Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[Br-].[CH2:19]1COC[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH2:6][C:5]2([CH:19]=[CH2:20])[OH:17]
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CC1(O)CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (383 mg, 1.30 mmol) in anhydrous THF (10 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 1.95 mL, 1.95 mmol) dropwise within 10 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl, and extracted with ethyl acetate (2×30 mL). The combined organic phases are washed with H2O, brine, dried over Na2SO4, and filtered. The filtrate is concentrated to give crude 6-bromo-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil, which is used for the next step without further purification. MS ESI+ve m/z 305 (M+H—H2O)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCCCCC.C(OCC)(=O)C>O1CCOCC1>[C:10]1([C:9]2[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=2[OH:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCc1cccc(-c2ccccc2)c1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=Cc1cccc(-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2-hydroxy-3-phenylbenzyl alcohol (2.00 g, 10 mmol) in dioxane (100 ml) was added 2,3- dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (2.50 g, 11 ml) at room temperature. The reaction mixture immediately became a black solution. This solution was stirred at room temperature for 2 hours and further heated under refluxing for 2 hours. The solvent was removed under reduced pressure to obtain deep-black oily residue. This was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.63 g (82%) of 3-phenylsalicylaldehyde as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:39][CH3:40])=[C:4]([N+:36]([O-])=O)[C:5]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])=[C:6]([C:8]2[C:9]3[CH:18]=[N:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(O)(=O)C>O1CCCC1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[Fe]>[NH2:36][C:4]1[C:5]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])=[C:6]([C:8]2[C:9]3[CH:18]=[N:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=[C:2]([Br:1])[C:3]=1[NH:39][CH3:40]
Reactant: CNc1c(Br)cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNc1c(Br)cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
A suspension of 4-[5-bromo-2-(2,4-difluorophenoxy)-4-(methylamino)-3-nitrophenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.209 g, 0.328 mmol) in tetrahydrofuran (1.38 mL) was treated with iron (0.183 g, 3.28 mmol), followed by the addition of acetic acid (1.38 mL, 24.3 mmol). The resultant reaction mixture was warmed to 60° C. and stirred at 60° C. for 1.5 h. The reaction mixture was treated with iron (0.0917 g, 1.64 mmol) and stirred at 60° C. for 14 h, after which time the reaction mixture was filtered through the pad of Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give a crude residue. The crude residue was diluted with saturated solution of sodium bicarbonate and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (104 mg, 52%) as a white solid. LCMS calculated for C26H31BrF2N5O3Si (M+H)+: m/z=606.1, 608.1. found: 606.0, 608.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([NH:9][NH2:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH:18]=O.C(O)C>S(=O)(=O)(O)O.O>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH:18]=[N:10][NH:9][C:7](=[O:8])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=1)[OH:12]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NNC(=O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 5-chlorosalicylhydrazide (213.9 mg, 1.2 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (190 μL, 1.2 mmol), concentrated sulfuric acid (3 drops) and ethanol (5 mL) was refluxed for 30 minutes. 3,5-Bis(trifluoromethyl)benzaldehyde (100 μL, 0.61 mmol) was added and the mixture was refluxed for further 1 hour. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) and washed with n-hexane under suspension to give the title compound (362.6 mg, 76.8%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O.O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: OCCn1ccnc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C

Procedure:
To a stirring mixture of the methyl 2-(4-hydroxyphenyl)acetate (1.4 g, 1 EQ) and 2-(1H-imidazol-1-yl)ethanol (1.0 g) in THF (0.5 mL, 0.5 M) at 0° C. was added PPh3 (2.9 g). To this mixture was added dropwise DIAD (2.2 mL) over 10 min. The reaction mixture was warmed to ambient temperature overnight. A normal aqueous workup with water and EtOAc was followed. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel chromatography to give methyl 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate. Method[1], MS (ESI) 261.1, Retention time=0.782 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:12][S:11][C:10](=[O:13])[NH:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][Br:25])=[O:23])=[CH:18][CH:17]=1>C(O)C>[Br-:25].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][N+:1]2[CH:2]=[CH:3][C:4]([C:7]3[CH2:12][S:11][C:10](=[O:13])[NH:9][N:8]=3)=[CH:5][CH:6]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C1NN=C(c2ccncc2)CS1
Solvent: CCO
Product: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)SC3)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
5-(4-Pyridyl)-3H,6H-1,3,4-thiadiazin-2-one (386 mg, 2 mmol) and 4'-methoxyphenacyl bromide (550 mg, 2.4 mmol) were dissolved in absolute ethanol (6 ml), refluxed for three hours and then stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with absolute ethanol to obtain the titled compound (814 mg) as light brown powder.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[N:30]([C:32]([O:36]N1N=NC2C=CC=NC1=2)=[N+:33](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][CH2:54]N(C(C)C)C(C)C>CN(C)C=O>[CH2:53]([O:36][C:32]1[N:30]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:33]=1)[CH3:54]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 600 mg (1.08 mmol, purity 75%) of the carboxylic acid from Example 56A in 20.0 ml of N,N-dimethylformamide were added, at RT, 657 mg (1.73 mmol) of HATU and 0.57 ml (419 mg, 3.24 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 225 mg (1.84 mmol, purity 85%) of ethyl W-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature for 2 h. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate was taken up in toluene (68 ml), admixed with 4 Å molecular sieve and stirred under reflux for 2 days. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 320 mg (61% of theory)
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:22])[CH2:20][CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C([O-])(=[O:25])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl>[O:25]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2
Reaction time: 0.25 h

