Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(Cl)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 32.3 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.4 g of 4-chlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.1 g of 4-(4-chlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (14)), m.p.: 100.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-])=O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>[Pd].CCOC(C)=O>[C:18]([NH:15][C:3]1[CH:4]=[C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(=O)CCC(=O)O)ccc1C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
10% Pd/C (100 g) was added to a solution of 4-(4-methyl-3-nitrophenyl)-4-oxobutanoic acid (73) (3.40 kg, 14.3 mol) and EtOAc (20 L) in 40 L Parr reactor. Acetic anhydride (2.40 L, 25.4 mol) was added. The mixture was stirred under about 5 bar H2 atmosphere overnight. The reaction was concentrated under reduced pressure. To the resulting grey solid was added EtOH (14 L) and H2SO4 (˜35 mL). The mixture was stirred in the 40 L Parr vessel under about 5 bar H2 pressure overnight at rt. The reaction mixture was poured into 2 N aqueous NaOH (35 L), stirred overnight at rt, and then filtered through of Celite® rinsing with water. The filtrate and washings were combined and concentrated under reduced pressure to remove EtOH. The aqueous residue was washed with tert-butyl methyl ether (7 L). The aqueous layer was acidified with 2 N aq. HCl. The precipitate was collected by filtration rinsing with water (2×14 L) and dried to afford 4-(3-acetamido-4-methylphenyl)-4-oxobutanoic acid (74) (2.70 kg, 76% yield). 1H NMR (300 MHz, DMSO): δ 12.03 (s, 1H), 9.25 (s, 1H), 7.50 (s, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.88 (d, J=7.6 Hz, 2H), 2.56 (m, 2H), 2.28 (m, 2H), 2.16 (s, 3H), 2.04 (s, 3H), 1.74 (m, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)[OH:6].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CO>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:3][CH2:4][CH:5]([OH:6])[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CSc1nccc(C(O)CN)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSc1nccc(C(O)CNC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
2-Amino-1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanol dihydrochloride salt (0.339 g, 1.83 mmol) was dissolved into a minimum of MeOH and diluted with 10 mL of THF. To this was added t-butyl-4-oxo-1-piperidinecarboxylate (0.478 g, 2.40 mmol), AcOH (0.458 mL, 8.00 mmol) and sodium triacetoxyborohydride (1.696 g, 8.00 mmol) and the reaction was stirred overnight. LC-MS analysis indicated complete consumption of the starting material. The mixture was concentrated on a rotary evaporator, the residue dissolved in CH2Cl2 and applied to a SiO2 column and purified (0–10% MeOH/CH2Cl2) to give 511.0 mg, 57.8% yield of 4-[2-hydroxy-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][CH:9]=[C:8](OC)[C:4]=1[C:5](Cl)=[O:6].C[NH:15]CCC#CC1C=CC=CN=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[C:5]([NH2:15])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:3]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 11.9 %

Procedure:
2,6-Dimethoxy-benzoyl chloride (81 mg, 0.41 mmol) was added to a solution, of methyl-(4-pyridin-2-yl-but-3-ynyl)-amine (50 mg, 0.31 mmol) and DIEA (69 μL, 0.41 mmol) in chloroform (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min, at room temperature for 14 hours, quenched by the addition of water and extracted twice with chloroform. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 95:5) to yield 2,6-dimethoxy-N-methyl-N-(pyridin-2-yl)but-3-ynyl)benzamide (12 mg, 37 μmol, 12%).
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=NCCCN(C)C)C.[C:13]([O:17][C:18]([N:20]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:21]1[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.CNC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl.O1CCCC1>[CH3:2][N:4]([CH3:5])[C:22]([C@@H:21]1[CH2:25][C@H:26]([F:28])[CH2:27][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[O:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
19.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice cooling to a 200 mL tetrahydrofuran solution of 19.9 g of the compound obtained in step 2-2 and 17.3 g of 1-hydroxybenzotriazole monohydrate, and the reaction mixture was stirred for 30 minutes at the same temperature. After this, 9.24 g of a 50% dimethylamine aqueous solution was added to the reaction solution, and the reaction mixture was stirred for 1 hour while the temperature was raised to room temperature. 150 mL of solvent was distilled off under reduced pressure, and to the residue thus obtained was added 100 mL of chloroform and 100 mL of a 10% potassium carbonate aqueous solution. After liquid separation, the aqueous layer was extracted with chloroform, and the combined organic layer was washed with saturated brine and then dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 20.5 g of the titled compound (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: C#CC1CC1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)c(F)c3)[nH]c2=O)c1
Yield: 12.8 %

