Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:34]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH2:35]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 57.1 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 91 (57.1% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.86 and 3.03 (2t, 2H), 3.51 and 4.04 (2t, 2H), 3.72-3.78 (m, 6H), 3.87 and 3.92 (2s, 6H), 4.43 and 4.94 (2s, 2H), 6.65-7.27 (m, 3H), 7.68-8.18 (m, 6H); MS (ESI) m/z 486 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:21]([NH:23][O:24][CH3:25])=[O:22].[F-].[K+]>CS(C)=O>[C:4]([C:3]1[C:2]([NH:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:21]([NH:23][O:24][CH3:25])=[O:22])=[N:9][C:8]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:7]([F:16])[CH:6]=1)#[N:5]
Reactant: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Reactant: CONC(=O)c1ccc(C)c(N)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(NCC(C)(C)C)c(F)cc2C#N)c1
Temperature: 150 °C
Yield: 1 %

Procedure:
A mixture of 2-chloro-6-[(2,2-dimethyl-propyl)-amino]-5-fluoro-nicotinonitrile (150 mg, 0.62 mmol), 3-amino-N-methoxy-4-methyl-benzamide (150 mg, 0.83 mmol) and potassium fluoride (30 mg, 0.51 mmol) in DMSO (1 mL) was heated to 150° C. overnight. The reaction mixture was allowed to cool to room temp and then partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (2.5 mg, 1%) was obtained after purification by silica gel chromatography with 30% EtOAc in hexane as eluent. C20H24FN5O2 MS m/e=386 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][C:40]([SH:42])=[N:39][N:38]=2)=[CH:33][CH:32]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[O:41][C:40]([SH:42])=[N:39][N:38]=5)=[CH:35][CH:36]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc(-c2nnc(S)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(-c5nnc(S)o5)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol (23 mg, 0.12 mmol) in pyridine (10 mL) was added POCl3 (0.3 mL, 3.29 mmol) at 0° C., the reaction mixture was stirred at room temperature for 6 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, methanol (20 mL) were added and filtrated. The filtrate was collected, concentrated and purified by a silica column chromatography (silica gel 200-300 mesh, eluting with dichloromethane:methanol=40:1) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)piperidine-3-carboxamide (8.0 mg, 11.3%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.42 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.86-7.78 (m, 4H), 7.66 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 6.81 (brs, 1H), 4.81 (d, 1H, J=11.7 Hz), 4.66 (d, 1H, J=13.2 Hz), 3.69 (s, 3H), 3.63 (s, 3H), 3.15-3.07 (m, 1H), 3.01-2.93 (m, 1H), 2.73-2.61 (m, 1H), 2.07-1.74 (m, 3H), 1.78-1.74 (m, 1H). LC-MS: 591 [M+H]+, tR=1.56 min. HPLC: 97.80% at 214 nm, 97.26% at 254 nm, tR=5.91 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:18]=2[N:17]=1.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][O:31][C:33](=[O:35])[CH3:34])[C:18]=2[N:17]=1
Reactant: CC(=O)Cl
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)CO)c2cc1OC
Solvent: c1ccncc1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)COC(C)=O)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 68, 8-(6,7-dimethoxy-isoquinolin4-ylmethyl)-3-(3-hydroxy-2-methyl-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione (63 mg, 0.14 mmol) and acetyl chloride (18 ml, 0.25 mmol) in pyridine (1 ml) is heated at 50° C. for 18 hours. After evaporation, flash chromatography (19:1 dichloromethane-methanol elution) affords acetic acid 3-[8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-2-methyl-propyl ester, [MH]+ 482.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:6]=1.[BH4-].[Li+]>O1CCCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]
Reactant: COC(=O)Cc1cccc(CNCc2ccccc2O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cccc(CNCc2ccccc2O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A solution of {3-[(2-hydroxy-benzylamino)-methyl]-phenyl}-acetic acid methyl ester (0.81 g) in anhydrous tetrahydrofuran (20 mL) was treated with lithium borohydride (186 mg) and the whole stirred at room temperature for 30 minutes. The reaction mixture was then heated at 60° C. for 2 hours under nitrogen. After cooling to room temperature the mixture was partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer was separated and treated with excess solid sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane and the combined organic washings were dried, filtered and evaporated under reduced pressure to yield the sub-titled compound (400 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.IC.[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([SH:26])=[N:21][N:20]=1)[CH3:18])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([S:26][CH3:1])=[N:21][N:20]=1)[CH3:18])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)NC(C)C
