Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:31][C:16]1[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 90 °C
Yield: 41.2 %

Procedure:
A mixture of 6-bromo-9H-purine (110 mg, 0.56 mmol), 6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (0.086 g, 0.28 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (49 mg, 41%). LCMS calculated for C21H19ClFN6O (M+H)+: m/z=425.1. found: 425.0.
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][CH:23]1[CH:27]=[CH:26][CH:25]([CH3:28])[NH:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([N:24]1[CH:25]([CH3:28])[CH:26]=[CH:27][CH:23]1[CH3:22])=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: CC1C=CC(C)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C=CC(C)N1C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2.1 g of 2-[(N-Boc)amino]-3-(4-cyanophenyl)propionic acid are mixed with 0.715 g of 2,5-dimethyl-2,5-dihydropyrrole in 10 ml of DMF, 3.9 g of BOP are added and the pH is adjusted to 7 by addition of Et3N. After stirring for 18 hours at RT, the mixture is evaporated to dryness and is then taken up in EtOAc, washed with NaHCO3 solution, with KHSO4 /K2SO4 and with saturated NaCl solution. The resulting solution is dried over Na2SO4 and then evaporated. The residue is taken up in an ether/hexane mixture and then dried over Na2SO4. 1.4 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]=[CH:8][N:9]3[C:14]([S:15][CH3:16])=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]=[CH:8][N:9]3[C:14]([S:15]([CH3:16])=[O:27])=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)Cc1nnc(SC)n1C=C2
Product: COc1ccc2c(c1)Cc1nnc(S(C)=O)n1C=C2

Procedure:
By a procedure similar to that described in Example 17, 9-methoxy-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 9-methoxy-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from methanol), m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: O=Cc1ccccc1
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC(O)c1ccccc1
Yield: 95.2 %

Procedure:
125.40 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 60.00 g of benzaldehyde, 180 g of toluene, 240 g of 5% acetic acid and 73.88 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 98.23 g of 2-chloroallylphenylcarbinol. The results were as follows.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(O)(C)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C[C@H](O)CCl
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were charged 58.35 g (0.3 mol) of t-butyl 4-chloroacetoacetate and 120 ml of t-butyl alcohol, and solution of 250 mg (0,00015 mol) of Ru2Cl4 [(R)-(+)-BINAP]2Et3N in 2 ml of methylene chloride was added thereto. The mixture was stirred at 100° C. under a hydrogen pressure of 10 to 15 kg/cm2 for 2 hours to conduct hydrogenation, The solvent was evaporated, and the residue was distilled under reduced pressure to give 53.0 g (percent yield: 90%) of t-butyl (S)-(-)-4-chloro-3-hydroxybutyrate as a colorless clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccc2c1CC(N)CC2
Product: COc1cccc2c1CC(NC(=O)C(C)C)CC2
Yield: 71 %

Procedure:
Using a procedure similar to that described in Example 1, 0.22 g of 8-methoxy-2-amino-tetralin yielded 0.18 g (71%) of 8-methoxy-2-iso-butyramido-tetralin following treatment with iso-butyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[C:19]([CH2:20]C4C=CC(C#N)=CC=4)=[CH:18][N:17]=[CH:16]3)=[CH:10][C:9]2=[O:29])[CH:5]=[CH:4][CH:3]=1.[C:30]([N:49]1C=C(CC2C=CC(C#N)=CC=2)N=C1)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[C:19]([CH2:20][C:33]4[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=4)[C:30]#[N:49])=[CH:18][N:17]=[CH:16]3)=[CH:10][C:9]2=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)n3)c(=O)c2)cc1
Product: N#Cc1cccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)n3)c(=O)c2)c1

Procedure:
3-[3-(6'-chloro-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(6'-chloro-2-oxo-2H-[1,2'] bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile, but substituting 3-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile for 4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile in Step 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22]C)=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].S(=O)(=O)(O)O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Yield: 33 %

