Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](Cl)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C-]#[Si+].[C:17]([O-])([O-])=[O:18].[K+].[K+]>>[CH3:17][O:18][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1OC
Agent: [C-]#[Si+]
Agent: [K+]
Product: COc1cc(OC)c([N+](=O)[O-])cc1OC

Procedure:
Into a two liter flask, provided with a cooling device, were introduced successively a solution of methanolic potash (100 g of KOH and 500 cm3 of methanol), then 100 g (0.46 mole) of 4,5-dimethoxy 2-nitro chlorobenzene and carborundum. The mixture was brought to boiling under reflux for 6 h. After cooling, the reaction medium was filtered; the precipitate obtained was washed with methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]([NH:11]CC2C=CC(OC)=CC=2)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.CCOC(C)=O>C(Cl)Cl.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>[NH2:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(CNc2c([N+](=O)[O-])ccc(Cl)c2CN2CCCCC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc(Cl)c1CN1CCCCC1

Procedure:
To a solution of (3-chloro-6-nitro-2-piperidin-1-ylmethyl-phenyl)-(4-methoxy-benzyl)-amine (22) (0.389 g, 1 mmol) in CH2Cl2 (5 mL) and H2O (0.25 mL), DDQ was added at room temperature under vigorous stirring. The dark reaction mixture was monitored by TLC (SiO2, Hexanes:EtOAc, 8:2) and additional DDQ (0.345 g, 1 mmol) was added. The reaction mixture was filtered after additional 2 hours of stirring and diluted with saturated aqueous NaHCO3 solution (100 mL). The product was extracted with CH2Cl2 (2×100 mL), and the extracts were washed with saturated NaCl solution (2×200 mL) and dried (MgSO4). Dark oil (1.68 g) was chromatographed (SiO2, Hexanes:EtOAc, 9:1 to 8:2) twice to give the desired aniline derivative as a yellow solid. Yield: 0.68 g, 25%. 1H-NMR (CDCl3) δ 1.43 (m, 2H), 1.53 (m, 4H), 2.38 (m, 4H), 3.75 (s, 2H), 6.6 (d, 1H, J=9.2 Hz), 7.95 (d, 1H, J=9.2 Hz). MS (CI) m/z 270 (M+H), 272 (M+2H). Anal Calcd for C12H16N3O2Cl: C, 53.44; H, 5.98; N, 15.58. Found: C, 53.76; H, 5.91; N, 15.01.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:25])=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:25])=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(C)c(-c4ccccc4)n(Cc4ccccc4)c3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 1-benzyl-6-(4-methoxy-phenyl)-3-methyl-2-phenyl-1H-indole (1.017 g, 2.861 mmol) was reacted with BBr3 (3.4 ml of a 1M solution in CH2Cl2) to give the product (0.726 g, 1.864 mmol, 65%) as a white solid, mp 141-143° C. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 5.37 (s, 2H), 6.80 (d, J=8.6 Hz, 2H), 6.85 (d, J=7.2 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 7.18 (t, J=7.0 Hz, 2H), 7.30 (dd, J=1.5, 8.3 Hz, 1H), 7.38-7.49 (m, 7H), 7.51 (d, J=0.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 9.40 (s, 1H); IR (solid) 3300, 3030, 1600, 1520, 1450, 1350, 1260, 1230 and 1180 m−1; [ESI(+)], m/z 390 (M+H)+; Anal. Calcd. for C28H23NO: C, 86.34; H, 5.95; N, 3.60; Found: C, 85.88; H, 6.21; N, 3.36.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)NCc2c[nH]c(=S)n2[C@H]2CCc3c(F)cc(F)cc3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.30 g, 1 mmol), prepared as in Example 31, and 4-butylbenzoyl chloride (0.21 mL, 1.1 mmol) in 10 mL of dry pyridine was stirred under argon at approximately 0° C. for 1 hour and then at approximately 25° C. for an additional 2 hours. The mixture was concentrated and the residue was treated with water. The mixture was extracted with ethyl acetate (3×) and the combined extracts were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to give (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]-4-butylbenzamide (0.25 g, 0.55 mmol), m.p. 242°-243° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=C(C#N)[CH:22]=1.C1([Mg]Br)CCCC1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:22]1)=[O:29]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Agent: Br[Mg]C1CCCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)C2CCCC2)c1N

Procedure:
Similar procedure as in Example 17B except 3-[5-amino-4-(3-cyano-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide was used in place of 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide and cyclopentylmagnesium bromide was used in place of phenyl magnesium bromide. HPLC (4 minute 10-90 gradient) tR 2.54 min; MS m/z 353.19 [M+H]+.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:11][NH2:12]>C(O)(C)C>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[NH:12][N:11]=1
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(N)n[nH]1
Yield: 96.4 %

