Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO.CCOCC>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[CH3:2])=[CH:7][CH:6]=1
Reactant: N#CCCCCCOc1ccc(Cl)cc1
Reactant: CI
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(N)CCCCCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
Magnesium (120 mg, 5 mmol) was added to Et2O (15 mL), followed by Methyl iodide (310 μl, 5 mmol). After reflux has ceased, the mixture was heated to reflux for 20 min. The solution was than cooled to 0° C. and 6-(4-chloro-phenoxy)-hexanenitrile (1119 mg, 5 mmol) was added. The ice bath was removed and the mixture was stirred at ambient temperature for 20 h. The mixture was then diluted with dry THF (5 mL) ad cooled to −78° C. NaBH4 (190 mg, 5 mmol) was added followed by MeOH (3.5 ml) and stirring was continued at −78° C. for 4.5 h. The reaction was quenched by careful addition of 1M aqueous HCl (20 mL). The layers were separated, the aqueous layer was washed with Et2O (1×25 mL), the organic layer was extracted with 1M aqueous HCl (3×30 mL). The aqueous layers were adjusted to pH 12 by addition of 10M aqueous NaOH (8 mL) and extracted with EtOAc (3×50 mL). The combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound (ca 30% of total by integration of HPLC trace at 218 nm) together with two more hydrophobic byproducts (total: 766 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
3-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF, and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature, and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl m-nitrophenyl ether (1.02 g 80% yield, m.p 44-5° C.) as a yellowish solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]([N:17]=[CH:18][N:19](C)C)=[S:16])[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].NOS(O)(=O)=O.N1C=CC=CC=1.O1CCOCC1>C(O)C.CO>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]2[S:16][N:19]=[CH:18][N:17]=2)[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Agent: NOS(=O)(=O)O
Solvent: CCO
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncns3)[C@H]2SC1
Temperature: 25 °C

Procedure:
A mixture of 60 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 14 mg of hydroxylamine-O-sulfonic acid and 17.14 mg of pyridine in a mixture of 3 ml of ethanol and 1 ml of methanol was stirred at room temperature. A 0.5 ml portion dioxane was added to enhance solubility. After 1 hour the mixture was concentrated, dichloromethane added to the residue, the solution washed with 10% hydrochloric acid and brine, then decolorized, filtered and evaporated, giving the desired product.
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:19](=[O:21])=[O:20]>CCOCC>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:19]([OH:21])=[O:20])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: Cc1sc2cc(CO)ccc2c1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1sc2cc(CO)ccc2c1C(=O)O
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromo-6-hydroxymethyl-2-methylbenzo[b]thiophene (2.11 g.) in dry ether (150 ml.) was added dropwise over 20 minutes to a stirred solution of n-butyl lithium (25 ml. of 1.5 M solution in hexane) in dry ether (150 ml.) at -70° C. under an atmosphere of dry nitrogen. The mixture was stirred at -70° C. for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water and the aqueous layer was separated and acidified with concentrated hydrochloric acid. The solid was filtered off, washed well with water and dried to give 6-hydroxymethyl-2-methylbenzo[b]-thiophene-3-carboxylic acid (1.26 g.), m.p. 195°-196° C., raised to 196°-197° C. on crystallization from ethanol/water.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:37])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18](OCC)[O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:37])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(COc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1Cl
Reaction time: 3.5 h

Procedure:
At 0° C. 2 mL TFA and 0.15 mL water was added to a solution of 50 mg (0.011 mmol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2,4-dichloro-phenoxy)-acetamide in 2 mL dichloromethane and the mixture was stirred for 3.5 hours. 200 ml of 2 M aqueous sodium carbonate solution was added and exhaustively extracted with dichloromethane. The combined org. extracts were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, EtOAc/hexane 1:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4c(Cl)cccc4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.0918 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,6-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.137 g, 69%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20]I>>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CC(C#N)c1ccc2oc(-c3ccccc3)nc2c1
Product: CC(C)(C#N)c1ccc2oc(-c3ccccc3)nc2c1

