Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=3)[N:26]=2)=[CH:21][C:20]1=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:39])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cc1cc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(-c3ccn([C@H](CO)c4ccc(Cl)c(F)c4)c(=O)c3)n2)ccn1
Reaction time: 1 h
Yield: 22.6 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.028 g, 0.049 mmol) was placed in THF (5 mL). TBAF (0.054 mL, 0.054 mmol) was then added, and the reaction was stirred for 1 hour, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:40-500:50 DCM/MeOH) to give the product (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.005 g, 22% yield). m/z (APCI-pos) M+1=452.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2ncc(Br)cc2[N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.2621 g, 0.930 mmol), 3-methoxyphenylboronic acid (0.155 g, 1.02 mmol), tetrakis(triphenylphosphine)-palladium (0.076 g, 0.065 mmol), and 2.0M sodium carbonate (2.4 mL, 4.80 mmol) in toluene (3.0 mL) and ethanol (1.0 mL) was heated to 70° C. After 2.5 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a yellow solid as 5-bromo-2-(3-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, d, J=2.2 Hz), 8.27 (1H, d, J=2.2 Hz), 7.42 (1H, m), 7.14 (3H, m), 3.86 (3H, s).
Reaction SMILES: [CH:1]([CH:5]1[NH:10][NH:9][C:8](=[S:11])[N:7]([CH3:12])[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+].[CH3:16]I>O>[CH:1]([C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8]([S:11][CH3:16])=[N:9][N:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C1NNC(=S)N(C)C1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)c1nnc(SC)n(C)c1=O

Procedure:
1 ml of 3-benzyl-4-hydroxy-biphenyl polyglycol ether, as an emulsifier, and 995 g (5 mol) of 6-sec.-butyl-4-methyl-5-oxo-3-thioxo-tetrahydro-1,2,4(2H,4H)-triazine (IX) were added to a solution of 202 g of NaOH in 5 liters of water. 724 g (5.1 mol) of methyl iodide were added dropwise and the mixture was subsequently stirred until the slightly exothermic reaction had ended and the pH value had reached 7-8. After filtering off the product, washing it with water and drying it at 30° C. in vacuo, 907 g (85% of theory) of the compound (IIb) of melting point 45°-50° C. were obtained. The crude product was sufficiently pure for further reaction. A sample recrystallised from pentane melted at 54°-55° C.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[N:19]=2)=[C:9]1[CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:30]1([N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]=3[CH3:36])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:29])=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Cc1c(C2=NN(C3CCCCC3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(C3CCCCC3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
[3-(2-Cyclohexyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 Amok) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.08 (d, 1H), 7.88 (t, 1H), 7.81 (t, 1H), 7.42 (m, 2H), 6.91 (m, 2H), 4.55 (s, 2H), 4.29 (m, 1H), 2.23 (s, 3H), 1.88 (m, 5H), 1.65 (m, 2H), 1.47 (m, 2H), 1.11 (m, 1H) ppm. MS calculated for C24H24FN3O4S—H: 468, observed: 468.
Reaction SMILES: [CH2:1]([S:5]([N:8](S(CCCC)(=O)=O)[C:9]1[CH:29]=[CH:28][C:12]2[O:13][C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:22]1([C:14]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:13][C:12]3[CH:28]=[CH:29][C:9]([NH:8][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[CH:10][C:11]=3[O:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCS(=O)(=O)N(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)S(=O)(=O)CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCS(=O)(=O)Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
N,N-Bis(butylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine (Example 80, 79 mg, 0.15 mmol) was dissolved in tetrahydrofuran (4 ml). Tetrabutylammonium fluoride solution in tetrahydrofuran (1M, 0.16 mL, 0.16 mmol) was added dropwise at room temperature and the solution was stirred at room temperature overnight. The reaction was heated to reflux for 30 minutes, poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as the eluant. Crystallization from hexane yielded the product as white crystals (45 mg, 74%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([CH3:38])=[CH:40][CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccc(CN)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(C)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-methylbenzylamine, m.p. 179-180° C. MS [(+)ESI, m/z]: 556 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.57; H, 6.01; N, 7.50.
Reaction SMILES: O.O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+].[C:16]([NH:19][CH:20]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])[CH3:17].[OH-].[Na+]>O.CC(C)=O>[C:16]([NH:19][C@H:20]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCCC2)NC(C)=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(C)=O

Procedure:
20 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) were added to a solution of 28.3 g (159 mmol) disodium hydrogen phosphate dihydrate in 500 mL water at a temperature of 37° C. and by the addition of sodium dihydrogen phosphate the pH was adjusted to 7.5. Then 22.0 g (76.0 mmol) ethyl 2-acetylamino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate dissolved in 130 mL acetone was added dropwise at 37° C. with stirring. The pH value of the reaction mixture was kept in the range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 3 h at 37° C. and overnight at RT. The reaction mixture was extracted three times with tert-butylmethylether, the combined organic extracts were washed with 15% K2CO3 solution, dried and evaporated down under reduced pressure.
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(O)(=O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:26][C:21]3[C:20]([NH2:27])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: Nc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.4 %

