Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Step A was taken up in 100 mL of methylene chloride and cooled in an ice bath. To the solution was added 7.6 mL of benzyl chloroformate and after 5 min 20 mL of DIPEA was added dropwise over 5 min. After stirring at r.t. for 3 h, the reaction was poured into water containing 50 mL of 2N HCl and was extracted twice with methylene chloride. The organics were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a solid. This was triturated with hot 5% ethyl acetate in hexanes, cooled, filtered and air dried to afford 16.5 g of title compound as an off white solid. T.l.c. (30% ethyl acetate in hexanes) Rf =0.75
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:9]=[C:10]([N:17]([CH3:19])[CH3:18])[C:11]2[C:12](=[CH:14][S:15][CH:16]=2)[N:13]=1.[NH2:20][C@H:21]1[C@H:25]([OH:26])[CH2:24][N:23]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:22]1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.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].O1CCOCC1>[CH3:18][N:17]([CH3:19])[C:10]1[C:11]2[C:12](=[CH:14][S:15][CH:16]=2)[N:13]=[C:8]([NH:20][C@H:21]2[C@H:25]([OH:26])[CH2:24][N:23]([C:27](=[O:40])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH2:22]2)[N:9]=1
Reactant: CN(C)c1nc(Cl)nc2cscc12
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: NN1CCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)c1nc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)nc2cscc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.5 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.13 g) in ethanol (5 mL) were added 2,4-dichlorothieno[3,4-d]pyrimidine (0.20 g) and triethylamine (0.10 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.156 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.068 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.27 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylaminothieno[3,4-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.037 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:77][N:78]([CH3:82])[CH2:79][CH2:80][NH2:81]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:81][CH2:80][CH2:79][N:78]([CH3:82])[CH3:77])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a mixture of 0.0604 g (0.131 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0172 g (0.197 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-ethoxy-benzamide (I-219) as a white solid.
Reaction SMILES: NC1(C2N[C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18]C)C(=O)N(CCC)[C:9]=3[N:8]=2)CCCC1.C(C(C(Cl)=O)C(Cl)=[O:28])C>O1CCCC1.N1C=CC=CC=1>[CH2:17]([NH:12][C:13](=[O:16])[CH2:14][C:9]([NH2:8])=[O:28])[CH3:18]
Reactant: CCCn1c(=O)c2[nH]c(C3(N)CCCC3)nc2n(CCC)c1=O
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)CC(N)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.5 g di 8-(1-aminocyclopentyl)-1,3-dipropylxanthine in 45 ml of anhydrous tetrahydrofurane, 1.4 ml of pyridine are added and, after cooling to 5° C., 2.26 ml of ethyl malonyl chloride are dropwise added. The mixture is stirred at room temperature for 2 hours, followed by concentration under vacuum, addition of 1N HCl and extraction with ethyl acetate. The organic phase is washed with water, dried and evaporated, thereby obtaining 6.5 g of raw product which is purified by column chromatography (SiO2). 2.6 g of mono malonamide mono ethyl ester are obtained, which is finally saponified by treatment with tetrahydrofurane (26 ml) and NaOH 1N (30 ml) at room temperature for 1 hour.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.[OH-].[NH4+]>[CH3:4][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:26])=[CH:9][C:8]=2[N:7]=[CH:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)n1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)n1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a solution of 23.5 g (0.104 mole) of 1-(1,1-dimethylethyl)-1H-imidazo[4,5-c]quinoline in 200 mL of chloroform was added 23.4 g (0.115 mole) of metachloroperbenzoic acid. The mixture was stirred at about 20° C. for 24 hours. The solution was basified with saturated sodium bicarbonate solution, then dried over magnesium sulfate. Filtration of the mixture, followed by evaporation in vacuo provided a cream colored solid. The solid residue was slurried in dilute ammonium hydroxide, then filtered, washed with water and dried, to provide white solid 1-(1,1-dimethylethyl)-1H-imidazo[4,5-c]quinoline-5-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](F)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CC(O)C.CN1CCOCC1>O>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(F)nc(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CC(C)O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl 4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (42.5 g, 139 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (36.2 g, 167 mmol) was added IPA (425 mL) followed by 4-methylmorpholine (18.40 mL, 167 mmol). The reaction mixture was stirred at 60° C. for 20 hours under a nitrogen atmosphere. HPLC analysis indicated that the reaction was complete. The reaction mixture was subsequently cooled to room temperature and water (890 mL) was added slowly. The suspension was cooled in an ice/water bath to 6° C. and was stirred for 1 hour. The solids were collected by filtration and washed with water (30 mL) used to rinse the reaction vessel. The filter cake was washed with additional water (350 mL) and allowed to dry on the filter. The filter cake was subsequently dried in a vacuum oven at 60° C. over the weekend to afford the title compound (64.78 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.50 (s, 9H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49 (m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d, J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C22H30ClFN4O6, 501. found, 501.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12].N(OCCC(C)C)=O.[I-:21]>C(Cl)(Cl)Cl>[I:21][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc2c(cc1N)CCC2
Reactant: [I-]
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-aminoindane-5-carbonitrile (48.5 mg, 0.307 mmol), isoamyl nitrite (82 μL, 0.614 mmol) and iodide (85.7 mg, 0.338 mmol) in dry CHCl3 (2 mL) was stirred at room temperature for 0.5 h. The mixture was then heated at 80° C. under N2 for 2 h. The reaction mixture was quenched with saturated Na2S2O3 and partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 6-iodoindane-5-carbonitrile. LCMS calc.=270.0; found=270.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (s, 1H), 2.96 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.16-2.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)=[N:3][C:4]3[C:9]([N:10]=2)=[CH:8][C:7]([C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:5]=3)=[CH:13][CH:14]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)c1ccc2nc(Cl)c(-c3ccc(F)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol, 1.00 equiv), 1-(pyridin-2-yl)piperazine (207 mg, 1.27 mmol, 2.00 equiv), potassium carbonate (436.7 mg, 3.16 mmol, 5.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 5×50 mL of dichloromethane and the organic layers combined. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 157.4 mg (56%) of methyl 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:29][NH:30][C:31]1[S:32][C:33]([S:37]([NH2:40])(=[O:39])=[O:38])=[C:34]([CH3:36])[N:35]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:40][S:37]([C:33]1[S:32][C:31]([N:30]([CH3:29])[C:15](=[O:17])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)=[N:35][C:34]=1[CH3:36])(=[O:38])=[O:39]
