Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:4]([Cl:7])([Cl:6])[Cl:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>O>[CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:24](=[O:26])[CH3:25])[C:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: COC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(NC(=O)c1ccccc1OC(C)=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To 2.5 g of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide was added 20 g of pyridine and maintained at below -10° C., 1.5 g of acetyl chloride was added dropwise and then allowed at room temperature for about 30 minutes, and poured into water to give a crystal which was recrystalized by using methanol to obtain 2.2 g white crystal of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-acetoxy benzamide.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:37]=2)[NH:32]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:43][CH2:44][N:45]([C:21]([C:20]4[CH:24]=[CH:25][C:17]([O:16][C:13]5[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]6[CH:26]=[CH:27][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=6)=[CH:11][CH:12]=5)=[CH:18][CH:19]=4)=[O:23])[CH2:46][CH2:47]3)[CH:37]=2)[NH:32]1
Reactant: O=C1CCc2cc(CN3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccc(Oc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(CN3CCN(C(=O)c4ccc(Oc5ccc(NC(=O)c6ccc(C(F)(F)F)cc6)cn5)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)-piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH2:6](Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C>C(OCC)(=O)C>[O:8]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][O:4][C:1](=[O:5])[CH2:2][OH:3]
Reactant: O=C(O)CO
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CO)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
A mixture of 7.61 g of glycolic acid, 19.90 g of phenacylbromide and 13.9 ml of triethylamine in 300 ml of ethyl acetate was stirred for 20 hours at room temperature. Then, the mixture was filtered. The filtrate was washed with 2N HCl, saturated sodium bicarbonate, and brine. Then, the filtrate was dried, filtered again, and evaporated to dryness. The resulting white solid was purified by recrystallization to yield 11.85 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:20][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1F
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3F)c21
Yield: 26.6 %

Procedure:
The title compound was prepared as a white powder in 26.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:32][CH:31]=1)[CH2:35][CH3:36]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1ccc(CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 141 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (401 mg), 3-(4-propoxyphenyl)propyl methanesulfonate (1017 mg) and potassium carbonate (310 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 70° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)c(F)c1
Yield: 98 %

Procedure:
A mixture of 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid (3.45 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionate (3.56 g, yield 98%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.60–2.71 (2H, m), 2.92–3.03 (2H, m), 3.69 (3H, s), 7.22–7.65 (3H, m), 8.23 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[C:4]([F:29])[CH:3]=1.I[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[C:4]([F:29])[CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CCI
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4F)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 110 above, using compound from Example 141, 3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11](O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: Nc1ncnn2cc(C(=O)O)c(-c3ccc(Nc4nc5cc(F)cc(F)c5[nH]4)cc3)c12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3cc(F)cc(F)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a suspension of 4-amino-5-{4-[(5,7-difluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (75.0 mg, 0.178 mmol) in DMF (3 mL) was added tert-butylamine (0.021 ml, 0.196 mmol), benzotriazolyloxytris(dimethlyamino)phosphonium PF6 (86.6 mg, 0.196 mmol), and 4-methylmorpholine (0.039 ml, 0.356 mmol). The reaction was stirred for 3 hr at rt and then purified directly by HPLC using 25-85% acetonitrile in water to afford the desired product (75.3 mg, 89%). 1H-NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.02 (s, 1H), 7.80-8.02 (m, 3H), 7.38 (dd, J=6.7, 2.0 Hz, 2H), 7.00 (dd, J=8.9, 2.2 Hz, 1H), 6.85 (ddd, J=10.7, 10.7, 2.4 Hz, 1H), 6.54 (s, 1H), 4.96-5.21 (br s, 1H), 1.16 (s, 9H); ES-MS m/z 477.1 (MH)+; HPLC RT (Method B) 2.54 min.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[SH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu].O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: Fc1ccc(F)c(S)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2cc(F)ccc2F)c(C=O)c1
Temperature: 150 °C
Yield: 51.8 %

Procedure:
A mixture of 19.7 g of 2-bromo-5-methoxybenzaldehyde (of Example 9, reference above), 14.1 g of 2,5-difluorothiophenol (of Example 11, reference above), 14.0 g of potassium carbonate, 75 ml dimethylformamide and 2.1 g of copper catalyst is stirred and heated to 150° C. for 6 hours. It is then diluted with 150 ml of water and extracted with benzene. The extract is washed with water, dried with magnesium sulfate and evaporated. The residue is processed by distillation. There are obtained 13.3 g (52%) of 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde boiling at 163°-165° C./40 Pa. The product is crystallized from cyclohexane and melts in a pure state at 67°-68° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)nc(N2CCC(c3ccc(F)cc3)CC2)c1C#N

