Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH2:18][CH2:17]1
Reactant: O=Cc1ccccc1F
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(OC2CCN(c3ccccc3C=O)CC2)nc(-c2ccncn2)cc1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (1.00 g, 3.48 mmol) and 2-fluorobenzaldehyde (475 mg, 3.83 mmol) in dimethyl sulfoxide (3.50 ml) was added potassium carbonate (1.44 g, 10.4 mmol). The mixture was stirred at 120° C. for 4 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzaldehyde as a yellow solid (711 mg, 1.82 mmol, 52%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH:17]([CH3:19])[CH3:18])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: CC(C)O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, isopropanol and DBU in DME. EI-MS m/e (%): 254 (M+, 41), 212 ([M—C3H6]+, 55), 184 (35), 170 (100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:12]#[C:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(N)(C)C.CO.[Cu]Cl>[OH:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: CC(C)(O)C#CBr
Agent: Cl[Cu]
Solvent: CC(C)N
Solvent: CO
Product: COc1cccc(C#CC#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
50 mg of copper (I) chloride were dissolved in a mixture of 10 ml of isopropylamine and 15 ml of methanol in an atmosphere of argon, and 660 mg of 3-ethynylanisole were then added to the reaction mixture, followed by stirring at room temperature for 10 minutes. 1300 mg of 1-bromo-3-hydroxy-3-methyl-1-butyne were then dropwisely added to the solution over a time of about 2 hours, followed by stirring at room temperature for 2 hours. The solvent was then evaporated from the reaction mixture, and the residue was then neutralized and diluted by 1N hydrochloric acid, and subjected to extraction with dichloromethane three times. The organic layer was then dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using benzene as an eluent to obtain 800 mg of 5-hydroxy-5-methyl-1-(3-methoxyphenyl)hexane-1,3-diyne.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[O:19]([C@@H:27]1[CH2:31][C:30](=[O:32])[CH:29]=[CH:28]1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C([Sn](Cl)(CCCC)CCCC)CCC.Br[CH2:48][C:49]#[C:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>O1CCCC1.CCOCC.CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([C@H:28]1[C@H:27]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:31][C:30](=[O:32])[C@@H:29]1[CH2:48][C:49]#[C:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: [Li]CCCC
Reactant: CCCCCC#CCBr
Agent: CCCCP(CCCC)CCCC
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC#CC[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCCC
Temperature: 19 °C
Yield: 16.5 %

Procedure:
Cuprous iodide (198 mg; 1.04 mmole) was weighed into a 150 ml reaction tube purged with argon, and the inside of the tube was dried under reduced pressure. Then, the reaction tube was again purged with argon. Dry tetrahydrofuran (10 ml) and tributylphosphine (0.673 ml; 2.70 mmoles) were introduced into the reaction tube, and stirred at 19° C. with stirring to form a uniform solution. The solution was cooled to -78° C., and n-butyllithium (1.60M, 0.647 ml, 1.04 mmoles) was added, and the mixture was stirred at -78° C. for 10 minutes. Then, a solution of (R)-4-t-butyldimethylsiloxy-2-cyclopentenone (200 mg, 0.942 mmole) in tetrahydrofuran (15 ml) was added dropwise at -78° C. over 0.8 hours using a syringe drive. The mixture was stirred at -78° C. for 10 minutes. Then, hexamethylphosphoric triamide (2 ml) was added, and the mixture was stirred for 40 minutes at -78° C. Tributyltin chloride (0.28 ml, 1.04 mmole) was added, and the temperature was raised to -30° C. A solution of 1-bromo-2-octyne (197 mg, 1.04 mmole) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for 17.5 hours. Ether (10 ml) was added to the reaction mixture, and the mixture was successively washed with a saturated aqueous ammonium chloride solution (10 ml), a saturated aqueous potassium thiocyanate solution (10 ml) and a saturated aqueous sodium chloride solution (10 ml). The separated organic layer was dried over anhydrous sodium sulfate. The dried product was filtered and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (Merck 7734, 6% water, 20 g; hexane:ethyl acetate=30:l) to give (2R,3R,4R)-3-butyl-4-t-butyldimethylsiloxy-2-(2-octynyl)cyclopentanone (58.8 mg, 0.155 mmole, 16%) which coincided with the product obtained in (i) above.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH2:10][C:11]1[S:12][C:13]2[C:18]([NH:19][C@H:20]([CH3:23])[CH2:21][OH:22])=[N:17][C:16]([SH:24])=[N:15][C:14]=2[N:25]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.CN1CCCC1=O>[NH2:10][C:11]1[S:12][C:13]2[C:18]([NH:19][C@H:20]([CH3:23])[CH2:21][OH:22])=[N:17][C:16]([S:24][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[F:1])=[N:15][C:14]=2[N:25]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Fc1ccccc1CBr
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Yield: 35 %

