-cyano-2-oxo-ethylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in the form of a foam is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]([NH2:34])[C@H:26]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@@H:26]2[OH:35])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:17][C:18]([F:45])([F:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>COCCOC>[F:17][C:18]([F:44])([F:45])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:40])=[CH:37][CH:36]=1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield the product.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13]>>[CH:1]1([CH2:7][NH:9][CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCC(CO)CO
Reactant: O=CC1CCCCC1
Product: OCC(CO)CNCC1CCCCC1

Procedure:
In a manner similar to Preparation 8, react cyclohexanecarboxaldehyde with 2-aminomethyl-1,3-propanediol to obtain the title compound.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]=[C:22]2[N:26]([CH2:27][O:28][CH3:29])[CH:25]=[CH:24][S:23]2)[CH:18]=[CH:17][CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[Si:6]([O:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]=[C:22]2[N:26]([CH2:27][O:28][CH3:29])[CH:25]=[C:24]([F:40])[S:23]2)[CH:18]=[CH:17][CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCn1ccsc1=Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCn1cc(F)sc1=Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5 ml of tetrahydrofuran was cooled to −78° C., and then 1.05 ml of butyllithium (1.6 M, hexane solution) was dropped thereinto. Into the resulting reaction solution was dropped a solution of 280 mg of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-(3-(methoxymethyl)thiazol-2(3H)-ylidene)pyridin-2-amine in 5 ml of tetrahydrofuran, followed by stirring at −78° C. for 30 minutes. A solution of N-fluorobenzenesulfonimide in 5 ml of tetrahydrofuran was dropped thereinto. After having the temperature of the resulting reaction solution allowed to −30° C., 230 μl of acetic acid was dropped thereinto. The resulting reaction solution was diluted with ethyl acetate, and then washed with water and brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=3/1) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:30])[CH:25](Br)[CH:26]([CH3:28])[CH3:27])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:26]([CH3:28])[CH3:27])[CH3:22]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1:1 mixture of 7: ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19%) as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:29])([F:28])[C:13]1[NH:17][CH:16]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH:15]2[N:14]=1.C(N(CC)CC)C>ClCCl>[F:29][C:12]([F:11])([F:28])[C:13]1[NH:17][C:16]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20][C:15]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(C(F)(F)F)NC2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2nc(C(F)(F)F)[nH]c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To oxalyl chloride (0.124 mL, 2.0M in dichloromethane) in dichloromethane (2 mL) at −78° C. was added dimethylsulfoxide (0.035 mL) in dichloromethane (0.2 mL). The mixture was stirred for 10 min and the product from Step D (69 mg) was added as a solution in dichloromethane (2 mL). The reaction mixture was stirred for 30 min at −78° C. and triethylamine (17 mL) was added rapidly. After 30 min, the −78° C. bath was removed and the reaction warmed to ambient temperature over 30 min at which point the reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL) The phases were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and used without further purification. LC/MS 278.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9](=[O:10])[C:8]2=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O>CO.[BH4-].[K+]>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:18][CH:19]=1)[C:9](=[O:10])[N:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH:12]2[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[CH:6]=[C:7]2[C:8]([CH:9]([OH:10])[N:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:12]2=[O:13])=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2cc(C(C)(C)C)ccc2C1O
Product: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1O
Temperature: 20 °C
Reaction time: 19 h

Procedure:
5-tert-Butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are prepared as described in Example 1, starting with 10.4 g of 4-tert-butyl-N-isobutylphthalimide in 60 cm3 of methanol and 2.3 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 19 hours and is then cooled to a temperature in the region of 0° C. and 50 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., followed by addition of a further 50 cm3 of distilled water. The aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 9.9 g of a mixture of 5-tert-Butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a yellow foam (Rf=0.26 and 0.30 unassigned, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CC1CN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC(C)O1
