Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[Mg].S(=O)(=O)(O)O>CCOCC>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][CH:8]=[CH:9][C:10]=1[C:4]([OH:6])([CH3:5])[CH2:3][CH2:2][OH:1]
Reactant: CC(=O)CCO
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
0.44 g. of 1-hydroxy-3-butanone in 40 ml. of ether is added dropwise at 20°, with stirring, to a Grignard solution prepared from 2.33 g. of 4-bromobiphenyl and 0.24 g. of magnesium in 100 ml. of ether. The mixture is stirred for a further two hours, the resulting alcoholate is decomposed by means of dilute sulfuric acid, and standard working up gives 3-p-biphenylyl-1,3-butane-diol, m.p. 115°-117°.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.C(N(CC)CC)C.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C@H:2]1[N:3]([C:8]2[N:9]=[N:10][C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[CH2:4][CH2:5][N:6]([C:37]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:38])[CH2:7]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)N2CCOCC2)CCN1c1nnc(-c2ccccc2)c2ccncc12
Reaction time: 4 h

Procedure:
To a solution of (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[3,4-d]pyridazine 16 (105 mg, 344 μmol) in 5 mL of CH2Cl2 was added triethylamine (96 μl, 688 μmol) followed by 4-morpholinylcarbonyl chloride (55 μl, 413 μmol). After 4 h, the reaction was diluted with 60 mL of EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (R)-(3-methyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)(morpholino)methanone 36. MS 418.2 (calc'd) 419.2 (M+H, found).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:34]=[C:33]5[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]5)=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)oc2cc(Oc3ncnc4c3cnn4C3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Yield: 14 %

Procedure:
4-[4-(4-Methyl-2-oxo-2H-chromen-7-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 14%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 7-hydroxy-4-methylcoumarin (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 15 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol). Mass spectrum MH+=478.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30]>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[C:20]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[CH:21]=1)#[N:24]
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)c(OCC(F)(F)F)c1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2OCC(F)(F)F)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 66.1) was coupled with 4-aminomethyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile according to general procedure B to give (RS)-N-[4-cyano-2-(2,2,2-trifluoro-ethoxy)-benzyl]-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless solid. MS 445.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)C(C#N)CCCCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.5 g (17.2 mmol) of 5-(4-chlorophenyl)pentyl bromide, 3.36 g (17.2 mmol) of (4-methylphenyl)sulfonylacetonitrile, 2.26 g (17.2 mmol) of 1,8-diazabicyclo(5,4,0)undec-7-ene and 30 ml of benzene is stirred at room temperature for 6 hours. Then the reaction mixture is washed with water; the organic phase is dried, and concentrated. The concentrate is chromatographed with a mixture of toluene and dioxane (10:1) on silica gel. Yield: 4.2 g (65% of theory) of the title compound, a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:22][CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
To a solution of 4- hydroxyphenylacetic acid (3.00 g) in ethanol (50 ml) was added sulfuric acid (5 ml). The mixture was refluxed with heating for 4 hours. Aqueous sodium bicarbonate solution was added to the reaction solution so as to make basic. Then, the reaction solution was extracted with chloroform. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum to yield a raw product of ethyl 4-hydroxyphenylacetate. In a manner similar to Reference Example 1, this raw product was reacted with geranyl bromide (7.10 g) and then hydrolyzed to yield 3.54 g (61%) of 4-geranylophenylacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](N(CC)CC)C.IC>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.18 mmol) and triethylamine (49 μL, 0.35 mmol) in DMF (1 mL) at −78° C., iodomethane (177 μL, 0.17 mmol, 1.0M in DMF) was added. The reaction was allowed to stir for 1 h while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 30 mg (34%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (dd, 1 H), 3.75 (dd, 1 H), 3.37-3.26 (m, 1H), 2.98 (dd, 1H), 2.70-2.65 (m, 2H), 2.56-2.50 (m, 1H), 2.47-2.30 (m, 1H), 2.26-2.18 (m, 2H), 2.14 (s, 3H), 2.11-2.01 (m, 1H), 1.61 (t, J=10.5 Hz, 1H); LC-MS [M+H]+=495, RT=2.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:26](COCC[Si](C)(C)C)[C:25]([O:35][CH:36]3[CH:40]4[O:41][CH2:42][C@H:43]([OH:44])[CH:39]4[O:38][CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[O:22][CH3:23])=[CH:10][CH:9]=1.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:26][C:25]([O:35][CH:36]3[CH:40]4[O:41][CH2:42][C@H:43]([OH:44])[CH:39]4[O:38][CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[O:22][CH3:23])=[CH:10][CH:9]=1
Reactant: COc1c(F)cc(F)cc1-c1ccc(-c2nc3nc(OC4COC5C4OC[C@@H]5O)n(COCC[Si](C)(C)C)c3cc2Cl)cc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1c(F)cc(F)cc1-c1ccc(-c2nc3nc(OC4COC5C4OC[C@@H]5O)[nH]c3cc2Cl)cc1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
Combined (3S)-6-[6-chloro-5-[4-(3,5-difluoro-2-methoxy-phenyl)phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexa-hydrofuro[3,2-b]furan-3-ol (36.8 mg, 0.057 mmol), formic acid (0.6 ml, 15.6 mmol), and saturated aqueous KHSO4 (0.05 ml) in a flask. The yellow solution was heated to 40° C. with stirring. After 22 hours, the reaction mixture was cooled to room temperature before being cooled to 0° C. in an ice bath. Then 5N NaOH (3 ml) was added to the reaction mixture and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with THF (2.0 ml) to give a hazy mixture. After 20 minutes, 2 N aqueous HCl (1.1 mL) was added. The reaction mixture was partitioned between EtOAc (35 ml) and water (20 ml), then the organic phase was washed with brine (1×10 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to a give the product as a solid. LC-MS: calculated for C25H20ClF2N3O5 515.11 observed m/e: 516.10 (M+H)+ (Rt 1.22/2 min)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Cl.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.[Pd]>[N:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccncc2)cc1