Procedure:
To a solution of ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 3, 300 mg) obtained in Example 3 in methanol (6 ml), concentrated sulfuric acid (0.4 ml) was added and the mixture was stirred under reflux for 8 days. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/2) and then crystallized from diisopropyl ether to yield methyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 22; 95 mg) as colorless powdery crystals.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41]O)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc2ncccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ncccc2c1
Temperature: 30 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of isoindoline-1,3-dione (6.47 g, 44.0 mmol) and triphenylphosphine (11.53 g, 44.0 mmol) in THF (70 mL) at 0° C. was added a solution of quinolin-6-ylmethanol (7 g, 44.0 mmol) in THF (30 mL) and (E)-diisopropyl diazene-1,2-dicarboxylate (8.89 g, 44.0 mmol) dropwise over a period of 30 min. The mixture was heated at 30° C. and kept stirring for 20 h. After cooling and concentration, the resulting residue was purified by Analogix silica gel with gradient hexanes/EtOAc to provide 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (12.04 g, 95%). LCMS (method A): [MH]+=289, tR=4.89 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 81.4 %

Procedure:
4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (0.15 g, 0.45 mmol), (prepared as described for the starting material in Example 50), potassium carbonate (94 mg, 0.68 mmol) and 7-hydroxyquinoline (79 mg, 0.54 mmol) were suspended in anhydrous DMF (1.5 ml) and heated to 90° C. overnight. The compound was precipitated upon addition of water. The precipitate was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-methylsulphonylpropoxy)4-(quinolin-7-yloxy)quinazoline (161 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][C:9](=[O:11])[C:16]([C:14]#[N:15])=[C:7]2[OH:12]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2cc(Cl)ccc2[nH]c1=O

Procedure:
A solution of 6-chloro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (2 g, 10.1 mmol, Eq: 1.00), ethyl cyanoacetate (1.15 g, 1.08 ml, 10.1 mmol, Eq: 1.00) and triethylamine (14.5 g, 20.0 ml, 143 mmol, Eq: 14.2) in DMF (1.00 ml) was stirred at RT for 65 h. Then 1N HCl was added and the reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed brine. An off-white solid precipitated and was filtered off (337 mg). MS (ESI): 219.1 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[S:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=5[S:13][CH2:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CS2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CS2
Yield: 13 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzothiazin-3(4H)-one (Intermediate 50) (0.9 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (180 mg, 1.1 mmol), and sodium cyanoborohydride (110 mg, 1.76 mmol) were reacted as described under Example 21 to give 55 mg (13%) product as a dry film.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ncn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(C#N)ncn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a solution [6-(6-cyano-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.556 mmol) in THF (3 mL) was added a solution of LiOH (0.041 g, 1.69 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 hours, acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-cyano-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a white solid (0.015 g). 1H NMR (400 MHz, DMSO-d δ 9.18 (s, 1H), 8.82 (d, J=10.0 Hz, 1H), 7.45 (d, J=6.0 Hz, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 5.51 (m, 1H), 3.07 (m, 1H), 2.31 (s, 3H), 2.16 (m, 1H). MS (ESI) m/z: 324 [M−1]−. HPLC purity: 96.94% (Maxplot), 98.24% (220 nm).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(Cl)nc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-chloro-3-pyridyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.[H-].[Na+]>CN(C)C=O>[C:12]1([CH3:19])[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[C:4](=[O:21])[N:3]([CH3:22])[C:2]([N:1]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:7][C:6]=2[N:8]([CH3:20])[CH:9]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N4CCCCC4)n(C)c(=O)c23)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.063 g, 0.212 mmol) in N,N-dimethylformamide (1 mL) was added 1,5-dibromopentane (0.029 mL, 0.212 mmol) and sodium hydride (66% in oil, 0.015 g, 0.426 mmol) at 0° C., and the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (10:1-3:1). The oil obtained was crystallized from diisopropyl ether-hexane to give 0.052 g (67%) of the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]5[CH2:35][O:34]C(C)(C)[O:32]5)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:32])[CH2:35][OH:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2cnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)s2)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(C(O)CO)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole (470 mg) in tetrahydrofuran (3 mL) was added 1M hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (280 mg, yield 64%) as a colorless amorphous solid. MS: 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([C:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[S:23][C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: ClCCl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(Cl)nc2)cc1
Yield: 31 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 6-chloronicotinic acid and 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 31% yield as a yellow solid following flash chromatography (SiO2; CH2Cl2).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.O.[NH2:13][NH2:14]>C(O)(C)C>[NH:13]([C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1)[NH2:14]
Reactant: NN
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: O
Solvent: CC(C)O
Product: Cn1c(NN)cc(=O)n(C)c1=O

