Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[N:34][C:33]([N:36]([CH3:47])[CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:30]1[N:35]=[N:34][C:33]([N:36]([CH3:47])[CH:37]2[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)=[CH:32][CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)OB(c2cc3ccc(O)cc3cc2OCc2ccccc2)OC1(C)C
Product: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 89.3 %

Procedure:
7-(Benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (1.25 g, 2.366 mmol, 89% yield) was prepared from the 7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.45 g, 3.85 mmol) and Intermediate 1-1 (0.75 g, 2.65 mmol) using General method 1-1 for Suzuki coupling. M+1=497.8. 1H NMR (400 MHz, METHANOL-d4) δ 7.91 (s, 1H), 7.76 (d, J=9.54 Hz, 2H), 7.66 (d, J=8.78 Hz, 2H), 7.34-7.40 (m, 2H), 7.31 (s, 2H), 7.18-7.27 (m, 2H), 6.97-7.05 (m, 2H), 6.91 (dd, J=8.78, 2.26 Hz, 1H), 5.18 (m, 3H), 2.92 (s, 3H), 1.60-1.68 (m, 2H), 1.45-1.55 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](O)[CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:16]([O:18][C:21]1[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](C)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
From 3.6 g of MA-Ala-Val-Ala-OH (0.012 mol), 1.5 g (0.012 mol) of p-nitrophenol, and 2.5 g (0.0125 mol) of dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran was prepared 2.0 g (40% yield) of MA-Ala-Val-Ala ONp; m.p. 174°-6° C. Recrystalized from ethylacetate/hexane. Molar extinction coefficient, ε274 nm =9300 (DMSO).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 3-(3-methylindazol-5-yl)-5-[(S)-4-Boc-3-benzylpiperazin-1-yl]-[1,2,4]triazine 124 (0.012 g, 0.025 mmol) was added a solution of trifluoroacetic acid in dichloromethane (20% v/v, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. Methanol (1 mL) and dichloromethane (9 mL) were added. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-5-[(S)-3-benzylpiperazin-1-yl]-[1,2,4]triazine 12 (0.0041 g, 0.0106 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncccc1C=NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
To a solution of 2-amino-3-formylpyridine (1.00 g, 8.19 mmol) in pyridine (20 mL) was added hydroxylamine hydrochloride (854 mg, 12.3 mmol) at room temperature, which was stirred for 1 hour and 40 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=10:1) to obtain the title compound (951 mg, 85%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.S(O)(O)(=O)=O.[NH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:34]=[CH:35][N:36]=[C:32]1[NH:31][C:23]([C:22]1[C:16]2[O:15][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2o1)c1cc2ccccc2cn1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2o1)c1cc2ccccc2cn1

Procedure:
Isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-benzooxazol-2-yl]-amide was synthesized according to General Procedure A using 137 mg (0.411 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid, 111 mg (0.822 mmol) 2-aminoimidazole sulfate, 171 mg (0.45 mmol) HBTU, 0.29 mL (1.65 mmol,) of DIEA and 2 mL of DMF stirring at 90° C. for 2 h. 98.9 mg (0.248 mmol, 60%) of the product was obtained. LCMS: 399 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)C(N=[N+]=[N-])=O)([O-:3])=[O:2].S(=O)(=O)(O)O.[NH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH2:23])([O-:3])=[O:2]
Reactant: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: N
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
The 3,5-dinitrobenzoyl azide thus obtained (5 g., 0.021 mol) was heated gently in 20 ml. of concentrated sulfuric acid until nitrogen evolution was complete. The resulting solution was poured over 200 ml. of ice/water and then made basic to pH 10 with concentrated aqueous ammonia solution. The solid was filtered to give 3,5-dinitroaniline.
