Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]#[N:11].S(Cl)(Cl)=O.O.[CH3:17][N:18]([CH3:21])[CH:19]=O>>[C:10]([C:3]1[C:4]([CH:7]([CH3:9])[CH3:8])=[N:5][S:6][C:2]=1[N:1]=[CH:17][N:18]([CH3:21])[CH3:19])#[N:11]
Reactant: CC(C)c1nsc(N)c1C#N
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)c1nsc(N=CN(C)C)c1C#N

Procedure:
To a solution of 6.7 g of 5-amino-4-cyano-3-isopropylisothiazole in 30 ml of dimethylformamide was slowly added 10.4 ml of thionyl chloride and the mixture was heated under reflux for 3 hours. The mixture was poured into 300 ml of water and the water-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethanol. The solution was treated with decolorizing charcoal, then was diluted with 300 ml of water. The small amount of solid which separated was removed by filtration and was discarded. As the solution stood undisturbed, tan solid separated which was collected and recrystallized from methylcyclohexane to give 3.0 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylformamidine, m.p. 95°-97°. A small amount was sublimed at 120° under 0.03 mm without change in melting point. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CO[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)=O>O1CCCC1>[CH3:3][NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Solvent: C1CCOC1
Product: CNc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
3.59 gram (6.81 mmol) of (−)-2-methoxycarbonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-2b-1)) was dissolved in 170 ml of tetrahydrofuran, under the flow of nitrogen. To the solution, 27.2 ml of tetrahydrofuran solution (2M) of borane-dimethyl sulfide complex was added at 0° C. over 30 minutes and the resultant mixture was stirred for 18 hours at 88° C. The resultant reaction solution was extracted with 300 ml of ethyl acetate, and the extract was washed with 100 ml of saturated aqueous solution of ammonium chloride and 100 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. To the residue, 272 ml of diethylamine was added and stirred at room temperature for 30 minutes. After evaporating diethylamine, the residue was purified using a silica gel column chromatography (eluent: 1:16 mixture of ethyl acetate and hexane) to obtain 3.05 gram of the titled compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31]([C:33]1[N:34]([CH3:39])[N:35]=[C:36]([NH2:38])[CH:37]=1)=[O:32]>>[CH3:29][O:30][C:31]([C:33]1[N:34]([CH3:39])[N:35]=[C:36]([NH:38][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:37]=1)=[O:32]
Reactant: COC(=O)c1cc(N)nn1C
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Product: COC(=O)c1cc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)nn1C
Yield: 17 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (Intermediate 8) afforded 5-{3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionylamino}-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a white solid (22.1 mg, 17%); ES+-HRMS m/e calcd for C25H26N5O5F3 [M+H+] 534.1959 found 534.1959. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.09 (m, 1H), 1.23-1.75 (m, 8H), 1.95 (m, 1H), 2.23 (m, 1H), 3.82 (s, 3H), 4.01 (s, 3H), 5.46 (dd, J=4.5, J=10.4 Hz, 1H), 5.93 (d, J=2.9 Hz, 1H), 6.95 (s, 1H), 7.53-7.60 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 8.19 (d, J=2.9 Hz, 1H), 11.06 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:22][C:23]#[N:24].[K+]>O.Cl>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:23]([NH2:24])=[O:22])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: N#C[O-]
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(OCCNC(N)=O)c2C1
Reaction time: 3 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were dissolved in 10 ml of water and 10 ml of 1N hydrochloric acid. A solution of 4.1 g (50 mmol) of potassium cyanate and 20 ml of water was then added dropwise at a temperature of +60° C. The mixture was stirred for 3 h at +60° C., the reaction product precipitating. This was filtered off under suction, and the residue was stirred with hot petroleum ether. After cooling, the product was filtered off under suction.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]=1[C:34](=[O:36])[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.Cl>C(OCC)(=O)C>[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:35][C:34]([C:11]2[C:12]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][C:14]([O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:10]=2[O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:36])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1c(OC(=O)c2ccccc2)cc(OC(=O)c2ccccc2)cc1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Oc1cc(OC(=O)c2ccccc2)c(C(=O)C=Cc2ccc(O)cc2)c(OC(=O)c2ccccc2)c1)c1ccccc1
Reaction time: 96 h