Procedure:
A mixture of Step 1 intermediate (17 g, 97.34 mmol) and hydrazine hydrate (119 ml) in isopropyl alcohol (280 ml) were refluxed for 1 h. The excess of solvent was removed under reduced pressure, solid obtained was filtered, washed with methanol (25 ml) and dried to obtain 8.1 g of the product as white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, 3H), 3.21 (s, 3H), 4.37 (br s, 2H), 5.10 (s, 1H), 8.02 (br s, 1H).
Reaction SMILES: N#N.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=1[NH2:14].[CH2:15](O)[CH3:16]>>[CH3:3][N:4]1[C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:12])[CH3:13])=[CH:7][C:6]=2[N:14]=[C:15]1[CH3:16]
Reactant: CNc1ccc(C(C)C)cc1N
Reactant: CCO
Agent: N#N
Product: Cc1nc2cc(C(C)C)ccc2n1C

Procedure:
A mixture of 6.66 g. (0.041 mole) of N2 -methyl-5-isopropyl-1,2-phenylenediamine and 10.02 g. (0.081 mole) of ethyl methylcarboximidate hydrochloride in 100 ml. of absolute ethanol was stirred at room temperature for 40 hours and then refluxed for 18 hours. The reaction mixture was distilled to dryness under reduced pressure, 100 ml. of 4N HCl was added to the residue and then the mixture refluxed for 22 hours. After cooling, the resultant mixture was filtered and the filtrate added dropwise to 200 ml. of stirred ice and water containing 50 ml. of conc. ammonium hydroxide. The precipitated product was isolated by filtration, washed with water and then air-dried. The crude product was dissolved in 75 ml. of refluxing cyclohexane, filtered and the filtrate allowed to cool. The desired product crystallized from the cooled cyclohexane and was removed by filtration to give 2.73 g. (35.8%), melting at 130°-131° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:15]=2)[CH:11]=[N:12][CH:13]=1.CO[CH2:33][CH2:34][O:35][CH3:36]>C(Cl)Cl>[C:21]([NH:20][C:18]1[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:15]=[C:14]([C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:10]3[CH:9]=[CH:8][CH:13]=[C:34]([O:35][CH3:36])[CH:33]=3)[CH:9]=2)[CH:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(-c2cncc(-c3cc(NC(C)(C)C)nc(-c4ccccn4)c3)c2)c1

Procedure:
To a solution of 3-Methoxy boronic acid (1.2 eq, 0.252 mmol, 32 mg) and 2M Na2CO3 (1 eq, 0.21 mmol, 0.1 ml) in dry DME (1 ml) under an inert atmosphere of argon are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-tert-butyl-amine (Example 2.48; Step 1) (1 eq, 0.21 mmol, 80 mg) and PdCl2dppf (0.1 eq, 0.021 mmol, 15 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours 30 mins. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 411.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[CH:22]=[CH:23][S:24][C:20]=3[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]2[CH2:25][CH3:26])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:27]C1SC2C3C=CC=CC=3C(C)N(S(C3C=CC(O)=CC=3)(=O)=O)C=2C=1>>[Br:27][C:23]1[S:24][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]([CH2:25][CH3:26])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21]=2[CH:22]=1
Reactant: CCC1c2ccccc2-c2sccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: CC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1
Product: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 20 %

Procedure:
Starting from 4-[(4-Methoxyphenyl)sulfonyl]-5-ethyl-4,5-dihydrothieno[3,2-c]isoquinoline in place of 4-[(4-Methoxyphenyl)sulfonyl]-5-methyl-4,5-dihydrothieno[3,2-c]isoquinoline (Step 1), the title compound (0.19 g tan solid, 20%, m.p. 183-85° C.) was synthesized in essentially the same manner as described in Example 6, Method B, Steps 1-2, for 4-[(2-Bromo-5-methylthieno[3,2-c]isoquinolin-4(5H)-yl)sulfonyl]phenol.