Reaction SMILES: C([O:3][P:4]([CH2:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.Br[Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:31]=[C:26]1[NH:27][CH2:28][C:29](=[O:30])[N:25]1[CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[OH:5]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Agent: C[Si](C)(C)Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)CNC1=O
Yield: 97.8 %

Procedure:
60 mg (0.13 mmol) of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester were dissolved in 1 ml of dichloromethane and the solution was stirred at room temperature for 3 hours in the presence of 1 ml of bromotrimethylsilane and 0.1 ml of trifluoroacetic acid. The solvent was removed by evaporation. The residue was treated three times with acetone/water (9:1) and the solvent was removed by evaporation each time. Finally, the product was triturated with diethyl ether to yield 55 mg of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2CCC(O)=O)[C:11]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=2[N:9]=1.C1C[O:39][CH2:38]C1>>[CH3:7][C:8]1[N:12]([C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][C@H:14]2[CH2:38][OH:39])[C:11]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=2[N:9]=1
Reactant: C1CCOC1
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1CCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (76 mg; 2 mmol) was added to a stirring solution of 4-(2,5-dimethylbenzimidazol-1-yl)-3-carboxyethyl-N-Boc piperidine (310 mg; 0.77 mmol) in THF (5 mL) under Ar at 0° C. After one hour, Na2SO4 decahydrate (500 mg; 1.55 mmol) was added carefully portionwise. The reaction mixture was stirred 2 h and the grey solid that formed during this time was removed by filtration through Celite®. Volatiles were removed under reduced pressure and the product racemic trans-4-(2,5-dimethylbenzimidazol-1-yl)-3-hydroxymethyl-N-Boc piperidine was isolated by flash chromatography (258 mg; 93%) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[CH:14]=[C:15](C(OC)=O)[CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.[OH2:23].Cl.[CH3:25][OH:26]>[OH-].[Na+]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[C:14]([C:25]([OH:26])=[O:23])=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)Cc1c-2[nH]c(=O)c2ccccc12
Reactant: O
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A suspension of Compound 18a in a mixture of methanol and 1M NaOH solution was refluxed for 1 h. Additional water was added, and the resultant mixture was refluxed for another 1 h. The resultant clear solution was cooled to room temperature and 1M HCl solution was added under stirring. The resultant solid was filtered and washed with water and methanol and dried to provide Compound 18b. 1H NMR (DMSO-d6): δ 12.38 (s, 1H); 8.25 (d, J=7.8 Hz, 1H); 8.11 (s, 1H); 8.04 (d, J=8.1 Hz, 1H); 7.97 (d, J=8.1 Hz, 1H); 7.76 (d, J=3.6 Hz, 2H); 7.51 (m, 1H); 3.97 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:4]2[CH2:3]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1
Reactant: CN1CCn2nc([N+](=O)[O-])cc2C1
Solvent: CCO
Product: CN1CCn2nc(N)cc2C1
Reaction time: 2 h
Yield: 988.6 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 113d (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. CELITE® 521 (1.0 g) was added, and the mixture was filtered through a pad of CELITE® 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 113e (3.31 g) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].P(OCC)(OCC)OCC.[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]Br)[C:30]([O:32][CH3:33])=[O:31].COC=C(C1C=CC=CC=1CN1C(=O)C=C(C(F)(F)F)N=C1OC(C)C)C(OC)=O>CCCCCCCC.[Cu-]=O.CC(C)=O.O>[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=[Cu-]
Agent: CCOP(OCC)OCC
Agent: COC=C(C(=O)OC)c1ccccc1Cn1c(OC(C)C)nc(C(F)(F)F)cc1=O
Solvent: CCCCCCCC
Solvent: O
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.72 g of copper(I) oxide were suspended in 50 ml of octane. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 1.66 g of triethyl phosphite was added, and, 30 minutes later, 2.41 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 20 hours at reflux of octane. The solution was cooled down to room temperature. 20 ml of acetone was added to it. Insoluble matter was filtrated, and further washed with 10 ml of acetone twice. The mixed solution of the obtained filtrate and washings was analyzed with high-performance liquid chromatography. Yields were 66.4% for the target compound, and as for byproducts 1.4% for methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin4-on-3-ylmethyl)phenyl]acrylate and 17.4% for 4-( α-methoxy)methylen-2H-chromen-3(4H)-one.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[CH2:6]2.[CH2:19]([OH:22])[CH2:20]O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:20]1[O:12][C:8]2([C:9]3[C:5](=[CH:4][C:3]([CH3:23])=[CH:11][CH:10]=3)[CH2:6][C:7]32[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]3)[O:22][CH2:19]1
Reactant: OCCO
Reactant: COc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC1(CCC(=O)CC1)C21OCCO1

Procedure:
A mixture of 2.06 g. (0.00905 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8 ] (prepared in Example 13B), 0.56 g. (0.50 ml.) of ethylene glycol and 0.1 g. of p-toluenesulfonic acid in 50 ml. of benzene is heated at reflux under a Dean-Stark trap for about 2 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution then water and evaporated to dryness. The residual solid is recrystallized from methylene chloride: cyclohexane to give 1.96 g. (86%) of 5'-methyl-spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal-[9], melting at 124° to 127° C.