Reactant: O=C(O)Cc1ccc(-c2ccccc2F)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.33 g (73.3 mmol) of (2′-fluoro[1,1′-biphenyl]-4-yl)acetic acid and 9.9 g (73.3 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 600 ml of dimethylformamide at room temperature. 16.84 g (81.4 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 15.58 g (81.4 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The dimethylformamide is substantially removed at 50° C. under high vacuum, and the residue is taken up in 400 ml of dichloromethane and then washed with 350 ml of each of water and 10% citric acid solution. Drying over magnesium sulfate and removal of the solvent in vacuo results in the compound of Example 57 in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(F)c(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cc(F)ccc5F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2,5-difluoro-phenyl)-pyridine.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:10]=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[C:19]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[C:28]([N+:34]([O-:36])=[O:35])[CH:29]=2)=[O:4])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a mixture of 2,2,2-trichloroethyl[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]carbamate (101 mg) and (4-methyl-3-nitrophenyl)amine (38 mg) in DMSO (1 mL) was added iPr2NEt (44 under a nitrogen atmosphere and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with EtOAc (2 mL) and successively washed with 1M HCl (2 mL×2), saturated aqueous NaHCO3 (2 mL) and brine (2 mL), dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with 2% MeOH in CH2Cl2 to give 1-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-(4-methyl-3-nitrophenyl)urea (96 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[O:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[C:17]=3[CH:16]=[C:15]([F:33])[CH:14]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pt].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[O:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[C:17]=3[CH:16]=[C:15]([F:33])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1oc2c(-c3ccn(C(=O)OC(C)(C)C)c3)cc(F)cc2c1Cc1cccc(F)c1
Agent: [Pt]
Solvent: CCO
Product: CC(=O)c1oc2c(C3CCN(C(=O)OC(C)(C)C)C3)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
3-[2-Acetyl-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-7-yl]-pyrrole-1-carboxylic acid tert-butyl ester (0.114 gm, 0.253 mmol) and platinum (5% on carbon, 0.035 gm) were added to ethyl alcohol (45 ml) and placed under hydrogen (balloon) at 55° C. for two hours. Additional platinum (5% on carbon, 0.065 gm) was added and heated at 60° C. under hydrogen for three hours. The mixture was filtered, concentrated and purified by column chromatography (ethyl acetate/hexane gradient) to give 3-[2-acetyl-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-7-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.096 gm, 83% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:25][CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(CCl)Nc1c(Cl)cccc1Cl
Product: COc1ccc(CNCC(=O)Nc2c(Cl)cccc2Cl)cc1OC

Procedure:
In a manner similar to Preparation 12, react 2-chloro-N-(2,6-dichlorophenyl)acetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound.
Reaction SMILES: [NH:1]1[C:6](=O)[CH:5]=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.O(Cl)[Cl:15].[P+3]>>[Cl:15][C:6]1[N:1]=[C:2]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]2=[CH:4][CH:5]=1
Reactant: O=c1ccc2c([nH]1)CCCCCC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1ccc2c(n1)CCCCCC2

Procedure:
5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2(1H)-one was heated with excess phosphorus (III) oxychloride at 100° C. for 8 h. The solvent was removed under vacuum. The residue was treated with ice and 1M aqueous potassium carbonate solution, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel, eluting with a mixture of 96% dichloromethane and 4% methanol gave 2-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine as a brown oil; 1H NMR (CDCl3, 300 MHz) 7.32 (d, 1H), 7.06 (d, 1H), 2.92 (m, 2H), 2.74 (m, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.38 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 161.86, 147.73, 140.19, 135.65, 122.26, 34.33, 32.30, 31.52, 30.83, 26.26, 26.14; MS (ES) 196/198 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([CH2:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.ClCCl>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH2:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: CCc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture containing (4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (325 mg, 0.601 mmol, Intermediate 25: step a) and manganese dioxide (308 mg, 3.01 mmol) in dioxane (3 mL) was heated to 100° C. After 2 hours, the mixture was cooled to 23° C. Dichloromethane (20 mL) was added and the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with hexanes-ethyl acetate provided the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:27]([C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[OH:28])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1[C@@H](C#CC(O)c2ccc(Cl)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.16 g; CAS 173065-16-2) in dry THF (20 ml) under an argon atmosphere at −78° C. was added dropwise a solution of n-butyllithium in hexane (10.5 ml, 1.6 M solution) and stirring continued for 30 min. A solution of 4-chlorobenzaldehyde (2.17 g) in THF (10 ml) was added dropwise and the mixture was stirred for a further 2 h at −78° C. The reaction mixture was then quenched by careful addition of water (12 ml) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with saturated brine. The combined organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[3-(4-chloro-phenyl)-3-hydroxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (mixture of epimers) as a yellow oil. MS (ISP): 426.1 ([{37Cl}M+OAc]−), 424.1 ([{35Cl}M+OAc]−).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:29]([C:15]2([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-fluoro-benzylamine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid chloride.