Procedure:
To 600 g of pivaloyl acetonitrile (compound I), there was added 800 ml of isopropanol. The mixture was heated with stirring, and 288 g of hydrazine hydrate was added dropwise thereto. The mixture was heated with stirring for 3 hours. After completion of the reaction, 400 ml of isopropanol was distilled off under reduced pressure. To the residue, there were added 2000 ml of ethyl acetate and saturated brine. The mixture was stirred and then left to stand for a while. The aqueous layer was removed, and the ethyl acetate layer was washed with saturated brine twice. The ethyl acetate solution was then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Subsequently, 2000 ml of n-hexane was added to the residue to precipitate a crystal. The crystal was recovered by filtration and dried. There was obtained 643 g (96.2%) of 3-amino-5-t-butylpyrazole (compound II). Melting point: 74.0° to 75.0° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:12][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC1CCCCC1O
Temperature: 120 °C
Yield: 92.4 %

Procedure:
A mixture of cyclohexene oxide (19.6 g), t-butyl amine (37.1 g), zinc chloride (2.5 g), and 50 ml of toluene were sealed under an inert atmosphere in a Diels-Alder flask. The contents were stirred and heated in a sand bath at 120° C. for 23 hours. After cooling the slurry was diluted with 100 ml of toluene, washed with dilute ammonium hydroxide solution (3×250 ml) and water (300 ml), dried (Na2SO4), filtered, and the solvents were removed under reduced pressure to give 31.6 g of N-2-hydroxycyclohexyl-N-t-butylamine as an off-white, waxy solid, m.p. 42°-44° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN.[C:15]([N:23]1[C:27]2[N:28]=[CH:29][C:30]3[C:31](OC4C=CC=CC=4)=[N:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[C:35]=3[C:26]=2[CH:25]=[N:24]1)(=O)[C:16]1C=CC=CC=1>>[C:2]1([NH:1][C:31]2[C:30]3[CH:29]=[N:28][C:27]4[N:23]([CH2:15][CH3:16])[N:24]=[CH:25][C:26]=4[C:35]=3[N:34]3[N:36]=[CH:37][N:38]=[C:33]3[N:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Reactant: Nc1ccccc1
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(Nc3ccccc3)nc3ncnn3c12