Procedure:
2',4'6'-tribenzoyloxyacetophenone (83.5 g) and 4-hydroxybenzaldehyde are dissolved in 850 ml of ethyl acetate. Hydrogen chloride is led in at a temperature of 0° for 6 hours. The reaction mixture is then kept at about 5° for 4 days and then freed from most of the hydrogen chloride with nitrogen passed through the solution. The ethyl acetate is evaporated and the residue mixed with 300 ml benzene and evaporated to remove the remaining hydrogen chloride. The residue is mixed with abs, ethanol (460 ml). A crystalline solid is formed, collected by filtration and then suspended in ether and reflexed with stirring for 2 hours. After cooling, filtration and washed with ether there is obtained 41 g of 4-hydroxy-2',4',6'-tribenzoyloxy-chalcone with m.p. 198°-200°. This compound is dissolved in 1400 ml dioxane and hydrogenated at room temperature and atmospheric pressure with 4 g of 10% Pd/C as catalyst. When the theoretical amount of hydrogen has been absorbed the reaction is stopped, the catalyst removed by filtration and the dioxane evaporated in vacuo. The residue is recrystallized twice from abs. ethanol and 28 g of 3-(4-hydroxyphenyl)-2',4' ,6'-tribenzoyloxypropiophenone is obtained with a m.p. of 156°-8°.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[CH:8]=1.[OH-].[Na+].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>>[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:23][CH:22]=2)[CH:8]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CNCCCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCCCc1cccc(Sc2ccc(C(F)(F)F)cc2)c1

Procedure:
N-Methyl-3-chloro-benzenepropanamine hydrochloride (13.14 g, 0.06 mol), 25%, by weight, sodium hydroxide solution (9.6 g of solution; 0.06 mol of sodium hydroxide), sodium hydroxide pellets (2.0 g, 0.05 mol and 4-trifluoromethylbenzenethiol (8.3 g, 0.05 mol) were reacted to provide N-methyl-3-[[4-(trifluoromethyl)phenyl]thio]benzenepropanamine as an oil. The oil was dissolved in 200 ml diethyl ether and hydrochloric acid gas was passed through the solution for about 15 minutes. The solvent was removed under reduced pressure to provide an oil which was dissolved in a 1:1:1 ethyl acetate:diethyl ether:hexane solvent mixture. The solvents were slowly removed under reduced pressure and crystals precipitated. The crystals were purified by preparing a slurry of the crystals partially dissolved in a 1:1:1 methylene chloride:ethyl acetate:diethyl ether solvent system. The mixture was chilled to 0° C. and the solids were recovered by filtration to provide 13.0 g of title compound. m.p. =125°-130° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ncc(C(=O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 40 h
Yield: 85.4 %

Procedure:
Ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (43.9 g) was dissolved in ethanol (200 ml), 2 M aqueous sodium hydroxide solution (330 ml) was added and the mixture was stirred at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure, and the aqueous layer was adjusted to pH 8 with 6 M hydrochloric acid. The mixture was concentrated under reduced pressure, and subjected to azeotropic distillation with 2-propanol. The residue was suspended in acetone, and insoluble powder was collected by filtration. The obtained powder was suspended in 1 M hydrochloric acid and the suspension was adjusted to pH 3. The suspension was concentrated under reduced pressure. The residue was subjected to azeotropic distillation with 2-propanol, and suspended in acetone. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give the object compound (32.8 g) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[C:34]([Cl:40])=[N:35][C:36](Cl)=[CH:37][CH:38]=1)=[O:32].C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][C:34]=1[Cl:40]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl-2,6-dichloro-pyridine-3-carboxylate and DABCO (21 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.2 [M+H+]
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[N:15]2)(=O)=O)=CC=1.[CH3:20][NH:21][CH3:22].C1COCC1>>[I:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][N:21]([CH3:22])[CH3:20])[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cn2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
2-(4-Iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (Preparation 58) (1.03 g, 2.63 mmol) was treated with dimethylamine in THF (2M, 10 mL, 20.00 mmol) and stirred at room temperature for 3 days. Solvents were removed under reduced pressure and the residue partitioned between DCM and saturated aqueous NaHCO3. The aqueous were extracted with DCM and the combined organic layers dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give the title compound (616 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc3ccccc3n2)cc1

Procedure:
5,6-dichloro-2-(4-formylphenyl)-1-(quinolin-2-ylmethyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-chloromethylquinoline by following General Procedure 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[C:27]([CH2:29]O)[CH:26]=[N:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Cn1cc(CO)cn1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Cn1cc(Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)cn1

Procedure:
Compound IIg was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and (1-methyl-1H-pyrazol-4-yl)methanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: C(O[C:6]([N:8]1[C@:12]2([CH2:16][CH2:15][N:14]([C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18])[C:13]2=[O:23])[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl.C(N(C(C)C)CC)(C)C.BrC[CH:42]=[CH:43][CH2:44][OH:45]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:22][O:21][C:19](=[O:20])[CH:17]([N:14]1[CH2:15][CH2:16][C:12]2([N:8]([CH2:6][CH:42]=[CH:43][CH2:44][OH:45])[CH2:9][CH2:10][CH2:11]2)[C:13]1=[O:23])[CH3:18]
Reactant: COC(=O)[C@H](C)N1CC[C@@]2(CCCN2C(=O)OC(C)(C)C)C1=O
Reactant: OCC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)C(C)N1CCC2(CCCN2CC=CCO)C1=O