Procedure:
4-Cyanophenylboronic acid (1.49 g, 10 mmol), 4-bromopyridine hydrochloride (1.97 g, 10 mmol), 10% palladium-on-carbon (322 mg) and anhydrous sodium carbonate (2.15 g, 20 mmol) were refluxed in a mixture of ethanol (12 mL) and water (3 mL), overnight under an atmosphere of argon. The reaction mixture was filtered through diatomaceous earth, then concentrated in vacuo. The resulting white solid was separated between ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was subjected to chromatography (SiO2; 50%, 60%, 70%, 80% ethyl acetate/iso-Hexane) to yield 4-(4-pyridyl)benzonitrile a crystalline white solid (1.60 g), 1H NMR (DMSO-d6) δ=7.77 ppm (dd,2H), δ=7.99 ppm (m,4H), δ=8.69 ppm (dd,2H); MS (M+H)+ 181.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2cccnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 3-bromoimidazo[1,2-b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et al. Synthesis (1981), 12, 987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), Cul (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(C[C:4]1[N:5]([CH3:23])[C:6](=[O:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([CH3:20])=[C:9]([CH3:21])[CH:8]=2)#N.Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH3:23][N:5]1[C:4]([CH2:26][C:25]([OH:28])=[O:27])=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][C:9]([CH3:21])=[C:10]([CH3:20])[CH:11]=2)[C:6]1=[O:22]
Reactant: Cc1cc2c(-c3ccccc3)c(CC#N)n(C)c(=O)c2cc1C
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc2c(-c3ccccc3)c(CC(=O)O)n(C)c(=O)c2cc1C
Temperature: 110 °C

Procedure:
A mixture of the compound (4.7 g) obtained in Step 1, acetic acid (150 ml) and hydrochloric acid (150 ml) was heated for 7 hours at 110° C. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water and dried (MgSO4), then the solvent was distilled off to leave the title compound as colorless crystals (3.7 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: O=C(Cc1ccccc1)Nc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2-phenyl-acetamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H29NO6 [M+H]+: 484.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[C:51]([CH3:52])=[N:50][O:49][N:48]=1.BrCCCCC>>[CH3:52][C:51]1[C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:48][O:49][N:50]=1
Reactant: Cc1nonc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: Cc1nonc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-4-methyl-1,2,5-oxadiazole to replace 1-bromopentane, 1′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (69%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.28 (m, 1H), 7.22-7.03 (m, 3H), 6.52 (s, 1H), 6.23 (s, 1H), 5.19 (ABq, 2H), 4.73 (ABq, 2H), 4.22-4.07 (m, 4H), 2.41 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 154.6, 151.4, 151.3, 144.2, 141.6, 137.8, 131.8, 128.7, 123.6, 123.4, 121.1, 111.2, 109.3, 98.7, 79.3, 64.2, 63.6, 57.2; MS (ES+) m/z 414.0 (M+23).
Reaction SMILES: [CH3:1][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:6])[C:3]([OH:5])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:57][Si:58]([CH3:64])([CH3:63])[CH2:59][CH2:60][O:61][NH2:62]>C(Cl)Cl>[CH3:6][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:1])[C:3]([NH:62][O:61][CH2:60][CH2:59][Si:58]([CH3:64])([CH3:63])[CH3:57])=[O:5]
Reactant: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)O
Reactant: C[Si](C)(C)CCON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)NOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a solution of 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-propionic acid (1.60 grams, 4.91 mmole) in methylene chloride (160 mL) was added triethylamine (2.3 mL, 16.5 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.4 grams, 5.41 mmole) and O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (0.92 grams, 5.41 mmole). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, aqueous saturated sodium bicarbonate solution, and brine. After drying over magnesium sulfate, the solvent was evaporated to afford a white foam from which the desired product, 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-N-(2-trimethylsilanylethoxy)-propionamide (220 mg, 10%), a white solid, was isolated by chromatography on silica gel eluting with 3:2 ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:11]=[C:18]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[N:8]2[CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: CCNc1nc(Cl)ncc1N
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2ccncc2)nc2cnc(Cl)nc21
Temperature: 140 °C
Yield: 15.4 %