Procedure:
The title compound was prepared according to the procedure, described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (step 1 of Example-149, 0.080 g, 0.155 mmol), ethynylcyclopropane (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II) chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO 4): δ 0.79-0.92 (m, 2H), 1.011 (m, 2H), 1.30 (s, 6H), 1.63 (m, 1H), 2.39 (m, 1H), 4.28 (d, J=5.7 Hz, 2H), 7.35 (m, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H); MS (m/z): 453.24 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:31]=[CH:30][C:29]=1[NH2:41].C(N(CC)C(C)C)(C)C.COCC(O)C.[O-]S(C(F)(F)F)(=O)=O>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH:31]=[CH:30][C:29]=1[NH:41][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1cc(CN2CCOCC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCOCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (72.9 mg, 0.195 mmol), 2-Methoxy-4-morpholin-4-ylmethyl-phenylamine (0.174 g, 0.782 mmol), N,N-Diisopropylethylamine (0.136 mL, 0.782 mmol), and 1-Methoxy-2-propanol (0.250 mL, 2.56 mmol). The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested little if any triflate SM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give (2-Methoxy-4-morpholin-4-ylmethyl-phenyl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine a brown solid (11 mg, 10%). LCMS (E/I+) 445.19 (M+H). NMR 1H (DMSO-d6)-9.81 (s, 1H), 8.99 (s, 1H), 8.24 (d, 1H, J=8.32 Hz), 7.73-7.82 (m, 2H), 7.48 (dt, 1H, JJ=1.19, 8.92 Hz), 7.22 (d, 1H, J=8.11 Hz), 7.17 (, s, 1H), 7.11 (t, 1H, J=7.40 Hz), 6.85-7.05 (m, 3H), 4.28 (bs, 2H), 3.90-4.02 (m, 5H), 3.79 (s, 3H), 3.62 (t, 2H, J=11.67 Hz), 3.26 (d, 2H, J=13.80 Hz), 3.08 (bs, 2H).
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.IC.[C-:19]#[N:20].[K+]>CN(C=O)C.O.C1COCC1>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][CH:5]=[C:4]2[CH2:3][C:19]#[N:20])([O-:15])=[O:14]
Reactant: CN(C)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c[nH]c2c([N+](=O)[O-])cccc12
Reaction time: 2 h

Procedure:
A solution of N,N-dimethyl-1-(7-nitro-1H-indol-3-yl)methanamine from Step A (3.3 g, 18.5 mmol) in DMF (3 mL), H2O (3 mL), THF (150 mL) and iodomethane (2.85 mL, 45.7 mmol) was heated at reflux for 15 min as a white precipitate formed. Potassium cyanide (6.0 g, 92.1 mmol) was added and reflux was continued for 2 h. The cooled solution was filtered and concentrated under reduced pressure and the residue was triturated with MeOH to give (7-nitro-1H-indol-3-yl)acetonitrile as a yellow solid. A suspension of this solid in MeOH (10 mL) was cooled to 0° C. and HCl (g) was bubbled in slowly for 30 min. The reaction mixture was aged for 1 h, then concentrated in vacuo. To the residue was added 6 M aqueous HCl (20 mL) and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (50 mL), then brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C@H:23]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N=C=N.C([NH+](CC)CC)C.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:22][C@H:23]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Reactant: CC(C)(C)OC(=O)C[C@H](N)Cc1ccccc1
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a mixture of 5.8 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 7.1 mg of tert-butyl (3R)-3-amino-4-phenylbutanoate, 2.7 mg of 1-hydroxybenzotriazole, 700 μl of DMF, and 19 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 20 hours. To the reaction mixture were added 50 mg of macroporous triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage), followed by stirring at room temperature for 2 hours. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 100 μl of 1,4-dioxane and 200 μl of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative HPLC to obtain 5.6 mg of (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbutanoic acid.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.621 g) and triethylamine (0.864 mL) in THF (12 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 1 g) in THF (20 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure, acidified with 2 M HCl, and extracted into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound (1.097 g) that was used without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])=[N+:8]=[N-:9]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1]([C:2]1[N:7]([CH:10]([CH3:18])[C:11]([OH:13])=[O:12])[N:8]=[N:9][CH:3]=1)=[O:4]
Reactant: CC(N=[N+]=[N-])C(=O)OC(C)(C)C
Reactant: C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cnnn1C(C)C(=O)O
Temperature: 100 °C