Procedure:
82 mg (0.25 mmol) (S,S)-7-(1-methoxycarbonyl-ethyl)-6-oxo-1,7-diaza-spiro[4.4]nonane-1-carboxylic acid tert-butyl ester are stirred at room temperature for three hours in 1 mL of a 4N HCl dioxane solution, evaporated, then taken up in toluene and evaporated again (twice). The residue is taken up in 2 mL dichloromethane and stirred at room temperature for 65 hours in the presence of 74 mg (0.2 mmol) tetrabutylammonium iodide, 0.035 mL (0.2 mmol) diisopropylethylamine and 30 mg (0.2 mmol) 4-bromo-but-2-en-1-ol. The reaction mixture is extracted with EtOAc and saturated aqueous sodium bicarbonate, the combined organic phases washed with brine, evaporated to dryness and the residue column chromatographed (silica gel, EtOAc/EtOH 9:1) to yield the desired product as a thick liquid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].O/N=[CH:8]/[C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][NH:18]2)=[CH:14][C:13]=1[CH3:21])=[O:10]>>[CH3:21][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]3[C:8](=[O:2])[C:9](=[O:10])[NH:11][C:12]=13)[NH:18][N:17]=[CH:16]2
Reactant: O=S(=O)(O)O
Reactant: Cc1cc2cn[nH]c2cc1NC(=O)/C=N/O
Product: Cc1cc2cn[nH]c2c2c1NC(=O)C2=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To concentrated sulphuric acid (119 ml) was added portionwise 2-[(E)-hydroxyimino]-N-(5-methyl-1H-indazol-6-yl)-acetamide (34.7 g, 146.3 mmol). The addition was strongly exothermic and the internal temperature was maintained at 70° C. with an ice bath. At the end of the addition the resulting reaction mixture was heated at 80° C. and stirred for 45 min at this temperature. According to LC-MS analysis, the reaction has then reached completion. The reaction mixture was cooled down to ambient temperature. The reaction mixture was poured onto 3.00 kg of ice. The resulting dark-brown suspension was stirred for 30 min and then filtrated. The filter cake was washed extensively with water and dried in vacuo at 55° C. The title product was obtained as a red-brown powder. LC/MS: 202 (M+H)+, 224 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J25) (215 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (142 mg, 37%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:37]>CCO>[NH2:37][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 88.2 %

Procedure:
A 20-mL sealed tube was charged with 2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.340 g, 0.627 mmol), concentrated ammonium hydroxide (5.00 mL, 38.5 mmol) and EtOH (5 mL). The reaction mixture was heated in an Initiator (Biotage, AB, Uppsala, Sweden) at 120° C. for 1 h. The reaction mixture was further heated in a heating block at 110° C. for 5 h. The reaction mixture was concentrated and purified by column chromatography (25 g of silica, 30 to 80% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.289 g) as a mixture of two enantiomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 30.2 %

Procedure:
30 g (0.935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of sodium imidazole in 60 ml of n-propanol at the reflux temperature. The reaction mixture is subsequently stirred under reflux for 48 hours and cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred into diisopropyl ether. The resulting crystalline precipitate is filtered off with suction and dried. 12.7 g (35% of theory) of 2,4-bis-(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanol of melting point 174° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCSc1cccc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(SCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A solution of 22.0 grams (0.105 mole) of methyl 3-(3-methylphenylthio)propanoate in 200 mL of methanol was stirred, and 40 mL of aqueous 10% potassium hydroxide was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature during an 18 hour period. GC analysis of the reaction mixture indicated that the reaction was not complete. An additional 30 mL of the aqueous 10% potassium hydroxide was added, and the reaction mixture was stirred for an additional three hours. After this time, 100 mL of water was added to the reaction mixture and the methanol was removed under reduced pressure. The residue was washed with three 50 mL portions of diethyl ether. The cooled residue was then acidified with aqueous 10% hydrochloric acid, and extracted with 100 mL of diethyl ether. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily residue. The residue was stirred with hexane and cooled, resulting in a solid material being formed. The solid was collected by filtration and dried, yielding 17.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[N:28]1([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:31]3[CH2:32][CH2:33][N:28]([C:34]4[S:35][CH:36]=[CH:37][N:38]=4)[CH2:29][CH2:30]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: c1csc(N2CCNCC2)n1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCN(c4nccs4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (30 mg, 0.083 mmol) in N,N-dimethylformamide (1 mL) were added 2-(piperazin-1-yl)thiazole (40 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mol) and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a white solid.