Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCCC1C=NC(C(F)(F)F)=NC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][CH2:34][C:35]2[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][CH:40]=2)N)=[CH:27][CH:26]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:64](=CC=1)[N:63]([CH2:67][CH2:68][C:69]1[CH:70]=NC(C(F)(F)F)=NC=1)[CH:62]=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:24][C:25]1[CH:30]=[C:29]2[C:28](=[CH:27][CH:26]=1)[N:31]([CH2:33][CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][CH:40]=1)[C:70]1[CH2:64][N:63]([CH3:62])[CH2:67][CH2:68][C:69]2=1
Reactant: NN(CCc1cnc(C(F)(F)F)nc1)c1ccc(Cl)cc1
Reactant: CNCCc1cn(CCc2cnc(C(F)(F)F)nc2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCc2c(n(CCc3cnc(C(F)(F)F)nc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 5-(2-bromoethyl)-2-(trifluoromethyl)pyrimidine, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [C:1]1([CH:7]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][O:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]=O>C(O)=O>[C:1]1([CH:7]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[C:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][O:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][N:10]([CH3:30])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNCCC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CN(C)CCC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)c1ccccc1

Procedure:
30 g of formic acid, is added dropwise to 38.5 g of 7-(1-phenyl-3-methylaminopropoxy)-isoflavone, while stirring and cooling, and 7 g of 25% formaldehyde solution is then added dropwise at 20°. The mixture is heated on a waterbath until evolution of gas ceases and is cooled, poured onto ice and worked up in the customary manner to give 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone. M.p. 128°-130°.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>ClC(Cl)Cl>[Cl:2][CH2:3][CH2:4][NH:5][C:18]([C:14]1[O:13][CH:17]=[CH:16][CH:15]=1)=[O:19]
Reactant: NCCCl
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCl)c1ccco1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 87 parts of 2-chloroethanamine hydrochloride and 300 parts of trichloromethane are added 224.2 parts of N,N-diethylethanamine, there is added dropwise, during a 1.50 hours period, a solution of 96 parts of 2-furancarbonyl chloride in 300 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, with a diluted hydrochloric acid solution and again twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 95 parts of N-(2-chloroethyl)-2-furancarboxamide as a residue.
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13](C)[C:14](=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOC(C)=O.CC(O)=O>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH3:14])[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: NCC(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (38 g, 0.506 mol) was added to crude B1 (107 g, 0.506 mol) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 7 h. Solvent was evaportated under suction with heating (50-60° C.). To the thick syrupy crude product was added 1 L of EtOAc followed by the slow addition of aqueous NaHCO3 (saturated) to adjust the pH to ˜7. Then 10 mL of 2 M NaOH was added to adjust the pH to ˜9-10. The mixture gave a solid along with organic and aqueous layers. The solid was filtered to give product containing some impurity. The solid was partitioned between 400 mL dichloromethane (DCM) and 200 mL NaHCO3, and the resultant slurry was stirred for 20 min, then filtered to remove an insoluble impurity. The DCM layer was separated and washed with 3% NaHCO3 and then brine (200 mL). The DCM layer was dried (MgSO4), filtered and concentrated to give 50 g of pure product. EtOAc layer was concentrated to give 67 g of solid product with some impurity. The aqueous layer was extracted with EtOAc (2×400 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give an additional 6.7 g of crude product. Total of 123.4 g of product was obtained, 50 g of which was very clean (yield quantitative). 1H NMR (300 MHz, CDCl3) δ 3.2 (s, 3H), 3.5 (m, 1H), 3.8 (m, 1H), 7.35 (d, 1H), 7.6 (m, 2H), 8.8 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].C1COCC1.S(Cl)([Cl:21])(=O)=O>O>[Cl:21][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccccc1CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1CC(=O)O
Temperature: -15 °C
Yield: 95 %

