Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7](=[O:13])[CH:6]=[N:5]2
Reactant: CCOC(=O)CI
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 85 %

Procedure:
Under a nitrogen atmosphere Na (0.25 g, 11 mmol) was dissolved in 100 ml of abs. ethanol and 6,7-dichloroquinoxalin-2(1H)-one (2.15 g, 10 mmol) (Liebigs Ann. Chem., (1982), 754) was added. The mixture was refluxed for 30 min., cooled to room temperature, and ethyl iodoacetate (1.43 ml, 12 mmol) was added. The clear reaction mixture was refluxed for 2 h during which time a precipitate was formed. This was filtered off, washed with abs. ethanol and dried to afford 2.56 g (85%) of 6,7-dichloro-1-ethoxycarbonylmethylquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 8.05 (s, 1H), 8.17 (s, 1H), 8.38 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3nccs3)n2)c1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2nccs2)n1

Procedure:
4-methyl-3-(4-thiazol-2-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 10 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.OC[CH2:13][CH2:14][S:15][C:16]1[C:24]2[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=2[S:18][C:17]=1[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CCOCC>[OH:9][CH:5]([CH3:6])[CH2:13][CH2:14][S:15][C:16]1[C:24]2[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=2[S:18][C:17]=1[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCC(C)O)c(Cc3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dimethylsulfoxide (0.113 ml) in anhydrous dichloromethane (1 ml) was added to a solution of oxalyl chloride (0.093 ml) in anhydrous dichloromethane (5 ml) at −78° C. under nitrogen. After 5 minutes, a solution of 5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g) in anhydrous dichloromethane (4 ml) was added dropwise. After 10 minutes, triethylamine (0.372 ml) was added and the mixture was warmed to room temperature. Ether (30 ml) was added and the mixture was washed with 2M hydrochloric acid (10 ml) then with saturated sodium hydrogen carbonate solution (10 ml), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was dissolved in anhydrous tetrahydrofuran (10 ml), cooled to −78° C. under nitrogen and treated with methyl magnesium chloride (3.0M solution in tetrahydrofuran, 0.265 ml). The mixture was warmed to room temperature, then added to saturated sodium hydrogen carbonate solution (30 ml) and then extracted with ethyl acetate (2×30 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered through a small silica pad and evaporated. The residue was purified by preparative normal-phase HPLC with ethyl acetate/isohexane gradient elution followed by recrystallisation from ethyl acetate/isohexane to give the title compound (58 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH3:15][C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:22]([C:19]1[CH:20]=[N:21][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:24]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1394.9 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (1 g, 4.99 mmol) in DMF (5 ml) was added 6-methyl-3-pyridinecarboxylic acid (0.685 g, 0.340 mmol), HOBT.H2O (0.765 g, 4.99 mmol) and HBTU (1.894 g, 4.99 mmol). Finally DIPEA (2.62 ml, 14.98 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. Solvent was removed by evaporation and EtOAc was added to the residue and the solution was extracted with saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic layer was evaporated to dryness and dissolved in dioxane (100 ml) and stirred with 4M HCl in dioxane (15 ml) and water (0.25 ml) overnight. The solution was evaporated to dryness and purified using an ion exchange column (SCX, Biotage) to give the title compound as an oil (1.04 g)
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[C:7]1=[O:16])C>Cl>[CH:4]([CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[C:7]1=[O:16])=[O:3]
Reactant: CCOC(CC1C(=O)N(C)c2ccccc21)OCC
Agent: Cl
Product: CN1C(=O)C(CC=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
To 114 g of 3-(2,2-diethoxyethyl)-1-methyloxindole was added 110 ml of 5% hydrochloric acid aqueous solution, and the mixture was stirred at a room temperature for 3 hours. The reaction mixture was filtered and the filtrate was neutralized with sodium carbonate, then extracted with chloroform. The chloroform layer was washed with a saturated sodium chloride aqueous solution, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 89 g of 3-formylmethyl-1-methyloxindole.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: COC(OC)c1cccc(Oc2ccncc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccncc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-pyridyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(4-pyridyloxy)-phenyl]-1,8(2H,5H)-acridinedione. Purification by column chromatography on silica gel using dichloromethane/methanol (95:5) as the eluent gave a beige solid of melting point 186-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C)C=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:13]1[C:12](=[O:15])[CH2:11][C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:14]1)[CH3:33]
Reactant: O=C1Cc2ccc(Cl)cc2C(c2ccccc2Br)CN1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1500 mg of the compound from Example 10A (4.28 mol) are dissolved in 30 ml of dimethylformamide, and 2788 mg of caesium carbonate (8.56 mol) are added. 0.95 ml of ethyl bromoacetate (1429 mg, 8.56 mol) is added drop wise, and the suspension is stirred at room temperature overnight. Water is added, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 450 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(CCCC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4-Methoxyphenyl)butyric acid (2.0 g, 10.3 mmol) was treated with thionyl chloride (20 mL). The reaction was stirred at rt for 3 h, heated at 65° C. overnight and then concentrated under reduced pressure to give 4-(4-methoxyphenyl)butyryl chloride (2.3 g) as a yellow oil which was used without farther purification. IR (NaCl): 1795, 1510, 1244 cm-1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[O:54][N:53]=[C:52]2[CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:57]=[CH:58][C:51]=12>CN(C=O)C>[N:50]1[O:54][N:53]=[C:52]2[CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:57]=[CH:58][C:51]=12
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3nonc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5nonc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 85.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-benzo[1,2,5]oxadiazol-5-yl-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 88% yield: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C(O)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC(=O)c1ccccc1
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1O
Reaction time: 200 h