Reactant: CCn1c(S)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCn1c(SC)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (17.4 ml) and iodomethane (7.7 ml) were added to a tetrahydrofuran (200 ml) solution of the [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester (28.12 g) obtained in Example 8-(3). The mixture was stirred for 1 hour at room temperature, and then precipitated crystals were filtered. The filtrate was concentrated, and the resulting crude crystals were washed with a hexane-ethyl acetate solvent mixture (3:1, 200 ml), followed by drying, to obtain [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester as a white powder (29.5 g).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])#[N:2].[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[C:1]([N:3]=[C:4]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[CH3:17])[CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])#[N:2]
Reactant: CCOC(CC(C)c1ccccc1)=NC#N
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(CC(C)c1ccccc1)=NC#N
Temperature: 25 °C

Procedure:
A mixture of Example 52C (0.1 g, 0.44 mmol) and 2-methylbenzylamine (0.2 mL) was heated to 90° C. for 2.5 hours. The mixture was cooled down to room temperature and purified by flash chromatography (eluting with 35% ethyl acetate/hexanes) to give the title compound as a white solid. MS (ESI/NH3) m/z 292 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.26 (d, 3H) 2.17 (s, 3H) 2.79-2.82 (d, 2H) 3.38-3.40 (m, 1H) 4.25-4.29 (m, 2H) 7.08-7.32 (m, 9H) 9.01 (t, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.[Si:18](OS(C(F)(F)F)(=O)=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N#CC1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(C#N)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
6.4 g (51.1 mmol) of 4-hydroxy-cyclohexanecarbonitrile (121) were dissolved in 120 mL of dichloromethane, cooled to 0° C. and 14.9 mL (13.7 g, 128 mmol) of 2,6-lutidine and 15.4 mL (14.9 g, 56.2 mmol) of tert-butyldimethylsilyltrifluoromethanesulfonate were added. The reaction mixture was stirred for 16 h at room temperature, then additional 5.0 mL of tert-butyldimethylsilyltrifluoromethanesulfonate were added and stirring continued for 1 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 100 mL of water, 80 mL of saturated aqueous sodium bicarbonate solution and 50 mL of brine. The organic phase was dried over magnesium sulphate, filtered, concentrated in vacuo and purified by silica gel chromatography (heptanes:ethyl acetate) to give 9.76 g of the desired product. Rt=0.95 min (Method 18). Detected mass: 240.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cccc(F)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 3-fluoro-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 92.7% yield as a yellow crystalline solid, m.p. 70.3° C. (Rf=0.25 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [C:1]([NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=2)[CH:7]=1)#N.CN>O>[CH3:1][NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=2)[CH:7]=1
Reactant: N#CNC=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Agent: CN
Solvent: O
Product: CNC=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 69.2 %

Procedure:
4 gm of N-cyano-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine were added all at once to 40 ml of 35% methylamine in water (40 ml). A few minutes later, the reaction product separated out of the solution. This solid was filtered, washed with water and dried, yielding 2.66 gm of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[C:12](\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH2:28]([NH:30][CH2:31]C)C>C(O)C>[CH3:14][CH2:13]/[C:12](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)\[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]([CH3:31])[CH3:28])=[CH:6][CH:7]=1
Reactant: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCl)cc1)c1ccccc1
Reactant: CCNCC
Solvent: CCO