Procedure:
A mixture of 118.8 g. of 7-(3,7-dimethyl-2,6-nonadienyloxy)-chromane, 26 g. of anhydrous sodium acetate in 910 ml. of chloroform is treated over a period of 1 hour with 80 g. of 40% peracetic acid while stirring and flushing with nitrogen at 0°-2°C. The resulting mixture is subsequently stirred for an additional 15 minutes. The mixture is washed successively with a saturated sodium chloride solution, 10% sodium bicarbonate 0.1-N sodium thiosulphate solution and water, dried over sodium sulphate and concentrated. By filtration over 600 g. of silica gel with hexane/ether (9:1) and subsequent molecular distillation, there is obtained 7-(6,7-epoxy-3,7-dimethyl-2-nonenyloxy)-chromane, nD20 = 1.5295.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23]>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:19]=[CH:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC([O-])[O-]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Product: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.15 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was stirred with 15 ml. ethyl orthoformate and 7.5 m. acetic anhydride at a bath temperature of 130° C., then evaporated in a vacuum at 70° C. to give a residue of crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[4,3-b]pyridazine. A sample thereof, triturated with ethanol, melted at 134° - 135° C. The residue thus obtained was dissolved in 20 ml. of a mixture of isopropanol and dioxan (7:3) and 2.3 ml. 4-methylpiperazine added thereto at 20° C., while stirring. The crystals formed were filtered off with suction after about 15 minutes, washed with isopropanol and water and dried in a vacuum for 2 hours at 120° C. There was thus obtained 1.22 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(4-methyl-piperazin-1-yl-methyleneamino)-s-triazolo[4,3-b]pyridazine which melts at 219° - 222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[NH:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[N:21][C:23](=[O:25])[CH3:24])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=N)n(C)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=NC(C)=O)n(C)c2n1

Procedure:
A mixture of 0.161 g (0.46 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3 -d]pyrimidin-7-ylideneamine from Example 19 and 1.0 mL of acetic anhydride was heated to solution at the boiling point. After 2 minutes of reflux, the solution was concentrated to one-half volume, whereupon crystals formed. The mixture was cooled, 2 mL of ether was added, and the product was filtered and washed with ether; mp 229°-231° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:1]
Reactant: CC(C)CCC(=O)CCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC(O)CCC(C)C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) δ0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:25]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
Triethylamine (14 mL) was added to a chloroform (120 mL) solution of methyl L-tryptophanate hydrochloride (5.0 g) under ice-cooling, and further acrylic acid (1.6 mL) was added thereto. Next, a methylene chloride (30 mL) solution of DCC (4.9 g) was added dropwise to the mixture. The mixture was stirred at room temperature for 24 hours, and thereafter a half the volume of the solvent was distilled off under a reduced pressure, acetone was added to the residual mixture, and the mixture was allowed to stand in a freezer overnight. Triethylamine hydrochloride and DC urea were filtered off, the solvents of the filtrate was distilled off under a reduced pressure, and the residual oily product obtained was purified by silica gel column chromatography (BW-127ZH, chloroform:methanol=19:1), to give the captioned compound (1.5 g, 28%) as an oily product.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([Br:33])[C:15]=1[OH:34].O[C@@H:36]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CCOCC>[CH3:40][O:39][C:37](=[O:38])[C@H:36]([O:34][C:15]1[C:14]([Br:13])=[CH:19][C:18]([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]=1[Br:33])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Reaction time: 4 h
Yield: 85301.9 %

