Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]([CH:12]=[O:13])=[O:11]>>[CH2:1]([P:9]1[CH:10]([OH:11])[CH:12]([OH:13])[P:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]([OH:11])[CH:12]1[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=CC=O
Reactant: CCCCCCCCP
Product: CCCCCCCCP1C(O)C(O)P(CCCCCCCC)C(O)C1O

Procedure:
Following the procedure of Example 1, 200 parts of mono-n-octylphosphine is reacted with 194 parts of glyoxal to give 1,4-di-n-octyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, a waxy solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[S:19].[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>O1CCCC1>[CH3:29][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[S:19])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=S
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=S)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
1,3-Dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-thione (400 mg, 1.5 mmole) and m-tolylisocyanate (194 μL, 1.5 mmole) were combined in 40 mL of dry tetrahydrofuran at 0° C. The reaction mixture was warmed to room temperature over a 1 hour period and diluted with 20 mL of tetrahydrofuran. The reaction mixture was filtered and concentrated under reduced pressure. The residual material was chromatographed on silica gel (96:4:0.4 chloroform-methanol-concentrated ammonium hydroxide) to give 480 mg of the title compound analytically pure after trituration with ether/petroleum ether:
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([Si:23]([O:18][C:15](=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)[CH:16]=[CH2:17])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CC(=O)Cc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of 104 mL (104.0 mmol, 1.2 equiv.) of a 1.0M solution of potassium tert-butoxide in THF and 100 mL dry THF under nitrogen atmosphere at −78° C. was added a solution of 14.2 g (86.6 mmol, 1 equiv.) of 1-(4-fluorophenyl)but-3-en-2-one (step B) and 13.0 g (86.6 mmol)tert-butylchlorodimethylsilane in 100 mL dry THF. The reaction mixture was stirred at −78° C. for 6 hr and at RT for 6 hr then quenched by the addition of 50 mL water. The resulting mixture was warmed to RT, diluted with 150 mL hexanes, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with 50 mL brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under vacuum to give 20.5 g of the crude title compounds which were used without further purification. 1H-NMR (CDCl3): δ: 7.52 (2H, m), 6.98 (2H, m), 6.33 (1H, dd, J1=13.2 Hz, J2=8.5 Hz), 5.97 (1H, s), 5.52 (1H, d, J=13.2 Hz), 5.17 (1H, d, J=8.5 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:35]=[CH:34][C:33]([N:36]([C:52]2[CH:57]=[CH:56][C:55](C3C=CC=CC=3)=[CH:54][CH:53]=2)C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:6]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:3]([N:36]([C:33]2[CH:32]=[CH:31][C:30]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:35][CH:34]=2)[C:52]2[CH:57]=[CH:56][C:55]([C:2]3[C:10]4[CH:11]=[C:12]5[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=4[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=4)=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[N:13]5)=[CH:54][CH:53]=2)=[CH:4][CH:5]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 8 h
Yield: 143.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-indeno[2,1-b]carbazole synthesized in Example 1 (3.0 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amine (4.3 g), a toluene/ethanol (4/1, v/v) mixed solvent (50 ml), and a 2M potassium carbonate aqueous solution (10 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.4 g), and stirred at 73° C. for 8 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-dichlorobenzene (140 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by recrystallization using 1,2-dichlorobenzene (100 ml) was performed to obtain a white powder of 7-[4-{bis(biphenyl-4-yl)amino}-phenyl]-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (3.7 g; yield 71.6%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(Cl)c1=O
Yield: 85.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.2 g (0.01 mol) of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 3.5 g (0.0105 mol) of 4-(4'-trifluoromethylphenoxy) benzyl bromide, and thereto was added 2.1 g (0.02 mol) of anhydrous sodium carbonate to effect reaction at 85° to 90° C. for 4 hours. After the reaction, the reaction liquid was allowed to cool, poured into water and then extracted with benzene. The benzene layer was washed with 5% aqueous solution of sodium hydroxide and then with water, dried over anhydrous sodium sulfate and then freed of benzene by distillation under reduced pressure. The oily residue was incorporated with n-hexane and the precipitated crystals were filtered off to obtain white crystals (yield: 85.5%).