Product: CC/C(=C(/c1ccc(I)cc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of E-1-[4-(2-chloroethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene (3.05 g) in 33% diethylamine in ethanol (60 ml) was boiled under reflux for 20 hours. The mixture was concentrated, a procedure made necessary only because of escape of the gaseous dimethylamine under these conditions, further 33% dimethylamine solution (60 ml) was added and reflux was continued for a further 20 hours. The mixture was again concentrated and the residue partitioned between ether (50 ml) and aqueous sodium hydroxide (1M; 50 ml). The ether solution was concentrated and the residue applied to a column of silica gel (Merck 15111, 40 g). Column chromatography was need to remove a small amount of unreacted starting material from the product which could not be removed by recrystallisation. This problem and the concentration step during addition of dimethylamine could have been overcome by carrying out the reaction in a sealed bomb. Elution with 5% methylamine in 1:1 ether-light petroleum (b.p. 40°-60° C.) gave 4-iodotamoxifen, which was further purified by recrystallisation from light petroleum (b.p. 40°-60° C.) (2.60 g, 84% yield), identical to that of Example 1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:13]#[C:14][C:15]2[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[S:11][CH:12]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[CH:9]=[C:10]([C:13]#[C:14][C:15]3[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[S:11][CH:12]=2)=[CH:32][CH:31]=1
Reactant: Brc1csc(C#Cc2ccc(OCCN3CCCC3)cc2)c1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2csc(C#Cc3ccc(OCCN4CCCC4)cc3)c2)cc1

Procedure:
Under an N2 atmosphere 5 mL 2 M Na2CO3 solution and 47 mg (0.41 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 310 mg (0.82 mmol) 1-{2-[4-(4-bromo-thiophen-2-ylethynyl)-phenoxy]-ethyl}-pyrrolidine and 129 mg (0.82 mmol) 4-chlorophenyl-boric acid in 10 mL 1,4-dioxane and the reaction mixture is refluxed for 1 h. The hot solution is filtered through a fibreglass filter, the filtrate is extracted with EtOAc, the organic phase is washed with water and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]([NH:25][C:7]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:33]1[O:34][C:35]([CH3:37])([CH3:36])[C:31]([CH3:38])([CH3:30])[O:32]1)[C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29])(=[O:28])[CH3:27]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2-acetylamino-2-[4-(4-chlorophenyl)-cyclohexyl]hex-5-enoic acid tert-butylamide (940 mg, 2.25 mmol) in dichloromethane (9 mL) was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (45 mg, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (54 mg, 6 mol %). After stirring for 30 minutes, 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (576 mg, 0.65 mL, 4.5 mmol) was added dropwise and the stirring was continued overnight. The reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave 2-acetamido-N-tert-butyl-2-(4-(4-chlorophenyl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (985 mg, 80%); 1H NMR (CDCl3, 300 MHz) δ 7.25 (d, J=7.5 Hz, 2H), 7.08 (d, J=7.5 Hz, 2H), 6.99 (br s, NH, 1H), 5.52 (br s, NH, 1H), 2.84 (td, J1=13 Hz, J2=3.0 Hz, 1H), 2.37 (t, J=12 Hz, 1H), 2.24 (t, J=12 Hz, 1H), 2.00 (s, 3H), 1.90 (m, 4H), 1.20-1.48 (m, 7H), 1.38 (s, 9H), 1.22 (s, 12H), 1.06 (m, 2H) and 0.75 (t, J=7.5 Hz, 2H); MS (+CI): m/z for C30H48BClN2O4: expected 546.3. found 547.3 (M+H)+, 569.3 (M+Na)+.
Reaction SMILES: [CH2:1](O)[CH3:2].[C:4](OCC)(=O)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[K+]>C(I)CC.CN(C)C=O.C1C([N+]([O-])=O)=CC=C(O)C=1.[N+](C1C=CC=CC=1)([O-])=O>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:4][CH2:1][CH3:2])=[CH:17][CH:18]=1)([O-:12])=[O:11].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CCO
Reactant: CCOC(C)=O
Agent: O=[N+]([O-])c1ccc(Nc2ccc(Cl)cc2)cc1
Agent: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCI
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCN(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; a mixture of equal parts by volume of ethanol and ethyl acetate was used as a solvent. 1-Nitro-4-[N-(4-chlorophenyl)-N-propylamino]benzene was prepared by an alkylation of 1-nitro-4-(4-chloroanilino)benzene with propyliodide in dimethylformamide as a solvent under the influence of KOH. 1-Nitro-4-(4-chloroanilino)benzene was formed by a coupling at high temperature of p-chlorobenzeneisocyanate and p-nitrophenol in nitrobenzene as a solvent.
