Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7](S(C)=O)[N:6]=1)([CH3:3])[CH3:2].C(NC1C(C(N)=O)=CN=C(S(C)(=O)=O)N=1)(C)C.CN1C(=O)CCC1.Cl.[NH2:42][C:43]12[CH2:50][CH2:49][C:46]([OH:51])([CH2:47][CH2:48]1)[CH2:45][CH2:44]2.CCN(C(C)C)C(C)C>>[OH:51][C:46]12[CH2:49][CH2:50][C:43]([NH:42][C:7]3[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=3)([CH2:48][CH2:47]1)[CH2:44][CH2:45]2
Reactant: CC(C)Nc1nc(S(C)=O)ncc1C(N)=O
Reactant: NC12CCC(O)(CC1)CC2
Agent: CC(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nc(NC23CCC(O)(CC2)CC3)ncc1C(N)=O
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To the solution of 4-(isopropylamino)-2-(methylsulfinyl)-pyrimidine-5-carboxamide and 4-(isopropylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide in NMP (from previous step, 2.8 mmol), 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (500 mg, 2.8 mmol), DIEA (1.1 g, 8.4 mmol) were added and heated at 100° C. for 3 d. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography to afford the final product (74.1 mg, 8.2% yield). 1H NMR (DMSO-d6) δ ppm 8.88 (br s, 1H), 8.31 (s, 1H), 7.5-6.5 (br s, 2H), 5.76 (s, 1H), 4:25 (s, 4.11 (brs, 1H), 2.05-1.97 (m, 6H), 1.61-1.54 (m, 6H), 1.24-1.12 (m, 6H); MS (ESI) m/z 320.2 [M+H]+; Purity=96.5% at 214 nm, Purity=97.7% at 254 nm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([O:13]CC2C=CC=CC=2)=[CH:11][CH:12]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Product: CCOC(=O)COc1ccc(O)nc1
Reaction time: 1 h
Yield: 91 %

Procedure:
The suspension of 0.64 g (2.23 mmol) (6-benzyloxy-pyridin-3-yloxy)-acetic acid ethyl ester and 0.064 g 10% palladium on charcoal was hydrogenated for 1 h at 1.7 bar. The reaction mixture was filtered over Dicalite Speed Plus, washed with ethanol and the filtrate was treated with silica gel and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient from heptane:ethyl acetate (100:0 to 0:100) followed by ethyl acetate:methanol (100:0 to 50:50) to give the product as a colorless solid (91%). MS (Turbo Spray): m/z=198.0 [M+H].
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]#[C:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH3:25])[CH2:34]4)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1Cc2ccc(N)cc2C1
Reactant: CN(c1ccccc1C#Cc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
N-Methyl-N-{2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl]-phenyl}-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.208 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (35.0 mg, 0.236 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.004 g, 4%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.56-7.49 (m, 2H), 7.47-7.35 (m, 3H), 7.20 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.89 (t, J=7.0 Hz, 1H), 3.96 (s, 2H), 3.90 (s, 2H), 3.61 (s, 3H), 3.21 (s, 3H), 2.61 (s, 3H). MS=473 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
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: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 35.9 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.24 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(4-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 34%) as a solid.
Reaction SMILES: [BH4-].[Na+].[CH:3](=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH3:4].O>C1COCC1.CO>[CH2:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH3:4]
Reactant: CC=Nc1c(C)cccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCNc1c(C)cccc1C