Procedure:
(R)-Acenaphthen-1-yl-amine•hydrochloride (25 g) was dissolved in water (200 ml) and the mixture was alkalified with potassium carbonate and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained (R)-acenaphthen-1-yl-amine (21 g, 124 mmol) was dissolved in ethanol (200 ml). Potassium carbonate (2.5 g, 18 mmol) and 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g) dissolved in water (100 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)-1-(acenaphthen-1-yl)-piperidin-4-one (22 g) as a red-yellow oil. (4) A solution of (R)-1-(acenaphthen-1-yl)-piperidin-4-one (12.6 g, 50 mmol) and 1,2-phenylenediamine (10.8 g, 100 mmol) in THF (100 ml) was cooled to (0° C.), sodium triacetoxy borohydride (30 g) and acetic acid (12 ml) were added thereto, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into water, and potassium carbonate was added for neutralization. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)—N-[1-(acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g) as yellow crystals. (5) (R)—N-[1-(Acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g, 26 mmol) was dissolved in THF (100 ml), and carbonyldiimidazole (5 g, 30 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8.8 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:12])[NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CN(C=O)C.[C:18]1([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH:9]=[C:10]1[CH3:12]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1nccc2[nH]c(C)cc12
Solvent: CN(C)C=O
Product: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of intermediate (3) (0.70 g, 4.69 mmole) in anhydrous DMF (40 mL) sodium hydride (60% in mineral oil, 0.28 g, 7.04 mmole) was added, the mixture was stirred for 1 h. To the mixture 2-phenylbenzyl bromide (0.95 mL, 5.16 mmole) was added dropwise. The mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated ammonium chloride solution (200 mL), the mixture was extracted with ethyl acetate (3×200 mL). The organic layer was separated and washed with water, dried over magnesium sulphate and concentrated. The residue was purified by column chromatography (3:1 Hex:EtOAc) to afford intermediate (4) as a yellow solid. Yield: 1.1 g 71%.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.O=S(Cl)[Cl:21]>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][Cl:21])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCC[C@H]1CC[C@H](CO)CC1
Solvent: c1ccncc1
Product: CCCC[C@H]1CC[C@H](CCl)CC1
Temperature: 25 °C

Procedure:
37 g (0.22 mol) of trans-4-butylcyclohexylmethanol and 18 g (0.23 mol) of anhydrous pyridine were given dropwise addition of 32 g (0.27 mol) of SOCl2 in an ice water bath while stirring, and then stirred for 3 hours at 105°-110° C. with a mantle heater. The reactant was cooled to room temperature, poured into a beaker containing concentrated HC1 and ice, the oily layer was taken off, the water layer was extracted with chloroform, combined with the oily layer and washed with 10% HCl and water. The chloroform was extracted, and the remaining oily substance was distilled under reduced pressure (b. p. 80° C./3 mmHg) to obtain 38 g (0.20 mol) of trans-4-butylcyclohexylchloromethane.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]>O>[CH3:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:3])[C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of HNO3 (27 mL, 70% solution) and H2O (14 mL) was cooled using an ice bath and 2-methyl-5-nitrophenol (10 g, 65 mmol) was added slowly, followed by NaNO3 (90 mg, 1.3 mmol). The reaction was stirred and warmed to RT. After 4 h, H2O was added and the reaction was filtered to collect a yellow solid. This yellow solid was purified by titration with CH2Cl2 to yield the title compound as a solid that is 98% the desired isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH:28][OH:29])=[NH:27])[N:8]=[CH:7]3.[O-2].[Mg+2].[CH:34]1([C:37](Cl)=O)[CH2:36][CH2:35]1>O1CCOCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]1[N:27]=[C:37]([CH:34]2[CH2:36][CH2:35]2)[O:29][N:28]=1)[N:8]=[CH:7]3
Reactant: COc1ccc(CN2Cc3c(C(=N)NO)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Reactant: O=C(Cl)C1CC1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(-c4noc(C5CC5)n4)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Yield: 37.8 %

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxamidine (1.9 g, 4.3 mmol), magnesiumoxide (0.156 g, 3.9 mmol), and cyclopropanecarbonyl chloride (0.5 mL, 5.3 mmol) were refluxed in dioxane overnight. Dioxane was evaporated and the residue dissolved in DMF (20 mL) and refluxed for 1 h. DMF was evaporated and the residue extracted with CH2Cl2 and water. The product crystallized upon concentration of the organic layer and dilution with ethyl acetate. One obtained a white solid (0.8 g, 39%). mp 198-205° C. m/z 492 (MH+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[CH2:1]([S:3]([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:35])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1S(=O)CC
Yield: 90.2 %