Procedure:
To a solution of 1.87 g (22.3 mmol) of methyl prop-2-ynoate in 40 mL of toluene was added 1.9 g (11 mmol) of tert-butyl 2-azidopropanate. The reaction mixture was heated at 100° C. for 3 h then cooled to ambient temperature. All volatiles were removed under reduced pressure and the crude residue purified by column chromatography on silica gel eluting with a 5 to 25% acetone in hexanes gradient to afford the title compounds.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:32][CH2:33][CH3:34])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:35].[Na+]>C(O)C>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:32][CH2:33][CH3:34])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]([NH2:13])=[O:35])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 0.70 g of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in 14 ml of 1N aqueous sodium hydroxide and 7 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the ethanol in the reaction mixture was removed by evaporation under reduced pressure, and ethyl acetate and 14 ml of 1N aqueous hydrochloric acid were added to the residue. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 0.45 g of the title compound as a powder, melting at 174°-176° C.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].ClCC#N.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:1]#[N:3])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: Cc1ccccc1
Product: N#CCN1CCC(Cc2ccccc2)CC1

Procedure:
40.8 ml of triethylamine and 22.2 g of chloroacetonitrile are dissolved in 180 ml of toluene, and 51.6 g of 4-benzylpiperidine are then added dropwise all at once.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH:37]([NH2:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH:37]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:35][CH:34]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-methoxybenzhydrylamine (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([F:15])[CH:14]=2)[CH2:4][O:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]([CH2:32][CH2:33][NH:34][C:35]3[C:36]4[S:43][CH:42]=[CH:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:30][N:31]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CS(C)=O>[CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:16][C:25]([NH:26][C:27]3[S:28][C:29]([CH2:32][CH2:33][NH:34][C:35]4[C:36]5[S:43][CH:42]=[CH:41][C:37]=5[N:38]=[CH:39][N:40]=4)=[CH:30][N:31]=3)=[O:24])[CH:12]=[C:13]([F:15])[CH:14]=2)[CH2:4][O:3]1
Reactant: O=C(Nc1ncc(CCNc2ncnc3ccsc23)s1)Oc1ccccc1
Reactant: CC1(C)OCC(COc2cc(N)cc(F)c2)O1
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Product: CC1(C)OCC(COc2cc(F)cc(NC(=O)Nc3ncc(CCNc4ncnc5ccsc45)s3)c2)O1

Procedure:
A solution of compound 70.1 (1.0 mmol), compound 16.1 (1.0 mmol) and DMAP (1.0 mmol) in DMSO (10 mL) is heated at 90° C. for 30 minutes. The reaction is cooled, and partitioned between EtOAC and 1.0 N NaOH. The organic layer is separated, washed with brine, dried and concentrated to give a residue that was purified by preparative TLC (6% MeOH in dichloromethane) to provide 1-[3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5-fluoro-phenyl]-3-{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-urea (compound 70.2).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccsc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccsc4C#N)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile as described in Example 65 to give 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]phenyl}thiophene-2-carbonitrile as a buff-coloured solid: δH (400 MHz, CDCl3) 1.57 (6H, s), 7.10 (1H, d, J 7), 7.41-7.44 (2H, m), 7.60-7.64 (1H, m), 7.71 (1H, d J 5), 7.84 (1H, dd, J 7 and 2), 7.87 (1H, s), 8.88 (1H, d, J 7).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].[CH3:31][O-:32].[Na+]>CO.CN1CCN(C)C1=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[O:32][CH3:31])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: C[O-]
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(OC)c21)c1ccccc1

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (0.6 g) obtained in Example 45, a 28% solution of sodium methoxide in methanol (0.3 g), methanol (20 ml) and 1,3-dimethyl-2-imidazolidinone (5 ml) is refluxed for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (0.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(-c3cnn(C)c3)c21
Product: CC1c2c(cccc2-c2cnn(C)c2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.