Procedure:
Sodium borohydride (19.0 g, 0.5 mol) was added in small portions to a stirred solution of N-ethylidene-2,6-dimethylaniline (36.3 g, 0.247 mol) in THF (150 mL) and methanol (150 mL). The reaction was exothermic and a water/ice bath was used to cool the mixture. After addition of sodium borohydride, the bath was removed and the mixture was allowed to react for another 30 min. Then, water (150 mL) was added to the reaction mixture, while stirring and cooling the mixture with a water/ice bath. The volatiles were removed in vacuo, the aqueous layer extracted with dichloromethane (3×150 mL) and the combined organic layers were dried with sodium sulfate. Filtration and rotatory vaporation of the volatiles yielded the desired product. Yield: 36.4 g (99%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH2:55]([O:62][NH2:63])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([O:62][NH:63][C:12](=[O:14])[CH2:11][C@H:10]([C:15]1[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: NOCc1ccccc1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)O)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(methoxycarbonyl)-5-methyl-1,3-oxazol-2-yl]hexanoic acid (Preparation 174) (2.48 g, 7.36 mmol) was cooled to 0° and treated with 1-hydroxybenzotriazole hydrate (994 mg, 7.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.12 g, 11.06 mmol) and N-methylmorpholine (1.21 ml, 11.04 mmol). The mixture was stirred for 15 minutes then treated with O-benzylhydroxyamine (1.17 g, 7.36 mmol) and further N-methylmorpholine (0.81 ml, 7.36 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed sequentially with water, a saturated solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (3.22 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14](O)(=[O:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of 4-(trifluoromethoxy)benzylamine (3.46 g, 57.6 mmol) in DMF (75 mL) and acetic acid (10.0 g, 52.3 mmol) at −10° C. were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (20.2 g, 62.8 mmol) and N,N-diisopropylethylamine (20.0 mL, 115 mmol) and the reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added and the organic phase was washed with water (100 mL), 0.25 M NaOH (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), 0.5 M HCl (100 mL), and water (100 mL), dried over MgSO4, and concentrated in vacuo to afford 11.2 g (92%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[C:6]=1[C:15](OC)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]3[NH:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[N:1]=[C:15]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:6]=3[C:7]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(Nc2ccccc2N)sc2ccc(C)cc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1ccc2sc3c(c2c1)C(N1CCN(C)CC1)=Nc1ccccc1N3

Procedure:
In the same manner as in Example 1 and using methyl 2-(2-aminoanilino)-5-methylbenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[Cl:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>Cl.O1CCOCC1>[ClH:15].[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[N:1]1[CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH2:6]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A sealed tube reactor was mixed with tert-butyl piperidin-4-ylcarbamate (1.0 g, 5.0 mmol) and 2-chlorobenzoxazole (2.3 g, 15.0 mmol). The reactor was sealed and the tube was heated while stirring at a temperature of 100° C. for 2.0 hours. The tube was cooled to RT and the resulting oily solid was dissolved in 4.0 N HCl in 1,4 dioxane (25 mL). The reaction stirred over 16.0 hours and was concentrated to dryness. The resulting solid was triturated with ether and filtered. The product was washed with ether and dried to give 1.1 g of crude solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:7]=[CH:8][CH:9]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:19]1([S:25]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a stirred slurry of 0.61 g (12.7 mmol), 50% dispersion of NaH in mineral oil, in 36 mL anhydrous THF was added 2.15 g crude 5-(3-chlorophenyl)indole (Step 1 of Example 45). The solution was allowed to stir at room temperature 15 min upon which time 1.2 mL (9.4 mmol) phenylsulfonyl chloride was added dropwise. The solution was allowed to stir at room temperature overnight and was poured into water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The crude product was chromatographed on SiO2 using 10-25% EtOAc-Hex to afford 1.46 g 1-benzenesulfonyl-5-(3-chlorophenyl)-1H-indole as a tan solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.C([O-])(O)=O.[Na+].[C:18](Cl)([Cl:20])=[O:19]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:18]([Cl:20])=[O:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1,4-dioxaspiro[4.5]decan-8-amine (785 mg, 0.005 mol; see Liebigs (1990) Ann. chem. 8:781-7) in CH2Cl2 and then add H2O (20 mL) followed by saturated NaHCO3 solution (50 mL). Add a toluene solution of phosgene (20% solution, 5 mL) to the reaction mixture and stir at room temperature for 1 hour. Dry the CH2Cl2 layer (Na2SO4) and concentrate under reduced pressure. Dissolve the resulting oil in dry toluene to produce a stock solution (˜0.2 M) of (1,4-dioxa-spiro[4.5]dec-8-yl)-carbamoyl chloride. B. 1′-(1,4-dioxa-spiro[4.5]dec-8-yl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: OCCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(OC(F)(F)F)cc1Cl
Yield: 96 %

Procedure:
To a solution of 2-chloro-4-trifluoromethoxyphenol (16.4 g, 0.077 mole) in 100 mL of acetonitrile was added 3-bromopropanol (12.87 g, 0.092 mole) and potassium carbonate (21.33 g, 0.154 mole). The resulted solution was refluxed at 75° C.-80° C. overnight. The solvent was then evaporated. The residue was dissolved in 100 mL of ethyl acetate and washed with 100 mL of H2O. The organic layer was separated, dried over MgSO4, filtered and the organic solvent was evaporated to yield 20 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[CH2:17]([O:19]P(CC(OCC)=O)(OCC)=O)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:19])[CH:18]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(C=NNc1ccc(Cl)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)cnn1-c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
First, 2 g of 3,3,3-trifluoro-2-oxo-1-propanal 1-(4-chlorophenylhydrazone) and 2 g of ethyl diethylphosphonoacetate were mixed with 20 ml of triethylamine, and the reaction was allowed to proceed at 50° C. for 24 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to column chromatography, which afforded 1.16 g of 2-(4-chlorophenyl)-5-trifluoromethylpyridazin-3-one (compound 1-332).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH2:8].[CH2:9](O)[CH2:10][CH2:11][CH3:12]>>[C:4]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:8])/[CH:3]=[CH:2]\[C:1]([O:6][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCO
Reactant: O
Product: CCCCOC(=O)/C=C\C(=O)OCCCC