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4])#[N:2].[NH2:15][OH:16].CCCCCCC>C(O)(C)C>[NH2:2]/[C:1](=[N:15]\[OH:16])/[C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: Cc1nnc(C(=O)NC(C)(C)C#N)o1
Reactant: NO
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nnc(C(=O)NC(C)(C)/C(N)=N/O)o1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
N-(2-cyanopropan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (II) (185 gms) was suspended in isopropyl alcohol (462 ml), heated to 50 to 55° C. Aqueous hydroxylamine (IIIa; 76 ml) was added and the reaction mixture stirred for 30 minutes at 60° C. After completion, reaction mass was cooled between 0 and 5° C. and heptane (462 ml) was added to the reaction mass. The resultant slurry was filtered, washed with heptane (185 ml) and the wet cake was dried to give N-[(1Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide (IVa).
Reaction SMILES: Cl[C:2]1[CH:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[CH:4]2[N:5]=[CH:6][N:7]=1.[CH3:15][NH2:16]>C1COCC1>[I:11][C:10]1[CH:3]2[CH:4]([N:5]=[CH:6][N:7]=[C:2]2[NH:16][CH3:15])[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=1
Reactant: CC(C)N1C=C(I)C2C(Cl)=NC=NC21
Reactant: CN
Solvent: C1CCOC1
Product: CNC1=NC=NC2C1C(I)=CN2C(C)C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Chloro-7,7a-dihydro-5-iodo-7-isopropyl-4aH-pyrrolo[2,3-d]pyrimidine (0.3 g, 0.93 mmol) from above was placed within a 15 ml pressure tube. 2 M methylamine in THF (15 ml) was added, and the reaction was left to stir overnight. The volatiles were removed in vacuo, and the residue was dissolved in methanol, 5 ml silica gel were added, and the volatiles were removed in vacuo. The adhered product was purified by silica gel chromatography (ethyl acetate:hexanes), and the requisite fractions were pooled and evaporated in vacuo to yield the desired product (0.25 g, 85% yield). 1H NMR (399.6 MHz, CDCl3) δ 1.43 (6H, d, J=6.8 Hz), 3.13 (3H, d, J=4.8 Hz), 5.0 (1H, sp, J=6.8 Hz), 7.02 (1H, s), 8.35 (1H, s).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)(C)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:14][C:9]2[C:8]([Cl:7])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ncncc1Cl
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Clc1cncnc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
2.1 g (19 mmol) of potassium tert-butylate are added to a suspension of 2.2 g (17.2 mmol) of 5-chloro-pyrimidin-4-ylamine in tert-butanol (50 ml) and the temperature is kept at 60° C. After stirring for 1 h, a solution of 4.1 g (17.2 mmol) of 4-benzyloxy-benzyl chloride in tert-butanol (40 ml) is added dropwise and the reaction mixture is stirred at this temperature for 1 h. The reaction mixture is cooled to room temperature and poured into water (300 ml). The precipitate is filtered off and the filtrate is extracted with ethyl acetate (2×200 ml). The combined organic layers are dried with magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on silica gel (toluene/dioxane=6:1) to yield 2.0 g (37%) of the title compound as a beige powder of m.p. 95°-100° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:29])[NH:13][C:14]2[CH:26]=[C:25]([Cl:27])[C:17]([O:18][CH2:19][CH2:20][O:21]C(=O)C)=[C:16]([Cl:28])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:25]1[CH:26]=[C:14]([NH:13][C:12](=[S:29])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:15]=[C:16]([Cl:28])[C:17]=1[O:18][CH2:19][CH2:20][OH:21]
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOC(C)=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCO)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethyl ester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL) is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (3 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([CH3:14])[CH:12]([CH3:15])[CH2:11][C:10]([CH3:16])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CC(C)=CC(C)N1C)C1C=CC=CC=1.N>O.Br.C(O)(=O)C>[CH3:14][N:13]1[CH:12]([CH3:15])[CH2:11][C:10]2([CH3:16])[CH2:9][CH:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: CC1=CC(Cc2ccccc2)N(C)C(C)C1
Agent: Br