Reaction SMILES: NC(C(O)=O)CCSC.[CH2:10]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([O:25]C)[CH:16]=1)[CH3:11]>CS(O)(=O)=O>[CH2:10]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([OH:25])[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cc(OC)cc2c1CCCC2
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: CCOC(=O)Cc1cc(O)cc2c1CCCC2
Temperature: 0 °C

Procedure:
DL-Methionine (1.11 g, 7.5 mmol) and compound of step b) is dissolved in methanesulfonic acid (9 ml) and kept at RT over night. The reaction is poured into a ice-cold saturated NaCl solution and extracted 3 times with methylene chloride. The organic layer is dried, concentrated and purified on silica gel (methylene chloride/methanol 95/5) affording the pure compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Br[CH2:37][CH2:38][OH:39]>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:37][CH2:38][OH:39])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: OCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CCO)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (400 mg, 1.0 mmol) in tetrahydrofuran (14 mL) was treated with triethylamine (350 μL, 2.5 mmol) and 2-bromoethanol (85 μL, 1.2 mmol) and stirred at 60° C. overnight. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.14 g, 31%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 6.24 (q, J=6.9 Hz, 1H), 4.41 (t, J=5.4 Hz, 1H), 4.12-4.03 (m, 1H), 3.97-3.88 (m, 2H), 3.64 (s, 3H), 3.38-3.34 (m, 2H), 3.09-3.01 (m, 2H), 2.55 (s, 3H), 2.41 (t, J=5.9 Hz, 2H), 1.72 (d, J=7.0 Hz, 3H). LCMS for C21H25ClN7O2 (M+H)+: m/z=442.2; Found: 442.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In a flask equipped with a Dean-stark trap was prepared a solution of 1-(4-Methoxy-phenyl)-propan-2-one (40 g), ethyl cyanoacetate (27.56 g), ammonium acetate (9.40 g), acetic acid (14.64 g) and toluene (150 ml) at room temperature. The solution was heated to reflux overnight. The solution was cooled to room temperature, washed with water and brine, and concentrated. The crude product was purified on a silica gel column, eluting with 10% ethyl acetate/hexane to afford colorless oil (40.76 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: Cl.[CH2:2]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:3]=[CH2:4].CCN(C(C)C)C(C)C.[Br:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.CCCCCC>CCO>[CH2:2]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][N:8]([C:29]2[N:30]=[CH:31][C:26]([Br:25])=[CH:27][N:28]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: Clc1ncc(Br)cn1
Reactant: C=CCC1(C(=O)OCC)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCCCCC
Product: C=CCC1(C(=O)OCC)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
To a solution of ethyl 4-allylpiperidine-4-carboxylate hydrochloride (1.30 g, 6.59 mmol) in EtOH (20.0 mL) was added DIPEA (3.0 mL, 16.47 mmol) and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (1.06 g, 5.49 mmol). The reaction was then heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 2.0% EtOAc:hexane to obtain the desired product as a yellow solid (1.0 g, 56% yield). 1H NMR (DMSO-d6): δ 1.19 (t, J=6.80 Hz, 3H), 1.44 (m, 2H), 2.02 (m, 2H), 2.27 (m, 2H), 3.10 (m, 2H), 4.13 (q, J=6.80 Hz, 2H), 4.29 (m, 2H), 5.06 (m, 2H), 5.66 (m, 1H) and 8.43 (s, 2H)