Procedure:
To a solution of 8.6 g (50 mmol, 1.0 eq.) of 2-chloro-N4-ethylpyrimidine-4,5-diamine (I-5) in 200 mL of 2% v/v AcOH/DMA was added 6.0 mL (65 mmol, 1.3 eq.) of 4-pyridine carboxaldehyde. The mixture was heated at 140° C. for 14 h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide 2.0 g (7.7 mmol, 15%) of 2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purine (I-6).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)OS(C)(=O)=O>CO.[Pd]>[F:20][C:2]([F:1])([F:19])[CH2:3][C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(C(OS(C)(=O)=O)C(F)(F)F)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(F)(F)F)cn1
Reaction time: 2 h

Procedure:
To a solution of methyl 5-(2,2,2-trifluoro-1-(methylsulfonyloxy)ethyl)picolinate (95 mg, 0.3 mmol) in 5 mL of MeOH was added 10% Pd/C (45 mg). Hydrogenation with 1 atm H2 was carried out at room temperature for 2 h. After the catalyst was removed by filtration, the filtrated was concentrated. The residue was dissolved in DCM and washed with sat. NaHCO3 (aq,), and brine. The solution was dried (MgSO4) and concentrated to give methyl 5-(2,2,2-trifluoroethyl)picolinate that was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:27]2[C:28]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 27.2 g (75.6 mmol) of 1,6-dibromopyrene, 13 g (75.6 mmol) of naphthalen-1-ylboronic acid, 0.87 g(0.756 mmol) of Tetrakis(triphenylphosphine)Palladium, 57 ml of 2M Na2CO3, 120 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 14 g (yield 45.5%) of beige product which was recrystallized from 1,4-Dioxane.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[C:5]([Br:8])[C:6]=1[CH3:7].[Li][CH2:11]CCC.S(OC)(OC)(=O)=O>C(OCC)C>[Br:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([Br:8])[C:6]=1[CH3:7]
Reactant: Cc1c(Br)sc(Br)c1Br
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: Cc1sc(Br)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
A solution of 2,4,5-tribromo-3-methylthiophene (50.2 g, 0.15 mol; Gronowitz, S.; Moses, P. Hakansson Arkiv. f. Kemi. 1960, 14, 267) in 400 mL of diethyl ether was cooled to -78° C., and a solution of nBuLi (100 mL, 1.6M) was added dropwise. The starting material precipitated out of solution, but when n-BuLi added, the reaction mixture became stirrable again. When the addition was complete, the reaction mixture was stirred for 20 min, and then a solution of dimethyl sulfate (75.7 g, 0.600 mol) in 200 mL of diethyl ether which was cooled to -50° C. was added by cannulation. When addition was complete, the reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with 100 mL of 6N NaOH solution and stirred for 2h. The mixture was transferred to a separatory funnel, and the aqueous layer was separated and extracted with additional ether. The organic layers were combined, washed with water and brine and dried (MgSO4). The suspension was filtered and concentrated to give an oil. Vacuum distillation provided 22.1 g (55%) of 2,4-dibromo-3,5-dimethylthiophene, A8, b.p. 71°-72° C. @ 0.4 mmHg. The 1H NMR in CDCl3 supported the assigned structure. ##STR58##