Solvent: O
Product: CC1CN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC(C)O1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(2,6-dimethylmorpholin-4-yl)quinoline and 6 ml of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 ml of water. The precipitated material is filtered off, washed with 20 ml of water. After drying 2.3 g of the title compound is obtained (MH+: 388).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:25])=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][CH2:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:25])[N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1sc(CCc2c(-c3ccc(F)cn3)noc2C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a suspension of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid methyl ester (1.02 g, 2.82 mmol) in THF (7 mL), water (7 mL) and MeOH (1.4 mL) was added lithium hydroxide monohydrate (237 mg, 5.65 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1 N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (867 mg, 88%) which was obtained as an off white solid. MS: m/e=346.2 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][N:16]1[C:20]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH2:37][CH2:38][C:39]5[N:40]([C:42]([C:45]([F:48])([F:47])[F:46])=[N:43][N:44]=5)[N:41]=4)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=CC=N1.OCCCN1C[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:48][C:45]([F:47])([F:46])[C:42]1[N:40]2[N:41]=[C:36]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]5[CH2:15][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[CH2:55][CH2:54]5)=[CH:29][CH:28]=4)[CH2:31][CH2:32]3)[CH:37]=[CH:38][C:39]2=[N:44][N:43]=1
Reactant: Cn1nccc1CCOc1ccc(N2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
DIAD (3.24 mL, 16.47 mmol) was added dropwise to 4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenol (obtained as described in Example 16, preparation of starting materials) (5 g, 13.72 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (CAS 132710-90-8, 5.03 g, 20.59 mmol) and triphenylphosphine (5.40 g, 20.59 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with EtOAc. Pure fractions were evaporated to dryness to give tert-butyl 4-[3-(4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenoxy)propyl]piperazine-1-carboxylate (3.66 g, 45%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:9][CH:8]=1)=[O:5])[CH3:2].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)O)cc3OC)c2c1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of ester (C) (0.7 g), lithium hydroxide hydrate (0.41 g), tetrahydrofuran (4 ml), methanol (4 ml), and water (1.6 ml) was stirred overnight. The mixture was then evaporated. The white solid obtained was dissolved in water (50 ml). Acidification of this homogeneous alkaline solution by dropwise addition of 10% v/v hydrochloric acid gave a fine white precipitate which was recrystallized from ethyl acetate (40 ml) to give 4-[6-(2-ethylhexanamido)indol-1-ylmethyl]-3-methoxybenzoic acid (D) (0.13 g; 30%) as a solid; mp 234°-235° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([N:16]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([NH:29][C:30](=[O:57])[CH:31]([S:47]CC3C=CC(OC)=CC=3)[CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:44](=[O:45])[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]3=[O:46])[C:17]2=[O:58])[C:9]([O:11]C(C)(C)C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]1([CH2:7][CH:8]([N:16]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([NH:29][C:30](=[O:57])[CH:31]([SH:47])[CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:37](=[O:46])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]3=[O:45])[C:17]2=[O:58])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSC(CCCCN2C(=O)c3ccccc3C2=O)C(=O)NC2CC(c3ccccc3)CCN(C(Cc3ccccc3)C(=O)OC(C)(C)C)C2=O)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(NC1CC(c2ccccc2)CCN(C(Cc2ccccc2)C(=O)O)C1=O)C(S)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine N-[hexahydro-1-[1-(phenylmethyl)-1-t-butoxycarbonylmethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-a-(p-methoxybenzylthio)-1,3-dioxo-2H-isoindole-2-hexanamide (0.16 g, 0.20 mmol), mercury (II) acetate (0.084 g, 0.26 mmol), and anisole (0.23 mL, 2.1 mmol) in dichloromethane (6.6 mL). Cool in an ice bath and degas by repeatedly cycles of vacuum and filling the vessel with nitrogen gas. Add trifluoroacetic acid (2.5 mL). After 1 hour, warm to ambient temperature. After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give the title compound.