Procedure:
3-methoxy-4-hydroxybenzaldehyde (20 gm, 0.132 mol) was added to the solution of acetophenone (20 gm, 0.125 mol) dissolved in acetic acid (20 mL) in a round bottom flask with constant stirring. Temperature of reaction was maintained below 15° C. with Occasional shaking for 200 hrs. Reaction mixture was poured in ice cold water and the product was extracted with chloroform. Chloroform extract was distilled under reduced pressure and the residue was chromatographed on SiO2 gel to obtain 1. m.p. 91° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[CH:38]=[C:37]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.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>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=4)[N:39]([CH3:43])[CH:38]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 106B) (160 mg, 0.557 mmol) in N,N-dimethylformamide (3.21 mL) was added saturated aqueous bicarbonate solution (1.07 mL) followed by bis(triphenylphosphine) palladium dichloride (21.06 mg, 0.030 mmol). The mixture was heated to 70° C. for 2 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. LCMS TFA(+) m/z 602.99 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
4-Chlorobenzenesulfonyl chloride (300 mg, 1.38 mmol) was added to a stirred solution of 8-aminoquinoline (200 mg, 1.38 mmol) in pyridine (2 ml). DMAP (cat.) was added and the reaction was stirred at room temperature for 4 h. After no further progress of the reaction was observed (monitored by TLC and LCMS), water was added and the mixture was extracted with DCM. The organic phase was washed with a sat. KHSO4 solution, dried (Na2SO4) and concentrated in vacuo. The crude residue was triturated with n-hexane to give the title compound (270 mg, 61%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 88.4 %

Procedure:
tert-Butyl (2-iodopyridin-4-yl)carbamate (2.41 g, 7.5 mmol), copper(I) iodide (50 mg, 0.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg, 0.3 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.1 mL, 8.1 mmol) under N2 at rt. 3-Ethynylaniline (0.75 mL, 7.2 mmol) was added and the mixture was stirred at rt for 40 hours. The reaction mixture was diluted with water. After removal of the solvent, the aqueous residue was extracted with EtOAc three times, followed by drying, filtration, and concentration to give the desired product as a brown solid (1.97 g, 89%). LCMS for C18H20N3O2 (M+H)+: m/z=310.1.
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]=3[CH:20]=[CH:21][CH:22]=2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:8][S:9][C:10]1[C:11]2[C:12]3[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([SH:24])[C:13]=3[CH:20]=[CH:21][CH:22]=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Solvent: c1ccncc1
Solvent: COS(=O)(=O)OC
Product: CSc1ccc2c3c(cccc13)C(S)=N2

Procedure:
Chlorosulfonation of benz(cd)indol-2-(1H-one yields the 6-sulfonylchloride derivative, which upon treatment with zinc dust in acetic acid-hydrochloric acid solution, yields 6-mercaptobenz(cd)indol-2-(1H)-one. Treatment with dimethyl sulfate in alkaline solution leads to 6-methylthiobenz(cd)indol-2-(1H)-one, which on heating with P2S5 in pyridine yields 6-methylthiobenz(CD)indol-2-thiol. The reaction of the latter compound with molar equivalents of 3-(4-pyridinyl)propanamine and mercuric acetate in ethanol, under the conditions of Example 55, leads to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 1-bromo-4-((E)-2-nitro-vinyl)-benzene (1 g, 4.37 mmol) described in Manufacturing Example 207-1-1 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (265 mg, 6.99 mmol), which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (948 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.Cl.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1>>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Agent: Cl
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)Nc2cnn(C)c2)nc1
Yield: 90 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine dihydrochloride instead of isopropylamine, to the title compound (113 mg, 90%), which was obtained as a white solid. MS: m/e=391.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:17]([Cu])#[N:18]>CN(C=O)C.O>[C:17]([C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:18]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Temperature: 140 °C
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added CuCN (0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.Cl.[CH3:41][NH:42][O:43][CH3:44]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[O:12])[N:42]([O:43][CH3:44])[CH3:41])=[CH:14][CH:15]=1)[CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:20][CH2:21]1
Reactant: CNOC
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CON(C)C(=O)c1ccc(N(Cc2cccc(Cl)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Yield: 83.4 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and N,O-dimethylhydroxylamine hydrochloride (11 mg, 0.11 mmol) afforded COMPOUND 88 as a white solid (36 mg, 84%). 1H NMR (CDCl3) δ 0.91-1.21 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.71-1.88 (m, 3H), 2.17 (t, 1H, J=11.4 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.24-3.30 (m, 1H), 3.30 (s, 3H), 3.57 (s, 3H), 3.65-3.72 (m, 1H), 3.84 (s, 2H), 3.84-3.90 (m, 1H), 6.52 (d, 2H, J=8.7 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.11 (m, 3H), 7.21-7.26 (m, 2H), 7.62 (d, 2H, J=8.4 Hz), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.54, 29.37, 30.69, 31.32, 34.49, 40.23, 43.97, 48.64, 52.50, 56.07, 60.93, 61.16, 111.89, 121.77, 124.65, 126.60, 127.34, 127.77, 128.88, 130.19, 131.09, 134.41, 134.85, 138.97, 142.35, 150.90, 169.94, 170.31. ES-MS m/z 591 (M+H). Anal. Calcd. for C34H43N4ClO3.0.3CH2Cl2: C, 66.84; H, 7.13; N, 9.09. Found. C, 66.87; H, 7.06; N, 8.94.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was added portionwise, allowing for gas evolution, to a solution of 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5 mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete, benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9 g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)+.