Procedure:
Diethylazodicarboxylate (DEAD, 0.077 mL, 1.15 mmol) was added to a stirred, room temperature suspension of 2,6-Dibromo-4-(dibenzothiophen-1-yl)-phenol (0.250 g, 0.576 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.208 g, 1.15 mmol), triphenylphosphine (0.302 g, 1.15 mmol) in benzene (3 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 16 h. More diethylazodicarboxylate (DEAD, 0.039 mL, 0.576 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.104 g, 0.576 mmol) and triphenylphosphine (0.151 g, 0.576 mmol) were added and the solution was stirred an additional 4 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (98:2 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0. 293 g, 85%): NMR (CDCl3): δ 7.89 (dd, J=8, 1 Hz, 1H), 7.85 (ddd., J=8, 1, 1 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.47 (dd, J=9, 8 Hz, 2H), 7.41-7.17 (m, 8H), 5.13 (dd, J=8, 6 Hz, 1H), 3.71 (s, 3H), 3.55 (dd, J=7, 4 Hz, 1H), 3.53 (dd, J=8, 4 Hz, 1H); MS (EI): [M+], 2 bromine isotope pattern, 594 (20%), 596 (40%) 598 (25%); Anal. Calc. for C28H20Br2O3S: C, 56.39, H, 3.38, N, 0.00. Found: C, 56.27, H, 3.21, N, 0.09.
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[CH2:13][CH2:14][C:15]3([OH:29])[CH2:20][CH:19]4[CH2:21][CH2:22][CH:16]3[CH:17]=[C:18]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:8][C:4]=2[CH:3]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[Cl:33][C:32]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[CH2:13][CH2:14][C@:15]3([O:29][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:20][C@H:19]4[CH2:21][CH2:22][C@@H:16]3[CH:17]=[C:18]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:6][C:5]=2[CH:31]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Product: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CC[C@]1(OC(=O)C2CC2)C[C@H]2CC[C@@H]1C=C2c1ccccc1

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(5,6-dichloro-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and cyclopropancarbonyl chloride.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 32.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added N-methyl piperazine (0.122 mL, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (72 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.25 (m, 2H), 3.88 (s, 3H), 2.50-2.25 (m, 10H), 2.15 (s, 3H), 1.95 (m, 2H), 1.23 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:14][C:15]1[C:20]([O:13][CH2:12][C@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: Cc1ncccc1OC[C@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 55.4 %

Procedure:
An ice cooled solution of the compound from step 41a (0.151 g, 0.81 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.092 g, 0.85 mmol) under the conditions of Example 2a, except that DEAD was replaced by di-t-butyl azodicarbonate, to yield the title compound (0.125 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.11 (dd J=4.6, 1.3 Hz, 1H), 7.20-7.10 (m, 2H), 4.54-4.53 (m, 1H), 4.36-4.35 (m, 1H), 4.09 (dd, J=10.0, 2.6 Hz, 1H), 3.95-3.88 (m, 2H), 2.55 (s, 3H), 2.42-2.30 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]([C:11](O)=O)=[N:8][NH:9][CH:10]=1.[Br:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([NH2:30])[C:21]=1[NH2:31].C(Cl)CCl.C1C=CC2N([OH:45])N=NC=2C=1>CN(C=O)C>[Br:19][C:20]1[C:21]2[N:31]=[C:11]([C:7]3[C:6]([NH:5][C:4](=[O:45])[C:3]4[C:2]([F:1])=[CH:17][CH:16]=[CH:15][C:14]=4[F:18])=[CH:10][NH:9][N:8]=3)[NH:30][C:22]=2[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: O=C(O)c1n[nH]cc1NCc1c(F)cccc1F
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.2 %

Procedure:
A mixture of 4-(2,6-difluorobenzylamino)-1H-pyrazole-3-carboxylic acid (520 mg, 1.96 mmol) (Example 16D), 3-bromo-5-trifluoromethyl-1,2-benzenediamine (500 mg, 1.96 mmol), EDC (413 mg, 2.15 mmol) and HOBt (290 mg, 2.15 mmol) in DMF (20 ml) was stirred at ambient temperature for 16 h and then reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4), filtered and evaporated. The amide intermediate was chromatographed using EtOAc-P.E. (1:4-1:0). The intermediate amide (271 mg), (LC/MS: Rt 3.31, [M+H]+ 505), was dissolved in AcOH (3 ml) then heated at reflux for 1 h. The reaction mixture was allowed to cool at which time a solid crystallised out, that was filtered, washed with P.E. and dried to give the title compound (50 mg). (LC/MS: Rt 3.42, [M+H]+ 486,488)