Agent: CC1=CC(C)N(C)C(Cc2ccccc2)C1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CC1CC2(C)CC(Cc3ccccc32)N1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 6-benzyl-1,2,4-trimethyl-1,2,3,6-tetrahydro-pyridine and 2-benzyl-1,4,6-trimethyl-1,2,3,6-tetrahydropyridine (from Example LV, 11.7 g) is combined with 48% HBr in water (30 mL) and 33% HBr in acetic acid (20 mL). The mixture is heated to reflux temperature and stirred at this temperature for 4 d. After cooling to ambient temperature, aqueous ammonia (32%, 45 mL) is carefully added and the resulting mixture is extracted with Et2O (3×50 mL). The combined organic extracts are extracted with 2 M hydrochloric acid (3×50 mL), the combined aqueous extracts are basified using 32% aqueous ammonia (20 mL), and the basic aqueous phase is extracted with Et2O (3×50 mL). The combined organic extracts are dried (MgSO4), the solvent is removed, and the residue is purified by chromatography on silica gel (EtOAc/MeOH/NH395:5.0.5->75:25:2.5). The title compound obtained thereafter is dissolved in iPrOH and treated with HCl in iPrOH to precipitate the HCl salt of the title compound from the iPrOH solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].IC.[C:16]([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:16])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(C(=O)C(C)C)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (1.13 g, 5.55 mmol, corrected for purity) was dissolved in 22 mL of acetonitrile and treated successively at 0° C. with iodomethane (0.36 mL, 1.05 eq.) and Cs2CO3 (1.998 g, 1.1 eq.), and the mixture then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=95/5), delivered 0.740 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:21]([NH:20][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[O:10])=[O:22])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide (0.48 g, 0.96 mmol) in methanol (20 mL) was added sodium borohydride (36 mg, 0.96 mmol). The reaction was stirred at room temperature for 5 min, treated with water, and concentrated in vacuo. The residual mixture was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.47 g (98%) of a white foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of pivaloyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (80 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:34][CH:35]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared by treating 4-(2-benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (20 mg, 1 eq) with 2-(4-bromomethyl-phenyl)-propionic acid (39 mg, 3 eq) and potassium carbonate (37 mg, 5 eq) in DMF (2 mL) at 150° C. overnight. After cooling, water was added and the pH adjusted to 1 (aq. HCl, 2M) followed by extraction with dichloromethane. Purification by preparative HPLC gave the desired product in 45% yleld.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:39])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.042 mmol) in anhydrous methanol (2.00 mL) was added 37% aqueous formaidehyde (0.012 mL, 0.16 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc (10 mL) and washed with sat. aqueous NaHCO3 (10 mL). The Aqueous was further extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL) and water (10 mL) then dried using a phase separation cartridge. The organics were concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was then taken up in minimal hot acetonitrile and water and freeze dried to give the title compound (6) (0.016 g, 74%) as a white solid; 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.27 (dd, J=8.3, 4.1 Hz, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.41 (m, 3H), 6.99 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.2, 1.6 Hz, 1H), 6.55 (s, 1H), 3.98 (s, 3H), 3.20 (m, 4H), 2.90 (m, 2H), 2.57 (m, 1H), 2.22 (s, 3H), 1.98 (td, J=11.2, 3.8 Hz, 2H), 1.78 (m, 4H). LCMS Method C: rt 4.97 min; m/z 514.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([O:31]C)=[O:30])=[CH:28][C:15]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:31])=[O:30])=[CH:28][C:15]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound 1a, 9.90 g, obtained in Example 1 was dissolved in a solvent mixture of 200 ml of methanol and 20 ml of water and 2.70 g of sodium hydroxide was added to the solution. The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in 200 ml of water. A pH was adjusted to 1.5 with 4N hydrochloric acid aqueous solution. The crystallized crude product was taken out by filtration and dried. The crude product was recrystallized from 300 ml of isopropanol to give 6.44 g of the desired compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[F:14][C:15]([F:34])([F:33])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([OH:27])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1>CCOCC>[F:34][C:15]([F:33])([F:14])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([O:27][C:7](=[O:9])[CH3:8])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OC(C)=O
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of 1.26 g (0.016 mol) of pyridine, 1.61 g (0.016 mol) of acetic anhydride and 5.0 g (0.016 mol) of product of Example 35 in 50 ml of ether was stirred for 3 hours and filtered. The filtrate was concentrated in vacuo to give 5.38 g (95%) of product as a solid; mp 49°-51° C.