Procedure:
By substituting aniline for the 3-dimethylaminopropyl amine in the procedure of Example 1 (c), N-phenyl-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5-amine is obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:7]2[CH:8]([C:15]([O:17]CC)=[O:16])[N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+:40]>CO>[Na+:40].[Na+:40].[CH2:1]([C:4]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:7]2[CH:8]([C:15]([O-:17])=[O:16])[N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:1]([C:4]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:7]2[CH:8]([C:15]([O-:17])=[O:16])[N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)N(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)[O-])N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (50.0 g) in methanol (500 ml) is added 4N aqueous sodium hydroxide solution (50 ml) under ice-cooling. The mixture is stirred overnight at room temperature, then evaporated. The residue is recrystallized from ethanol to give 2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylic acid disodium salt (44.3 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11].IC>C1COCC1>[CH3:8][O:9][C:10]([C:12]1([CH3:1])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of nbutyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooling to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR(CDCl3) consistent with crude, desired product.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37][B-](F)(F)F)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CCNC(=O)OCc4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 0 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (30 mg, 0.078 mol), potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate (30 mg, 0.11 mol), cesium carbonate (122 mg, 0.38 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) DCM complex (5 mg, 0.01 mol), toluene (0.75 ml) and degassed water (0.25 ml) were added in order. The mixture was heated at 80° C. for 16 hours, concentrated under a stream of nitrogen, diluted with DMF (1.5 mL), filtered and purified by HPLC to afford 6 mg (12%) of 204 as a white solid.
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH3:27][NH:28][CH3:29].O>C(O)C.CN(C=O)C>[CH3:27][N:28]([CH3:29])[CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:24][CH:25]=1
Reactant: Cc1cccc(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(O)CN(C)C)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
A mixture of 4-[4'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine (0.35 g), 33% dimethylamine in ethanol (10 ml) and DMF (5 ml) was stirred at room temperature for 4 hours. The mixture was poured into water, extracted with ethyl acetate and the organic phase evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[4'-(3-dimethylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino) pyrimidine in 54% yield, m.p. 192°-195° C.;
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:12][Cl:13])(=[O:16])[CH3:15]
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (1.5 g, 0.006 mol) and acetic anhydride (4.3 g, 0.042 mol) in dry acetone (50 mL), triethylamine (3.6 g, 0.035 mol) was added dropwise at room temperature. After an additional 16 h, the reaction mixture was evaporated to dryness. The residue was taken up in ethyl acetate (50 mL) and washed with dilute hydrochloric acid (3×10 mL), followed by water (3×10 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, treated with charcoal and filtered. On evaporation of the solvent a solid was obtained which, on recrystallization from ethanol, gave 1.1 g (62.8%) of the title compound: mp 148°-149° C.; 1H NMR (acetone-d6) δ 3.8-4.2 (m, 4 H, CH2CH2), 3.5 and 3.3 (2 s, 6 H, 2CH3SO 2), 2.4 (s, 3 H, CH3CO). Anal. (C6H13C1N2O5S2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][CH:15]2[CH:16]([CH3:19])[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:14]2)=[N:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)CCC4C)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1Nc1ncnc2[nH]ccc12
Temperature: 60 °C
Yield: 27.1 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(4-methyl-3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)ethanone (100 mg, 0.17 mmol) in MeOH:H2O (4:1 mL) was added K2CO3 (94 mg, 0.68 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted in EtOAc (50 mL). The EtOAc suspension was filtered through celite, the filtrate was dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (20 mg, 27%). 1H NMR (400 MHz, DMSO-d6): δ 11.61-11.45 (m, 1H), 8.19-8.06 (m, 1H), 7.08-6.43 (m, 5H), 6.22-6.15 (m, 1H), 4.59-4.21 (m, 2H), 4.15-3.75 (m, 3H), 3.25-2.98 (m, 2H), 2.78-2.45 (m, 1H), 2.15-1.99 (m, 1H), 1.86-1.7-62 (m, 2H), 0.98-0.77 (m, 3H). LC-MS: m/z [M+1]=433.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.NC1N=C(N2CCC3(CN(C(OCC4C=CC=CC=4)=O)[C@@H](C(OCC)=O)C3)CC2)C=C(O[C@@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Agent: CCOC(=O)[C@H]1CC2(CCN(c3cc(O[C@@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@H](Oc2cc(N3CCC4(CC3)CN[C@@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described above for (R)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1m) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Reaction SMILES: [CH2:1]([N:5]([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:33]([C:35]1[C:36](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:37][C:38]([CH3:42])([CH3:41])[C:39]=1[CH3:40])#[N:34].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=[CH:40][C:39]3[C:38]([CH3:41])([CH3:42])[O:37][C:36](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:35]=3[C:33]#[N:34])[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=O)CC(C)(C)C2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
In 6 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 239 mg (0.54 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2-methoxy-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 120 mg (0.60 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 42 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 2.5 hours. The solvent was evaporated off and the residue was purified by silica gel column chromatography to give 279 mg of a dark brown crystal (yield: 82.7%; mp: 244-246° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCC4COC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCC4COC4)cc3)cc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
To a mixture of 6-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carbaldehyde (70 mg, 0.2 mmol) in acetonitrile/t-butanol=1/1 (5 mL) was added 2-methyl-2-butene (0.5 mL). The reaction was cooled to 0° C. and an aqueous solution of sodium chlorite (180 mg, 2.00 mmol) and sodium dihydrogen phosphate (270 mg, 6.00 mmol) in water (0.5 mL) were added dropwise via additional funnel. Then ice bath was removed, the reaction was stirred at room temperature for 12 h. The reaction was quenched with sodium sulfite. The mixture was partitioned between EtOAc (20 mL×3) and water. The combined organics was concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (25 mg, 35% yield) as an off-white solid. MS (AP+) 358.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 4.74 (t, 2H), 4.46 (t, 2H), 4.26 (t, 2H), 3.44-3.42 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12]([CH2:18][C:19]#[N:20])(=O)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:18]=[C:19]([NH2:20])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 90.4 %

Procedure:
To a solution of commercially available 3-methoxyphenylhydrazine hydrochloride (1.0 g, 5.7 mmol) in toluene (5 mL) was added commercially available pivaloylacetonitrile (0.70 g, 5.5 mmol). The reaction mixture was heated at reflux for 5 h, filtered and washed with hexane to obtain 3-t-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-amine (1.22 g, 89% yield) as its hydrochloride salt as a pale yellow solid which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 7.35 (t, J=8.4 Hz, 1H), 7.04 (t, J=2.1 Hz, 1H), 7.00 (dd, J=1.5 and 7.5 Hz, 1H), 6.95 (dd, J=2.1 and 8.4 Hz, 1H), 5.90 (brs, 2H), 5.83 (s, 1H), 3.81 (s, 3H), 1.89 (s, 9H); MS (EI) m/z: 246 (M+H+).