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:2]([CH:3]([C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:16])[C:4]([O:6][CH3:7])=[O:5])(=[O:1])[CH3:8]
Reactant: COC(=O)CC(C)=O
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)C(C(C)=O)C(=O)OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A suspension of 3.2 g (27.5 mmol) of methyl 3-oxobutanoate, 5.6 g (55.0 mmol) of phenylacetylene and 700 mg (0.8 mmol) of *[ReBr(CO)3(THF)]2 in 55 mL of anhydrous toluene is stirred for 18 hours at 50° C. After cooling to room temperature, the medium is concentrated under reduced pressure. The residue obtained is taken up in 100 mL of DCM, washed successively with water (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 5 g of methyl 2-acetyl-3-phenylbut-3-enoate are obtained in the form of a yellow oil.
Reaction SMILES: CS(OCCCOC1C=CC=C(C2N(C3C=CC=C(Cl)C=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=1)(=O)=O.N.[CH:37]([OH:39])=[O:38].C(O)=O.[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([O:61][CH2:62][CH2:63][CH2:64][N:65](C)C)[CH:56]=3)=[CH:53][C:52]([C:68]([N:70]3[CH2:74][C:73](=[O:75])[NH:72][CH2:71]3)=[O:69])=[N:51]2)[CH:47]=[CH:48][CH:49]=1>CO>[CH:37]([OH:39])=[O:38].[NH2:65][CH2:64][CH2:63][CH2:62][O:61][C:57]1[CH:56]=[C:55]([C:54]2[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([Cl:43])[CH:45]=3)[N:51]=[C:52]([C:68]([N:70]3[CH2:74][C:73](=[O:75])[NH:72][CH2:71]3)=[O:69])[CH:53]=2)[CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: N
Solvent: CO
Solvent: O=CO
Product: NCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and a 7N solution of ammonia in methanol with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 29. 10 mg (10% of theory) of the title compound are obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[Cl:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]=[O:24].O>CCCCCC.C(OCC)C>[Cl:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[OH:24]
Reactant: Clc1sccc1Br
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccc2ccccc2c1)c1ccsc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Under nitrogen atmosphere, to a solution of 3.2 mL of 1.57 M n-butyllithium in hexane in 7 mL of diethyl ether was added a solution of 1.00 g of 3-bromo-2-chlorothiophene in 8 mL diethyl ether at −78° C., and stirred at this temperature for 1 hour. At the same temperature, 0.87 g of 2-naphthaldehyde was added, stirred for 3 hours while raising the temperature to room temperature, then added with water, extracted with ethylacetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20-1:5), to afford 1.18 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][NH:11]2)=[N:6][CH:7]=1.C(NC(C)C)(C)C.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:11]2[C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[O:26][C:25]([F:24])([F:36])[F:37])=[O:30])=[N:6][CH:7]=1
Reactant: C[C@H]1CCCN[C@H]1CNc1ncc(Cl)cn1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C[C@H]1CCCN(C(=O)c2ccccc2OC(F)(F)F)[C@H]1CNc1ncc(Cl)cn1

Procedure:
To a solution of the forementioned rac-cis-5-chloro-N-((3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine and diisopropylamine (3 eq) in DCM was added 2-(trifluoromethoxy)benzoyl chloride (1.2 eq) dropwise. The reaction was stirred at reflux for 3 h and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. (ESI) 429.1 (M+H).