Procedure:
In analogy to the procedure described in example 20b, the 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with the 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diiso-propylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid; MS: [M+H]+=344.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(CO)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (502, 0.20 g, 0.81 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.377 g, 0.89 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (503, 100 mg, 50.0%). MS (ESI) [M−H+]+=244.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1.[F:11][C:12]1[C:25]2[O:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:26](O)=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:26]([CH:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[C:25]=3[O:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:27])=[N:5][CH:4]=1
Reactant: Nc1ncc(C(F)(F)F)o1
Reactant: O=C(O)C1c2ccccc2Oc2c(F)cccc21
Product: O=C(Nc1ncc(C(F)(F)F)o1)C1c2ccccc2Oc2c(F)cccc21

Procedure:
The title compound, white solid, m.p. 228° C. and MS: m/e=379.2 (M+H+) is prepared in accordance with the general method of example 3c from 5-trifluoromethyl-oxazol-2-ylamine and (RS)-4-fluoro-9-xanthene-carboxylic acid.
Reaction SMILES: CSC.[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[CH:27]=[CH:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.[Cu]Cl>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[C@H:27]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(C=Cc1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Cu]
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(C[C@@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a precooled (−30° C.) mixture of copper-(I) chloride (21.0 g) and dimethylsulfide (45 ml) in dry tetrahydrofuran (150 ml) was added dropwise an ethereal solution of phenyl-magnesiumbromide (0.3 mol). The mixture was stirred 20 min at the same temperature and then cooled to −40° C. A solution of 3-[3-(2-Benzyloxy-5-bromophenyl)-acryloyl]-(4R)-4-phenyl-oxazolidin-2-one (50.0 mmol) in dry tetrahydrofuran (150 ml) was added during 10 min. The cooling bath was removed and stirring was continued for 18 hrs. The mixture was quenched with half-saturated aqueous ammonium chloride solution and the product was isolated by extraction with ethyl acetate.
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.C(C(C)=[O:19])C.O=O>C(O)(=O)C.O>[O:19]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12]([NH2:14])=[O:13])[CH2:2][CH2:3]1
Reactant: CCC(C)=O
Reactant: NC(=O)NC1CCCc2ccccc21
Agent: Br
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A mixture of 1,2,3,4-tetrahydro-1-naphthylurea (1.9 g), cobaltous acetate tetrahydrate (1.08 g), 30% hydrobromic acid in acetic acid (0.9 ml) and a 1:1 mixture of methyl ethyl ketone: acetic acid (30 ml) is shaken in a pressure vessel under 31 psig of oxygen for 7.5 hours. The vessel is then vented, the contents are mixed with an equal volume of water and extracted with chloroform (2×25 ml). The combined chloroform extracts are dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to afford 2.34 g solid. The solid is washed with cold methanol (30 ml) to afford 0.75 g of title compound, m.p. 210° C. to 214° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH:11]1[C:12]2[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28][CH3:29])=[O:27])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: COC(=O)c1cccc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccccc3Oc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a solution of phenoxazine (2.20 g) in tetrahydrofuran (30 ml) was added potassium tert-butoxide (2.69 g) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and then a solution of methyl 3-(chloromethyl)benzoate (2.44 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at 25° C. for 30 minutes, and then evaporated. The residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (40:1-20:1) and recrystallization from a mixture of hexane and ethyl acetate to give e methyl 3-(phenoxazin-10-ylmethyl)benzoate (1.12 g) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) was added dioxane (0.18M) and p-TSA (1.1 equiv.). The solution was heated to 100° C. for 4 h. Cooled to room temperature, worked up with sat. NaHCO3 and ethyl acetate, the organic phase was dried with Na2SO4 and concentrated. The crude was purified via silica gel column chromatography eluting with 100% DCM to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil (27% yield). LCMS (m/z): 203.1 (MH+), LC Rt=3.53 min, H-NMR (CDCl3): 9.02 (s, 1H), 8.70 (d, J=5.3, 1H), 7.30 (d, J=5.3, 1H), 6.15-6.17 (m, 1H), 6.02-6.11 (m, 2H), 2.35-2.38 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1
Reactant: CCCCOc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-butoxy-benzoic acid methyl ester (0.24 g, 1.1 mmol) prepared in Example 149 to give rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid methyl ester as a light brown solid (Yield, 0.14 g, 30%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH2:56])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:56][C:54]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][NH:51]2)=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:55]=1
Reactant: CC1(C)OB(c2cc(N)cc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 61.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.21 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine (110 mg, 0.43 mmol), sodium carbonate (55 mg, 0.52 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (52 mg, 0.06 mmol) in 1,2-dimethoxyethane (5.0 ml) and water (0.125 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 84 mg (56% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:10]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)Nc1ccccc1F

Procedure:
Following the procedure of Example 5, making variations only as required to use 2-flurophenylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (32% yield). 1H NMR (500 MHz, CDCl3) δ 7.90-8.30, 7.99, 7.75, 7.63, 7.57, 7.34, 7.10-7.17, 7.01-7.07, 3.94-4.01, 3.85-3.92, 3.56-3.66, 3.41-3.49, 3.24-3.29.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[CH:21][C:13]=4[CH3:12])[NH:17][C:16]3=[O:22])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1ccc2c(c1)CCO2
Product: Cc1cccc2c1C(=Cc1ccc3c(c1)CCO3)C(=O)N2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.