Procedure:
2-fluorobenzylbromide (0.369 g) was added portionwise to a solution of the product of example 32 step b) (0.5 g) and diisopropylethylamine (0.26 g) in DMSO/N-methylpyrrolidinone (4 ml/0.5 ml) at 50° C. and stirring maintained for 1 h. The mixture was partitioned between H2O (200 ml) and EtOAc (120 ml). The organics were recovered and washed flier with H2O (200 ml), dried over MgSO4 and concentrated onto silica gel. The subtitle compound was purified by flash chromatography using DCM then EtOAc as eluents to yield a white solid (245 mg, 35%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])([O-])=O.N.[H][H]>C(O)C.[Ni]>[NH2:1][CH2:4][CH:5]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccccc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC

Procedure:
A solution of 5.7 g of ethyl 3-nitro-2-phenylpropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 50 g of an 8% solution of ammonia in ethanol. To this are added 9 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.4 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[OH:11].[CH3:12]C[O-].[Na+].[Na].ClC[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(O)C>[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:10][O:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[O:11][CH3:12])[CH2:22][CH2:23]1
Reactant: CC[O-]
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc(Cl)cc(Cl)c1O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(Cl)cc(Cl)cc1OCCCN1CCOCC1

Procedure:
54 g of 3,5-dichloroguaiacol (0.28 mole) is added to sodium ethylate produced by reacting 6.44 g of sodium on 84 ml of ethyl alcohol. 51 g (0.28 mole + 10% excess) of 1-chloro-3-morpholinopropane is added to the resulting solution. The mixture is heated under reflux for 8 hours. Precipitation of sodium chloride is observed. Cooling is effected and then the mixture is dissolved in 300 ml of water and 30 ml of concentrated hydrochloric acid. The resulting solution is filtered, then ammonia is added to precipitate the base which is extracted with ether. The ether is eliminated and the residue is distilled under vacuum.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:28]=[CH:27][N:16]3[C:17](=[O:26])[C:18]([C:21]4[N:22]=[N:23][NH:24][N:25]=4)=[CH:19][N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)(C)([CH3:3])[CH3:2].COC1C=CC(CN2N=NC(C3C(=O)N4C=CC(C(O)=O)=C[C:44]4=[N:43][CH:42]=3)=N2)=CC=1.N1C=CC(C2N=C(N)SC=2)=CC=1>>[N:43]1[CH:44]=[CH:2][C:1]([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:28]=[CH:27][N:16]4[C:17](=[O:26])[C:18]([C:21]5[N:25]=[N:24][NH:23][N:22]=5)=[CH:19][N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)=[CH:3][CH:42]=1
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Agent: Nc1nc(-c2ccncc2)cs1
Product: O=C(Nc1nc(-c2ccncc2)cs1)c1ccn2c(=O)c(-c3nn[nH]n3)cnc2c1

Procedure:
Reactions were performed in the same manner as in Example 10, (F) by using 3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid (120 mg, 0.32 mmol) and 4-(4-pyridyl)-1,3-thiazol-2-amine (62 mg, 0.35 mmol) to obtain 35.7 mg (27% for the two steps) of the title compound as orange crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)COC1C=CC([C:37]#[N:38])=CC=1Br)(C)(C)C.C[Si](C#C)(C)C>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:37]#[N:38])=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(C#N)cc1Br
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: C#C[Si](C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#C[Si](C)(C)C
Yield: 87 %