Procedure:
Seventy grams (0.63 mole) maleic anhydride is dissolved in 300 mls n-butanol containing one gram p-toluene sulfonic acid. The solution is refluxed for 16 hours during which the water formed is removed with a Dean Stark trap. The excess butanol is then distilled in vacuo to give a residue of 200 g of dibutyl maleate (structure verified by NMR analysis).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 2.46 (s, 3H), 3.21-3.28 (m, 4H), 3.72-3.86 (m, 4H), 4.13 (s, 3H), 6.74-638 (m, 4H), 7.00-8.01 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([C@H:32](O)[CH3:33])[CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:11])[Cl:12])[C@H:3]1[C:15]([O:17][C@H:32]([CH3:33])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step D of Example 9, 6 g of (1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylic acid and 4.1 g of 1-(R)(3-phenoxy-phenyl)-ethanol were reacted to obtain after chromatography and elution with an 8--2 mixture of cyclohexaneethyl acetate 4.38 g of (R)α-methoxy-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [BrH:1].[NH+]1C=CC=CC=1.[CH3:8][O:9][N:10]=[C:11]([C:17]([O:21][CH3:22])([O:19][CH3:20])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[N:10][O:9][CH3:8])[C:17]([O:21][CH3:22])([O:19][CH3:20])[CH2:18][Br:1])[CH3:16]
Reactant: CCOC(=O)C(=NOC)C(C)(OC)OC
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=NOC)C(CBr)(OC)OC

Procedure:
Pyridinium hydrobromide perbromide (1.82 g) was added to a solution of ethyl 2-methoxyimino-3,3-dimethoxybutyrate (syn isomer, 1.0 g) in dry tetrahydrofuran (10 ml) and heated under reflux for an hour. The resultant solution was poured into water (30 ml) and extracted with diethyl ether (10 ml×2). The extract was washed with 5% aqueous sodium thiosulfate solution (5 ml×5) and a saturated aqueous solution of sodium chloride (10 ml×1) successively. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give ethyl-2-methoxyimino-3,3-dimethoxy-4-bromobutyrate (syn isomer, 2.02 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:18])[CH:15](Br)[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:18])[CH:15]([N:23]=[N+:24]=[N-:25])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(Br)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(N=[N+]=[N-])C2
Reaction time: 1.5 h

Procedure:
To a solution of 1-acetyl-4-bromo-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one (8.3 g., 0.029 mole) in dimethylformamide (70 ml.) containing 5 ml of acetic acid and cooled in an ice bath, is added a solution of sodium azide (3.8 g. in 17 ml. of H2O) at such a rate that the reaction temperature does not exceed 25° C. Stirring is continued for 1.5 hours with cooling. The reaction mixture is poured into water (200 ml.) and the dark solid that separates is recovered by filtration and dried. The yield of crude 1-acetyl-4-azido-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one is 7.0 g. (97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)[CH:11]=[CH2:10]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)c(Br)c1
Yield: 61 %

Procedure:
A mixture of 0.65 gm (3.43 mMol) 3-bromo-4-fluorophenol, 0.60 mL (6.86 mMol) allyl bromide, and 0.71 gm (5.15 mMol) potassium carbonate in 6 mL acetone was stirred at reflux for 13 hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 61% of the desired compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B(O)O)[CH:31]=2)[CH:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:31]=[C:32]5[C:27]([CH:26]=[CH:25][NH:24]5)=[CH:28][CH:29]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc4cc[nH]c4c3)c(C)sc2n1
Temperature: 120 °C
Yield: 16.9 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (16.6 mg, 0.038 mmol) was dissolved in 1,4-dioxane (0.6 mL) and water (0.2 mL). 1H-Indol-6-ylboronic acid (9.28 mg, 0.058 mmol), tetrakis(triphenylphosphine)palladium(0) (4.44 mg, 3.84 μmol) and potassium carbonate (10.63 mg, 0.077 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min. The crude mixture was purified by MDAP (acidic conditions) and then further purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (3 mg). LCMS (A) m/z: 468 [M+1]+, Rt 1.45 min (acidic).