Procedure:
To a 0° C. solution of 4.8 g (0.012 mol) of product of Example 33 in 30 ml of CH2C2 was added 4.08 g (0.024 mol) of MCPBA. The reaction was monitored by TLC. The reaction mixture was filtered, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo to give 4.56 g of solid which was purified by HPLC using 8% ehthyl acetate/cyclohexane to elute the first fraction (1.52 g) followed by 15% ethyl acetate cyclohexane to elute 1.46 g of the desired product. Recrystallization of the 1.46 g solid in hot hexane afforded 0.88 g (17.4%) of product as a white solid; mp 87°-88.5° C.
Reaction SMILES: CC1C=CN=C(NC2N=C(C3OC(NCC4C=CN=CC=4)=NC=3)C=CC=2)C=1.Cl[C:29]1[O:30][C:31]([C:34]2[CH:35]=[C:36]([NH:40][C:41]3[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:32][N:33]=1.FC(F)(F)C(O)=O.[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][C:60]1=[O:65]>CC(O)C>[CH3:55][O:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][N:62]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:41]4[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=4)[CH:35]=3)=[CH:32][N:33]=2)[CH2:61][C:60]1=[O:65]
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)c2)n1
Reactant: COCCN1CCNCC1=O
Agent: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCN(c2ncc(-c3cccc(Nc4nccc(C)n4)c3)o2)CC1=O

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from [3-(2-chloro-oxazol-5-yl)-phenyl]-(4-methyl-pyrimidin-2-yl)-amine and 1-(2-methoxy-ethyl)-2-oxopiperazine trifluoroacetic acid salt in iPrOH. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.35 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.31-7.20 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=5.0 Hz, 1H), 4.10 (s, 2H), 3.79-3.72 (m, 2H), 3.58-3.46 (m, 6H), 3.25 (dd, J=2.7, 2.2 Hz, 3H), 2.38 (s, 3H). (ESI+) m/z 409 (M+H)+. Retention time=2.94 mins (method 1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:22][CH2:23]O)[C:16]=3[CH:15]=[N:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[N:13]([C:8]3[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=3)[N:14]=[CH:15][C:16]1=2
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 85 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (512 mg, 1.65 mmol) in 20 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (462 mg, 1.40 mmol, 85%, oil).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:24]=[C:25]([CH:27]=[CH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:26]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16](/[C:19](=[N:22]\[H])/[NH:20][NH2:21])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.O.[C:40]([O-])(O)=O.[Na+]>C(O)=O>[N:21]1[NH:20][C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:24]=[C:25](/[CH:27]=[CH:28]/[C:29]5[CH:38]=[CH:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:26]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:22][CH:40]=1
Reactant: [H]/N=C(/NN)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=Cc4ccc5ccccc5n4)cn23)cn1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C(=C/c1cn2c(-c3ccc(-c4ncn[nH]4)nc3)cnc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of compound 5a (180 mg, 0.370 mmol) in formic acid (3 mL) was stirred in a 10 mL sealed tube at 100° C. for 2 h. After cooling to rt, water (20 mL) was added, and the pH of the solution was adjusted to 7 with saturated NaHCO3 solution. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 91 as a yellow solid (37 mg, 19% yield). 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.96 (s, 1H), 8.72 (d, J=8.4 Hz, 1H), 8.38-8.32 (m, 4H), 8.19-8.06 (m, 4H), 8.01-7.91 (m, 1H), 7.74-7.68 (m, 2H), 7.58 (s, 1H), 4.45-4.25 (m, 4H), 3.90-3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O: 502.2 (M+H). Found 502.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.Cl.[Br:24][C:25]1[C:26]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:37])([OH:36])[CH3:35])=[N:27][C:28](Cl)=[N:29][CH:30]=1>C(#N)C.O.O1CCOCC1>[Br:24][C:25]1[C:26]([NH:32][C@H:33]([CH3:38])[C:34]([OH:36])([CH3:35])[CH3:37])=[N:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])(=[O:12])=[O:13])=[O:9])=[CH:4][CH:3]=2)=[N:29][CH:30]=1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(CCO)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: C[C@@H](Nc1nc(Nc2ccc(S(=O)(CCO)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br)C(C)(C)O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of 200 mg (0.55 mmol) of (RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide in 2 ml of acetonitrile and 0.5 ml of water is mixed with 0.17 ml of a 4N solution of HCl in dioxane. 198 mg (0.67 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1.5 ml of acetonitrile is added, and the batch is stirred for 20 hours at 80° C. The solvent is removed, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 148 mg (0.24 mmol, corresponding to 44% of theory) of the product is obtained.