Procedure:
Following the general method as outlined in Intermediate 2, starting from tert-butyl(2-bromo-4-cyanophenoxy)acetate (Intermediate 44) and (trimethylsilyl)acetylene (Aldrich), the title compound was obtained as a dark brown sticky solid in 87% yield.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1)[CH:2]=C.[O:13]=[O+][O-]>ClCCl>[O:13]=[CH:2][CH2:1][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OCO1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OCO1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.3 g of pure (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:1][C:2]4=[N:3][CH:4]=[C:5]([Cl:26])[C:6]([N:11]5[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]6[S:22][CH:23]=[CH:24][N:25]=6)=[O:19])[CH2:13][CH2:12]5)=[C:7]4[N:8]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.028 g, 0.07 mmol) and EtOH (3.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.017 g, 0.09 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 ml, 0.30 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.006 g, 16%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 5.41 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.23 (d, J=3.5 Hz, 1H, thiazole H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.49 (d, 2H, thiazole-H, and pyrazole-H), 7.86 (d, J=1.84 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.89 min—534, 536 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 534.1595, calculated for C25H25ClN9OS (M+H)+: 534.1591.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](B(O)O)[CH:39]=2)[CH:34]=[CH:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:39]=2)[CH:34]=[CH:33]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2cc[nH]c2c1
Yield: 82.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 1H-indol-6-ylboronic acid (0.201 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.165 g (83%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][C:23]([O:25]C)=[O:24])[C:10]3=[N:9][C:8]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][C:23]([OH:25])=[O:24])[C:10]3=[N:9][C:8]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of (E)-methyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)hept-3-enoate (step 2) (30 mg, 0.070 mmol) in THF (3 ml):MeOH (1 ml) was added LiOH (10.08 mg, 0.421 mmol) in water (1 ml). The reaction mixture was heated at reflux for 1.5 h. After cooling to RT, 2M HCl was added until the pH of the mixture was below pH 5. The volatile solvent was removed in vacuo and the resulting mixture was extracted with EtOAc (2×15 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].[Li+].C(N(CC)CC)C.O.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>C(#N)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (17.5 g, 0.1 mol), triethyl phosphonoacetate (22.4 g, 0.12 mol), lithium chloride (5.1 g, 0.12 mol) and triethylamine (17 mL, 0.12 mol) in acetonitrile is stirred at room temperature for 1 hour and diluted with a water/ethyl acetate mixture. The organic phase is separated, washed with water dried over anhydrous Na2SO4 and concentrated in vacuo to give the title product as a yellow solid (42 g).
Reaction SMILES: OC1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[C:27]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)(N1C=CN=C1)=O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:6]2[CH:5]=[CH:4][C:3]3[CH:27]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et2O and washed with 5% aqueous NaOH, H2O, and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5% MeOH—CH2Cl2) afforded 50.0 mg (31%) of the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>>[ClH:22].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Product: Cc1csc(Nc2ncc(Sc3ccccc3Cl)cc2Oc2ccccc2)n1
Product: Cl

Procedure:
Prepared according to the method of Example 13, using 5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine and 2-chlorobenzenethiol. 1H NMR (d6-DMSO) δ 8.26 (d, 1H), 7.49 (dd, 1H), 7.42 (t, 2H), 7.29 (d, 1H), 7.27-7.12 (m, 4H), 6.96 (dd, 1H), 6.80 (s, 1H), 2.30 (s, 3H); Mass spectrum (esi) m/z=426.4 (M+H—HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl.CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
2,6Dichlorophenyl isocyanate (0.075 g) was added to a solution of 4amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.093 g) in a mixture of methylene chloride (2 ml) and DMF (0.1 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The resultant solid was isolated, redissolved in a 20:1 mixture of methylene chloride and methanol and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound as a white solid (0.029 g); NMR Spectrum: (DMSOd6) 1.3-1.4 (m, 2H), 1.7-1.8 (m, 4H), 1.85 (t, 1H), 2.1 (s, 3H), 2.8 (d, 2H), 3.9 (s, 3H), 4.0 (br d, 2H), 7.3 (br s, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.6 (s, 1H), 8.0 (br s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 490, 492 and 494.
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10]OS(C)(=O)=O)[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:10][CH2:9][C:4]2([CH:1]([CH3:2])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1(CCN[C@@H](C)c2ccc(Br)cc2)OCCO1
Yield: 38 %

Procedure:
To a solution of methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (12 g, 50 mmol) and (S)-1-(4-bromophenyl)ethanamine (19.9 g, 100 mmol) in CH3CN (250 mL) was added K2CO3 (8 g, 58 mmol), and the mixture was refluxed for 10 h. The solution was filtered, and the filtrate was concentrated to afford the crude product, which was purified by column chromatography to give [(S)-1-(4-bromophenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (6.5 g, 38%).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])C>O.C1COCC1.CO>[OH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)CNC(=O)c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccccc1O
Yield: 93 %

Procedure:
LiOH in water (82 mg in 2 mL of water) was added dropwise to (2-hydroxy-benzoyl amino)-acetic acid ethyl ester (110 mg, 0.49 mmol) in a mixture of THF and MeOH. The THF and MeOH were evaporated under reduced pressure and the residue was acidified using 10% citric acid solution. The product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (2-hydroxybenzoyl amino)-acetic acid in 93% yield. 1H NMR (DMSO-D6): δ 12.8 (s, 1H), 12.2 (s, 1H), 9.2 (t, 1H), 7.9 (d, 1H), 7.5 (dt, 1H), 7.0 (d, 2H), 4.0 (d, 2H).