Procedure:
A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15° C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.C(N(CC)CC)C.[F:22][CH:23]([F:27])[C:24](F)=[O:25]>C1(C)C=CC=CC=1>[F:22][CH:23]([F:27])[C:24](=[O:25])[C:10](=[CH:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C=CN1CC(C)OC(C)C1
Reactant: O=C(F)C(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CC(C)OC(C)C1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Methyl 3-(2,6-dimethylmorpholin-4-yl)acrylate (93.5%, 17.5 g, 82 mmol) and triethylamine (8.8 g, 87 mmol) were initially charged in toluene (150 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (10.0 g, 100 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. The residue obtained was 21.4 g of an orange solid which, according to GC analysis, consisted to 90.8% of methyl 4,4-difluoro-3-oxo-2-(2,6-dimethylmorpholin-4-ylmethylidene)butyrate (yield: 85.3%). 1H-NMR (CDCl3): δ=1.2 (s, 3H), 1.25 (s, 3H), 2.95 (m, 1H), 3.25 (m, 1H), 3.5 (m, 1H), 3.75 (m, 2H), 3.8 (s, 3H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][NH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9]=2[N:8]=[C:7]1[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.O.NN.[H][H]>[Pd]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:10]2[C:9]3[N:8]=[C:7]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[N:6]([CH2:5][CH2:4][NH:3][CH2:2][CH3:1])[C:14]=3[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11]2=[O:19])=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2,3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 3, this substance is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 4, 7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Product: COC(=O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of the N-phenylglycine (5.45 g, 36 mmol) in methanol (100 mL) was added hydrogen chloride (50 mL, 4.0 M solution in dioxane, 200 mmol) and the mixture was stirred overnight at rt. The organic solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (100 mL), washed with 1N sodium carbonate (3×50 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and finally dried in vacuo to afford 5.85 g (98%) of the title compound. 1H NMR (400 MHz, CDCl3) δ: 7.2 (m, 2H), 6.76 (m, 1H), 6.62 (m, 2H), 4.27 (brs, 1H), 3.93 (d, 2H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[C:26]([NH:28][C:29]3([C:32]([O:34]CC)=[O:33])[CH2:31][CH2:30]3)=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:44])[F:45])[CH:38]=3)[C:26]([NH:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]3)=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(C(=O)NC1(C(=O)O)CC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
78 mg (0.115 mmol) of the compound of Example 1 were dissolved in 2.2 ml of methanol, and 460 μl of a 1M aqueous lithium hydroxide solution (0.46 mmol) were added. The mixture was stirred at RT overnight and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 64 mg (86% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-cyano-pyridin-3-yl)-amide (0.12 g, 0.2 mmol) prepared in Example 182 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.36 g, 3 mmol), then aqueous solution (1N) of NaOH (1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-carbamoyl-pyridin-3-yl)-amide as a white solid (Yield 80 mg, 65%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH2:33][CH2:34][CH3:35]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27](=[O:26])[N:32]([CH3:31])[CH2:33][CH2:34][CH3:35])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CCCN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 29 μl of N-methyl-N-propylamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a mixture of petroleum ether and ethyl acetate (40/60 by volume) to give 61 mg of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-methyl-1-propylurea in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[F:26][C:23]([F:25])([F:24])[C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH2:13][C:11]3[CH:10]=[CH:9][C:7]4[N:8]=[C:4]([NH:27][C@@H:28]5[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]5[OH:34])[S:5][C:6]=4[CH:12]=3)[CH:15]=[N:16][C:17]=2[CH:22]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Temperature: 130 °C
Yield: 24.2 %

Procedure:
A stirred mixture of 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.20 g, 0.50 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (0.17 g, 1.5 mmol), DIEA (0.59 g, 4.6 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (54 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.54 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.39 (m, 1H), 2.01 (m, 1H), 1.80 (m, 1H), 1.59-1.62 (m, 2H), 1.17-1.23 (m, 4H); LCMS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:23]3[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(CC(=O)O)C3)c2CC1
Temperature: 75 °C

Procedure:
2.5 g (7.75 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, 1.1 g (9.1 mmol) azetidin-3-yl-acetic acid and 3 mL (17.4 mmol) DIPEA were suspended in 18 mL ethanol. The reaction mixture was stirred at 75° C. over night. The solvent was evaporated and the residue was taken up in EtOAc and water and was acidified using a KHSO4 solution. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by prep. HPLC to yield the corresponding acid (72% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]([O:11]CC)=[O:10])[N:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:4]=1)[CH3:2].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]([OH:11])=[O:10])[N:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(F)(F)F)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
Ethyl 5-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-acetate (1.34 g, 7.5 mmol) (i.e. the product of Example 16, Step B) in tetrahydrofuran (5 mL) was treated with sodium hydroxide (0.5 g) in water (3.5 mL). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether. The resulting aqueous layer was acidified with concentrated hydrochloric acid to give a white precipitate. The precipitate was filtered and dried in air to give 690 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][Cl:52].[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:49][CH2:50][CH2:51][Cl:52])[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCCCl)c3ccccc23)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of Compound 1 (5.0 g, 7.99 mmol) obtained in Example 1 in 50 ml of N,N-dimethylformamide was portionwise added sodium hydride (60%. in oil, 351 mg, 8.78 mmol) with stirring at room temperature, and 1-bromo-3-chloropropane (0.87 ml, 8.78 mmol) was added thereto, followed by stirring at room temperature for 4 hours. 1-Bromo-3-chloropropane (0.16 ml, 1.62 mmol) was added thereto and the mixture was stirred further for 4.5 hours. The reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride, and water was added thereto followed by extraction with ethyl acetate. 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 6.5 g of a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=1/3-1/1) to give 5.35 g (yield: 95%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:17][CH:16]=[N:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:17][CH:16]=[N:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cncs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cncs2)cc1
Temperature: 0 °C
Yield: 78 %

Procedure:
A stirred solution of 5-[(4-nitrophenyl)sulfonyl]thiazole (1.72 g, 6.4 mmol) and stannous chloride dihydrate (7.17 g, 31.8 mmol) in absolute ethanol (25 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, the aqueous solution basified with solid sodium bicarbonate and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed to yield an orange solid. Flash chromatography (eluted with 10% ethyl acetate in methylene chloride) and evaporation of the solvent yielded the title thiazole (1.20 g, 78%) as a pale yellow solid; mp 158°-160° C. 1H-NMR (250 MHz, d6 -DMSO): 6.35 (br s, 2H, NH2), 6.65 (d, 2H, J=8.9 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.39 (s, 1H, aromatic), 9.38 (s, 1H, aromatic). MS (CI, CH4): 241(M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC(O)C(=O)OCc1ccccc1

Procedure:
2-Hydroxy-4-methylpentanoic acid is reacted with benzyl bromide in ethyl acetate in the presence of triethylamine, to give benzyl 2-hydroxy-4-methylpentanoate.