Reaction SMILES: [I:1]I.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:5])[CH3:4]>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[C:3]([C:7]1[CH:12]=[C:11]([I:1])[C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: II
Reactant: COc1ccc(C(C)(C)C)c(F)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1cc(F)c(C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodine (1.24 g, 4.90 mmol) and silver sulfate (1.53 g, 4.90 mmol) were added successively to a stirred solution of 1-tert-butyl-2-fluoro-4-methoxybenzene and 3-fluororanisole (0.755 g, 4.90 mmol) in EtOH (38.3 mL) at room temperature under N2. The mixture was stirred at room temperature for 4 h, then filtered through a plug of Celite. The mixture was partitioned between 50% saturated Na2SO3 and Et2O. The aqueous layer was separated and extracted with Et2O (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to remove volatile byproducts and afford 1-tert-butyl-2-fluoro-5-iodo-4-methoxybenzene. Rf=0.34 (100% hexanes). 1H NMR (600 MHz, CDCl3): δ 7.63 (d, J=9.0 Hz, 1H); 6.53 (d, J=13.8 Hz, 1H); 3.84 (s, 3H); 1.33 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)[CH3:25].C(O)C>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCN1CCc2c(F)c(F)cc3c(=O)c(C(=O)OCC)cn1c23
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of ethanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 28 mg of the subject compound (181).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:18]([CH2:17][NH:16][C:14]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[CH:38][CH:37]=2)[CH:7]=[CH:6][CH:5]=1)=[O:15])#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: N#CCNC(=O)C1CCCCN1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cccc(N4CCCCC4C(=O)NCC#N)c3)cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-(3-bromophenyl)-N-(cyanomethyl)-2-piperidinecarboxamide (209 mg, 0.65 mmol), 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (219 mg, 0.71 mmol), and PdCl2(dppf) (41 mg, 0.05 mmol) in DMF (4 mL) was heated to 60° C. 2N Na2CO3 (0.65 mL, 1.3 mmol) was added dropwise, and the mixture was heated to 85° C. overnight. The mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with 1 M NaOH and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (50% EtOAc/hexanes) gave tert-butyl 4-[3′-(2-{[(cyanomethyl)amino]carbonyl}-1-piperidinyl)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]([OH:7])=[N:2][C:1]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:3]2
Reactant: COCCOc1cc(C(=O)O)c(CC#N)cc1OC
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COCCOc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Temperature: 130 °C
Yield: 61.6 %

Procedure:
A mixture of 2-Cyanomethyl-4-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (1.0 g, 3.77 mmol), 3-amino-5-methylpyrazol (0.73 g, 7.54 mmol) in acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 2 ml MeOH. This solution was added dropwise to 100 ml water, and the solid was collected and dried to give product (0.8 g, 61.6%). LC-MS: m/e 345 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=[O:10])=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:4]=[C:3]1[NH:5][C:6]2[CH:7]=[C:8]([CH:9]=[O:10])[CH:11]=[CH:12][C:13]=2[O:14][CH2:2]1
Reactant: O=Cc1ccc(O)c(NC(=O)CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)NC(=O)CO2
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
3-(Chloroacetylamino)-4-hydroxy-benzaldehyde (2.4 g, 13.2 mmol) and potassium carbonate (9.1 g, 66.1 mmol) are stirred at room temperature in 50 mL of acetonitrile for 12 hours. The acetonitrile is evaporated and the residue is taken up in 50 mL of water. After standing at room temperature for 10 minutes, the precipitate is collected by filtration and recrystallized from ethyl acetate to give 1.4 g (60% yield) of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde; mp 220-222° C.