Procedure:
By treatment of 2-(2-phenyl-5-benzoxazolyl)propionitrile with methyl iodide in the manner described in Example 12, there was obtained 2-(2-phenyl-5-benzoxazolyl)isobutyronitrile which, on treatment with concentrated hydrochloric acid as described in Example 1(f), yielded 2-(2-phenyl-5-benzoxazolylisobutyric acid, m.p. 92° - 95° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Br
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2,4-dibromobenzene-1-sulfonyl chloride (0.0620 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.0550 g, 57%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.24-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.53 (1H, dd, J=2.0, 8.4 Hz), 7.90 (1H, d, J=1.6 Hz), 7.97 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.52 (1H, s), 8.59 (1H, d, J=2.8 Hz), 8.84 (1H, s), 9.16 (1H, d, J=2.0 Hz). m/z=622.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1(O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCCCC1
Yield: 61.6 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (240 mg, 0.793 mmol) obtained in Referential Example 1 was dissolved in toluene (20 ml). After addition of cyclohexanol (0.11 ml, 1.0 mmol) and cyanomethylenetri-n-butylphosphorane (250 mg, 1.0 mmol), the resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool and then, cyclohexanol (0.22 ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.08 mmol) were added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=30:1) to give a white solid. The white solid was washed with hexane to give the title compound (188 mg, 62%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 3.3 g of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 85 ml of DMF, 10.6 ml of N,N-diisopropylethylamine and 3.2 ml of 2-(trimethylsilyl)ethoxymethyl chloride. After 5 h at RT, the mixture is poured into 8 volumes of ice-water. The aqueous phase is extracted with 3 times 200 ml of AcOEt, and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. Purification is carried out by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 2.1 g of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in the form of a white solid. MS (E/I): m/z=515 (M+); 1H NMR: −0.12 (s, 9H); 0.87 (t, J=8.0 Hz, 2H); 3.65 (t, J=8.0 Hz, 2H); 6.17 (s, 2H); 7.40 (t, J=8.0 Hz, 2H); 7.77 (m, 1H); 8.41 (broad s, 1H); 8.47 (dd, J=1.5 and 8.5 Hz, 1H); 8.77 (d, J=8.5 Hz, 1H). And, on the other hand, 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (white solid). MS (E/I): m/z=515 (M+); 1H NMR: −0.05 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.92 (s, 2H); 7.38 (t, J=8.0 Hz, 2H); 7.76 (m, 1H); 8.24 (broad s, 1H); 8.34 (dd, J=1.5 and 8.5 Hz, 1H); 8.69 (d, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:11].[K+].OO>C(O)(=O)C.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Nc1cccc2[nH]nnc12
Reactant: [Br-]
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2[nH]nnc12
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of 4-aminobenzotriazole(550 milligram (hereinafter “mg”), 4.1 mmol) in acetic acid (10 ml) was added potassium bromide (520 mg, 4.4 mmol ), ammonium molybdate(67 mg, 0.55 mmol) and hydrogen peroxide (0.5 ml, 30%). The mixture was stirred at 25° C. for 3 hors. The solvent was evaporated and chromatography of the resulting solid on silica gel (EtOAc/Hexane(1equiv./1equiv.)) gave the desired product(400 mg, 45%). 1H NMR (CD3SO2CD3): δ7.29 (d, 1H), 6.49 (d, 1H), 6.05 (bs, 3H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.07 min, MH+ 392. NMR: δH [2H6]-DMSO 10.11,(1H, s), 9.11,(1H, s), 8.83,(1H, t), 8.35,(1H, s), 8.30,(1H, dd), 7.85,(1H, s), 7.78,(1H, d), 7.67-7.63,(3H, m), 7.31,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(1H, m), 0.27,(1H, m).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1Br)CCNC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1Br)CCN(CCCCl)C(=O)C2
Reaction time: 0.17 h

Procedure:
First, 55% sodium hydride dispersion in oil (0.24 g, 5.5 mmol) is added to 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one (1.35 g, 5 mmol) in dimethylsulphoxide (15 ml) and the mixture is stirred for 10 minutes at 35°-40° C. The solution is added dropwise to 1-bromo-3-chloropropane (0.79 g, 5.5 mmol) in dimethylsulphoxide (5 ml), with stirring. Then the mixture is stirred for 2 hours at ambient temperature, poured onto ice water and extracted four times with methylene chloride. The methylene chloride extracts are washed several times with water, dried and concentrated in vacuo.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=4)[N:23]=3)[CH2:14][CH2:13]2)=[CH:4]1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([CH2:34][CH2:33][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:19]=[CH:20][C:21]5[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=5)[N:23]=4)[CH2:16][CH2:17]3)=[CH:4]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ccccc45)CC3)nn12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4cn(CCN5CCCC5)c5ccccc45)CC3)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 31 mg, 0.75 mmol) was added to 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 507) (150 mg, 0.39 mmol) suspended in DMF (2 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 30 minutes, then 1-(2-chloroethyl)pyrrolidine hydrochloride (72.6 mg, 0.43 mmol) in DMF (1 mL) was added. The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (52.0 mg, 27.7%) as a white solid.
Reaction SMILES: Br[CH:2]([C:4]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)OCC(C)(C)CO1)C.[C:19](=O)([O-:21])[O-:20].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH3:2])[C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: CC(Br)C1(c2ccc(O)cc2)OCC(C)(C)CO1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 36 h
Yield: 30 %

Procedure:
A mixture of 2-(1'-bromoethyl)-5,5-dimethyl-2-(4'-hydroxyphenyl)-1,3-dioxane (3.15 g; 0.01 mole), potassium carbonate (6.8 g; 0.05 mole), tetrabutylammonium bromide (0.06 g; 0.0002 mole) in dimethylformamide (30 ml) is heated while being stirred for 36 hours at 90° C. The mixture is then cooled to room temperature, poured into a 1N solution of HCl (300 ml), and extracted with toluene. The organic phase is evaporated and the residue is hydrolyzed as in Example 1c, to obtain 2-(4'-hydroxyphenyl)-propionic acid (0.49 g; 0.003 mole; yield of 30%). The characteristics of the acid are identical to those of Example 1.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:31])[C:27]([O:29]C)=[O:28])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:31])[C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)C(=O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1nc(C(=O)NCCC(=O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-oxobutanoate (34 mg, 0.08 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 2 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2) to give the title compound in 20 mg. MS: (−) m/z 404.14 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:26]([NH2:31])(=[O:30])[CH:27]([CH3:29])[CH3:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:11]=[C:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[C:7]=2[CH2:8][N:9]1[CH:12]([C:14]1[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=1)[CH3:13]
Reactant: CC(c1ccc(OCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Reactant: CC(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1nccc2c1CN(C(C)c1ccc(OCC(F)(F)F)nc1)C2=O
Temperature: 170 °C
Yield: 32 %

Procedure:
A mixture of 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.054 mmol, Intermediate 1, single enantiomer), isobutyramide (9.0 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170° C. for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated. The residue is purified by a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.3 mg (32% yield) of the title compound.